Dietary approaches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls Elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: study protocol for a randomized controlled trial

Dietary approaches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls... Background: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS) and contributes to diminishing quality of life. Although currently available interventions have had limited success in relieving MS- related fatigue, clinically significant reductions in perceived fatigue severity have been reported in a multimodal intervention pilot study that included a Paleolithic diet in addition to stress reduction, exercise, and electrical muscle stimulation. An optimal dietary approach to reducing MS-related fatigue has not been identified. To establish the specific effects of diet on MS symptoms, this study focuses on diet only instead of the previously tested multimodal intervention by comparing the effectiveness of two dietary patterns for the treatment of MS- related fatigue. The purpose of this study is to determine the impact of a modified Paleolithic and low saturated fat diet on perceived fatigue (primary outcome), cognitive and motor symptoms, and quality of life in persons with relapsing-remitting multiple sclerosis (RRMS). Methods/design: This 36-week randomized clinical trial consists of three 12-week periods during which assessments of perceived fatigue, quality of life, motor and cognitive function, physical activity and sleep, diet quality, and social support for eating will be collected. The three 12-week periods will consist of the following: 1. Observation: Participants continue eating their usual diet. 2. Intervention: Participants will be randomized to a modified Paleolithic or low saturated fat diet for the intervention period. Participants will receive support from a registered dietitian (RD) through in-person coaching, telephone calls, and emails. 3. Follow-up: Participants will continue the study diet for an additional 12 weeks with minimal RD support to assess the ability of the participants to sustain the study diet on their own. (Continued on next page) * Correspondence: terry-wahls@uiowa.edu University of Iowa, Iowa City, Iowa, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wahls et al. Trials (2018) 19:309 Page 2 of 16 (Continued from previous page) Discussion: Because fatigue is one of the most common and disabling symptoms of MS, effective management and reduction of MS-related fatigue has the potential to increase quality of life in this population. The results of this study will add to the evidence base for providing dietary recommendations to treat MS-related fatigue and other symptoms associated with this disease. Trial registration: ClinicalTrials.gov, NCT02914964. Registered on 24 August 2016. Keywords: Multiple sclerosis, Fatigue, Diet, Accelerometer, Quality of life, Intervention, Swank diet, Wahls elimination diet Background physical and mental performance [16–21]. The Swank Fatigue is one of the most common and disabling symptoms study found that the number of relapses and progression of multiple sclerosis (MS), diminishing quality of life (QOL) of disability was associated strongly with dietary satu- and contributing to early exit from the workforce [1, 2]. rated fat consumption [17–22]. The 50-year follow-up is MS-related fatigue is most commonly managed through a strength of the Swank study, but the absence of a con- multiple interventions, including disease-modifying drugs trol group and lack of brain imaging are limitations. and stimulants, exercise, energy conservation, and stress Consumption of vegetables has also been associated management techniques [3]. Although exercise augmented with favorable health outcomes related to MS. Notably, by electrical muscle stimulation can be modestly effective in the mean daily serving of vegetables is associated with reducing perceived fatigue [4, 5], studies investigating the ef- lower risk of developing obesity [23], which is a risk fac- ficacy of pharmaceutical therapies have shown conflicting tor for and a common comorbid diagnosis of those with results [6–8]. Because drug treatment has not been effective, MS. Increased consumption of vegetables is associated dietary interventions are being explored. Statistically and with lower Expanded Disability Status Scale scores [24], clinically significant reductions in perceived fatigue severity insulin sensitivity, blood pressure, body weight, and body in persons with progressive multiple sclerosis (pwPMS) have mass index (BMI). Considering these observations, re- been reported with use of a multimodal intervention searchers in a more recent randomized controlled trial consisting of a modified Paleolithic diet, stress reduction, used a vegetarian version of the Swank diet [25], also exercise, and electrical muscle stimulation [4, 5]. known as the McDougall diet. Measures included the Interventions considering the whole diet (vs. Fatigue Severity Scale (FSS), 36-item Short Form Health supplement-based, single-nutrient focus) have been Survey (SF-36) quality-of-life scores, lipids, weight, BMI, used in treating or preventing diseases, including psoriasis and brain magnetic resonance imaging (MRI) scans at [9], cancer [10, 11], and neurological diseases [12]. Emer- baseline and at 1 year [26]. Favorable reductions in ging data support the notion that environmental rather weight, BMI, and total cholesterol were observed, but no than genetic factors are likely the predominant causes of statistically significant differences in MRI findings or MS [13]. Given that food consumed is a major component SF-36 quality-of-life scores were reported [26]. of the environment, it is conceivable that improving the Anotherdietofinteresttothe MS communityisa quality of the diet may have a significant impact on the Paleolithic diet [27]. Dr. Loren Cordain’s recommendations development of MS. The relationship between the quality for a modern version of the Paleolithic diet stresses the of the diet and MS-related symptoms such as fatigue is consumption of meats, vegetables, and fruits; excludes unknown. In this study, we will compare two dietary grains, legumes, and dairy [27, 28]; and excludes night- patterns for the treatment of MS-related fatigue: the shade vegetables (potatoes, tomatoes, peppers, and egg- modified Paleolithic diet (Wahls elimination diet) and plants) [29] for persons with rheumatoid arthritis. Recently a low saturated fat diet (Swank diet). tested for its impact on various biomarkers in healthy One early dietary intervention for individuals with MS individuals, the Paleolithic diet was associated with im- was based on the observation that high levels of satu- provements in blood pressure, BMI [30], total cholesterol, rated fat in the diet were associated with increased risk insulin sensitivity, fasting insulin, and arterial distensibility for MS in Norway [14, 15]. Dr. Roy Swank theorized that [31]. In a study of patients with type 2 diabetes, the a diet high in saturated fats causes more rapid disease Paleolithic diet was shown to be more satiating per calorie progression. Dr. Swank followed 144 patients with mild than the American Diabetes Association (ADA) diet, which to more severe disability for 34 years. These individuals encourages increased intake of vegetables, dietary fiber, had agreed to consume a diet containing < 20 g of satu- whole-grain bread and cereal products, fruits, and berries rated fat per day and report their dietary adherence. The and decreased intake of total fat with more unsaturated fat patients’ clinical outcomes were monitored, including [32]. In a crossover study comparing the Paleolithic diet Wahls et al. Trials (2018) 19:309 Page 3 of 16 with the ADA diet, the Paleolithic diet was superior to the saturated fat diet (Swank diet) on perceived fatigue, ADA diet with respect to improving blood pressure, lipid cognitive and motor symptoms, and quality of life in profile, and glycemic control [33]. Finally, in a randomized persons with RRMS, a milder form of disease that often controlled study of obese persons with metabolic syn- transitions to a more progressive and severe form of MS. drome, comparison of the Paleolithic diet with the control We hypothesize that participants following the modified diet, which was an isoenergetic diet based on Dutch dietary Paleolithic diet will have a clinically greater reduction in guidelines, the Paleolithic diet was associated with greater FSS score than participants following the low saturated improvements in blood pressure, fasting levels of lipids, fat diet. and weight loss than the control diet [34]. A modified version of the Paleolithic diet was shown to Research hypothesis 1a reduce perceived fatigue in pwPMS (either secondary or After 12 weeks of the diet intervention, relative to the primary progressive multiple sclerosis [SPMS or PPMS, re- observation period, at least 15% of participants in the spectively]) [4, 5] as part of a multimodal intervention low saturated fat diet group will demonstrate decreased (modified Paleolithic diet, targeted vitamin supplementa- perceived fatigue (assessed by FSS score), 30% will have tion, stress-reducing practices, exercise, and electrical improvement in QOL mental health and physical health muscle stimulation). The study diet stressed the consump- scores (mean score increase of > 5 points), 50% will tion of more vegetables, with a target of 6 to 9 cups of demonstrate improved cognition (> 5% improvement in vegetables and fruit per day, and recommended somewhat mean Symbol Digit Modalities Test–Oral [SDMT-O] less meat than Paleolithic diets tested in the previously score), and 30% will demonstrate improved motor func- mentioned studies. At enrollment, study participants were tion (> 5% improvement in mean distance of 6 Minute consuming less than 1.5 servings of vegetables per day but Walk Test [6MWT]). In the modified Paleolithic diet raised this to an average of 8 servings per day by month 12 group, ≥ 60% of the participants will demonstrate de- [5]. The dietary component of the multimodal intervention creased perceived fatigue, 70% will have improvement in was significantly associated with favorable changes in QOL mental health and physical health score, 70% will mood and cognition between baseline and 12 months, demonstrate improved cognition, and 55% will demon- whereas the nondietary components were not [25]. It is strate improved motor function. unknown whether the dietary component of the multi- modal intervention also significantly contributed to the ob- Research hypothesis 1b served reduction in perceived fatigue [4, 5]; however, After 12 weeks of the diet intervention, participants in several participants anecdotally reported that deviations the low saturated fat diet group will not have clinically from the study diet resulted in a sharp worsening of their or statistically significant reductions in fatigue or im- fatigue and noted that the fatigue resolved with stricter provements in QOL measures or motor and cognitive adherence to the study diet. Data from another pilot ran- function relative to the observation period, whereas par- domized controlled trial also showed significant reductions ticipants in the modified Paleolithic diet group will have in perceived fatigue (as assessed by FSS) in individuals with clinically and statistically significantly reduced fatigue relapsing-remitting multiple sclerosis (RRMS) following a and improved QOL measures and motor and cognitive modified Paleolithic diet intervention [35]. function as measured by changes in mean scores of the To establish the specific effects of diet on MS symp- aforementioned measures. toms such as fatigue, this study focuses on diet only in- stead of the previously tested multimodal intervention. Research hypothesis 2a The modified Paleolithic diet continues to stress a high By 12 weeks after initiation of diet, participants in the intake of vegetables but also eliminates foods to which modified Paleolithic diet group will have a clinically some individuals may be sensitive: eggs and nightshade greater reduction, relative to the observation period, of vegetables [29]. To enhance adherence and reduce the perceived fatigue (assessed by FSS) than those in the low rate of dropout, which occurred early in the intervention saturated fat diet group. among participants in a nondiet control group [35], con- trol participants will be assigned a second diet, a low sat- Research hypothesis 2b urated fat (Swank) diet, which is also popular among the By 12 weeks after initiation of diet, participants in the MS community and has research to support its efficacy. modified Paleolithic diet group will have clinically greater improvement, relative to the observation period, Methods/design with respect to both motor function (gait, assessed by Aims of study the timed 25-ft walk test [T25FW] and by the 6MWT; In this study, we will compare the impact of the modi- hand, assessed by 9-hole peg test (9HPT); physical activ- fied Paleolithic diet (Wahls elimination diet) and a low ity outcomes, measured by accelerometer [e.g., increased Wahls et al. Trials (2018) 19:309 Page 4 of 16 daily steps, increased time spent in light-intensity activity, group assignment. The medical monitor will be blinded increased time spent in moderate-intensity activity, re- to group assignment. Unblinding of assessors and med- duced time spent sedentary]; sleep quantity, as measured ical monitors will not be permitted. To ensure that the by accelerometer) and cognitive function (assessed by the proposed study is conducted without bias toward either SDMT-O) than those in the low saturated fat diet group. of the study diets, Dr. Wahls will not have access to study participants or raw study data and will not be Research hypothesis 2c involved in data analysis. By 12 weeks after the initiation of diet, participants in the modified Paleolithic diet group will have clinically Eligibility criteria greater improvement, relative to the observation period, Adults with RRMS who can ambulate 25 ft with either with respect to quality of life (assessed by Multiple no support or unilateral support, living within approxi- Sclerosis Quality of Life 54 [MSQOL54] instrument) and mately a 500-mile radius of Iowa City, meeting eligibility mood (assessed by Hospital Anxiety and Depression criteria, and providing written informed consent will be Scale [HADS]) than those in the low saturated fat diet invited to participate. The inclusion criteria are outlined group. below: Research hypothesis 3 1. a. Willing to allow their neurologist to sign a letter After 24 weeks of the diet intervention, changes in the confirming MS diagnosis and criteria used to measures identified in hypotheses 1a and 1b observed at confirm diagnosis 12 weeks will be sustained in ≥ 80% of the participants b. Definitive diagnosis of RRMS based on the in both diet groups. revised 2010 McDonald criteria [36], confirmed by the treating neurologist Study Design 2. FSS score ≥ 4 obtained within 12 weeks of This 36-week randomized parallel group clinical trial scheduling their first study visit (Screened consists of three 12-week periods during which assess- participants with FSS ≥ 3 and < 4 will be contacted ments of perceived fatigue, quality of life, motor and again in 6 months to retake FSS to determine if cognitive function, physical activity and sleep, diet qual- they qualify, if participants desire.) ity, and social support for eating will be collected. The 3. Ability to shop for and prepare, or availability of 12-week periods will consist of: someone in the family to shop for and prepare, home-cooked meals according to the study diet 1. Observation: Participants continue eating their usual guidelines diet. 4. Willing to keep detailed food records of all 2. Intervention: Participants will be randomized to consumed foods and beverages either the modified Paleolithic or low saturated fat 5. Aged between 18 and 70 years at time of diet for the intervention period. Participants will enrollment into the study receive support by a registered dietitian (RD) 6. Willing to eat a diet that includes more vegetables through coaching telephone calls and emails. and excludes many comfort foods such as those 3. Follow-up: Participants will continue the study diet made with white flour for an additional 12 weeks with minimal RD 7. Willing to eat a diet that eliminates red meat ( support to assess the ability of the participant to beef, pork, lamb, veal), limits saturated fats (butter, sustain the study diet on their own. coconut oil, margarine, and hydrogenated oils found in processed foods) to 15 g per day, and Study evaluations will be done to compare the effects of includes unsaturated fats (e.g., vegetable oils, nuts, the two study diets on perceived fatigue (primary outcome fatty fish) to 20–50 g (4–10 teaspoons) per day if measured by FSS) and secondary outcomes (cognitive assigned to the low saturated fat diet but willing to function, motor function, QOL). The protocol was pre- eat saturated fats > 20 g per day if assigned to the pared according to the Standard Protocol Items: Recom- modified Paleolithic diet mendations for Interventional Trials (SPIRIT) guidelines 8. Not pregnant or planning to become pregnant in (see Figs. 1 and 2 and Additional file 1: SPIRIT Checklist). the next 12 months 9. Able to walk 25 ft without support or with only Study setting unilateral support (i.e., cane in one hand) Data collection will be completed at the University of 10. Have not been told by a physician or other health Iowa (UI) Preventive Intervention Center in Iowa City, care professional that they have celiac disease IA, USA, by trained research assistants blinded to the 11. Willing and able to eat gluten-containing grains Wahls et al. Trials (2018) 19:309 Page 5 of 16 Fig. 1 Dietary Approaches to Treat Multiple Sclerosis-Related Fatigue Study flowchart. MS Multiple sclerosis RRMS Relapsing-remitting multiple sclerosis 12. Lives within approximately a 500-mile radius of continue, with screening scheduled at least Iowa City, which includes Illinois, Indiana, Iowa, 12 weeks after the last relapse start date, if Kansas, Michigan, Minnesota, Missouri, Nebraska, relapse happened after consenting; participation Ohio, South Dakota, and Wisconsin will be continued.) 3. Undergoing treatment for cancer by radiation or The exclusion criteria are outlined below: chemotherapy within the prior 12 months other than for skin cancer (They will be contacted after 1. Taking insulin or warfarin the 12 months if participants desire.) 2. Having a relapse during the prior 12 weeks 4. Being diagnosed with kidney stones, heart failure, before consenting (The screening process will angina, or liver cirrhosis Wahls et al. Trials (2018) 19:309 Page 6 of 16 Fig. 2 (See legend on next page.) Wahls et al. Trials (2018) 19:309 Page 7 of 16 (See figure on previous page.) Fig. 2 Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT): the schedule of enrollment, interventions, and assessments. SPMSQ Short Portable Mental Status Questionnaire, FSS Fatigue Severity Scale, 9HPT 9-Hole Peg Test, T25FW Timed 25-foot walk, SDMT-O Symbol Digit Modalities Test–Oral, 6MWT 6-Minute walk test, MSQ Medical Symptoms Questionnaire, MFIS Modified Fatigue Impact Scale, MSQOL54 Multiple Sclerosis Quality of Life 54, FSMCF Fatigue Scale for Motor and Cognitive Function, MSIS v2 Multiple Sclerosis Impact Scale version 2, HADS Hospital Anxiety and Depression Scale, PSQI, PSS 10 Perceived Stress Scale 10, IPAQ-L International Physical Activity Questionnaire–Long, SF36 36-Item Short Form Health Survey, PDQ Perceived Deficits Questionnaire, MHI Mental Health Inventory, FFQ Food Frequency Questionnaire 5. Having a psychiatric disease, such as schizophrenia, Committee on Multiple Sclerosis (NARCOMS), the UI that makes study adherence more difficult Hospitals neurology clinic, the Iowa City VA neurology (Participants with depression and anxiety diagnoses clinic, the Swank Foundation, terrywahls.com, and other are allowed.) organizations to recruit study participants. 6. Having a diagnosis of an eating disorder such as anorexia, bulimia, binge eating, or orthorexia Randomization 7. Having BMI < 19 kg/m Participants will be randomized to the modified Paleolithic 8. Having a moderate to severe mental impairment as or low saturated fat diet on the basis of the screening FSS measured by the Short Portable Mental Status score that qualified them for the study. Two randomization Questionnaire (SPMSQ) [37] tables based on computer software will be used, one for 9. Participating in another research study investigating moderate perceived fatigue (a score ≥4 and < 5.5) and the MS or other medications, diet, supplements, other for high perceived fatigue (≥ 5.5), so that similar exercise, or other treatments mean FSS scores are achieved for each diet group. The 10. Having had gastric bypass surgery with their randomization tables are accessible (password-protected) treating physician believing it is medically unsafe to only by intervention dietitians. participate in this study 11. Having been told by a physician or other health Intervention care provider they have celiac disease Study diets 12. Have adverse physical reaction to eating gluten- The study diets are summarized in Table 1. containing products 13. Living outside a 500-mile radius of Iowa City Study diet 1 The modified Paleolithic diet stresses more 14. Not able or willing to comply with the study vegetables than other Paleolithic diets that have been protocol studied previously, and it limits meat to 6–12 oz per day. Like other Paleolithic diets, it excludes all grain, Exclusion criteria for continuation into the intervention legumes, and dairy (except for clarified butter or ghee) phase of the study are as follows: and additionally excludes eggs. Nightshade vegetables/ spices will be excluded during the first 12 weeks on the 1. Inability to obtain blood at visit 1 or 2 diet and then reintroduced during the second 12 weeks 2. Not providing a sufficiently detailed visit 1 food on the diet, if the participant desires, to safely test toler- record ance to nightshades while under study team observation. 3. Not mailing back visit 1 study materials by study Specific guidance will be provided to participants about day 28 how to reintroduce nightshades into the diet. 4. Not responding to queries for clarification of food record details within 7 days of the second attempt Study diet 2 The low saturated fat diet restricts satu- to contact rated fat to ≤ 15 g per day and limits unsaturated fat to 20–50 g (4–10 teaspoons) per day. (This diet is pro- Recruitment moted by the Swank MS Foundation [38] and includes Participants will be recruited from within a 500-mile ra- more emphasis on vegetables and whole grains than the dius of Iowa City. The North Central Multiple Sclerosis original Swank Diet.) Society Region, which serves Iowa and Nebraska, has over 8000 members. The research team will work with Dietary supplements the support groups of the National Multiple Sclerosis All study participants will follow the supplement regi- Society (NMSS) in communities within a 2-hour driving men outlined in Table 1, with the exception of vitamin distance of Iowa City to advertise the study to their D (amount prescribed will vary on the basis of vitamin members. Additionally, the study team will work with D level measured in the blood at visit 1 and subsequent regional MS centers, the North American Research visits as outlined in Table 2; target range, 40–80 ng/ml). Wahls et al. Trials (2018) 19:309 Page 8 of 16 Table 1 Study diets Modified Paleolithic (Wahls Elimination Diet) Low Saturated Fat (Swank Diet) Recommended � 2–3 cups (6 cups raw) leafy greens/day � 2 cups vegetables/day � 2–3 cups sulfur rich vegetables/day � 2 cups fruit/day (fresh preferred) � 2–3 cups colorful fruits/vegetables/day � 2 cups fat-free dairy/day � 6–12 oz. meat, fish, poultry or game/day � 4 servings grain and cereal/day (whole preferred) � Approved fats (Extra virgin olive oil, coconut � 4 oz. + skinless chicken/turkey breast, white fish oil/butter, ghee, avocado, flax, hemp, walnut, or shellfish/day sesame and sunflower oil, tahini, rendered � 4–10 tsp. (20–50 g) unsaturated fat/day animal fats and bacon grease) Encouraged or Limited � 12 oz. organ meat/week � Maximum 3 egg yolks/week � 16 oz. omega-3 fish/week � Maximum 3 cups caffeinated beverages/day � 1 serving seaweed, algae, nutritional yeast/day � Maximum 1 alcoholic beverage/day � 1 serving fermented food/day � Maximum 15 g saturated fat/day � Maximum 4 oz. nuts and seeds/day (soaked preferred) � Maximum 50 g unsaturated fat/day � Maximum 2 tbsp. flax, hemp and/or walnut oil/day � Flax and chia seeds to achieve 2 soft bowel movements/day � Maximum 1 alcoholic beverage/day (women) � Maximum 2 alcoholic beverages/day (men) � Maximum 1 tsp. approved sweetener/day (honey, molasses, maple syrup, stevia or sugar) Not Recommended � Dairy products (cow, goat, mare, soy milk, rice milk) � Red meat (beef, pork, lamb, veal, liver, kidney, � Grains with gluten heart, tongue) � Gluten-free grains � Chicken or turkey dark meat � Eggs � Rabbit, venison, elk, squab, pheasant � Legumes (beans, peas, soy, lentils, peanuts) � Dairy products with > 1 g saturated fat per serving � Nonallowed sweeteners; approved sweeteners > 1 tsp. � Foods containing hydrogenated fat or > 1 g saturated per day fat per serving such as desserts, snacks, candies, etc. � Nightshade vegetables/spices during first 12 weeks on diet � Butter, margarine, shortening, coconut oil and other s � White fruits/vegetables (apple, pear, white potato) aturated and hydrogenated fats � Vegetable oils (corn, soy, canola, palm kernel, cottonseed, grapeseed), partially hydrogenated � Monosodium glutamate � Irradiated, deep fried, or microwaved food Supplements � 1 tsp. cod liver oil � 1 tsp. cod liver oil � 1000 μg methyl B � 1000 μg methyl B 12 12 � 1000 μg methylfolate � 1000 μg methylfolate a a � 5000 IU vitamin D � 5000 IU vitamin D 3 3 � 1 multivitamin/mineral tablet for men aged 50+ � 1 multivitamin/mineral tablet for men aged 50+ without iron without iron Dose adjusted based on serum vitamin D After review of participant’s dietary supplement intake, home from visit 2. They will introduce one new sup- study staff will ask participants to discontinue plement every third day to allow time to identify any over-the-counter dietary supplements containing the potential adverse reactions. If side effects are noted, study supplement ingredients (fish oil, vitamin D, vita- the participant will be told to stop the supplement min B , folate, and/or multivitamins) and use study and contact study staff. supplements instead. Participants will be instructed to continue taking all other dietary supplements they have Nutrition counseling been using and not to begin any new supplements until Following randomization, participants will receive two after study completion. If the participant is asked to dis- in-person and five phone nutrition counseling sessions continue a supplement recommended by their physician with the intervention RD. Personalized emails with feed- or neurologist, the research team will send a letter to the back will be sent after participants return the diet check- treating physician, detailing which supplements have lists every 4 weeks. Participants may contact the been discontinued and which supplements have been intervention RD at any time to receive additional support. initiated as part of the study protocol. A final in-person counseling session will be conducted at Study staff will provide participants with a list of sup- visit 4. Nutrition counseling will be based on the plements to purchase and will reimburse participants for Self-Determination Theory and use the Motivational all study supplements. Participants will be instructed to Interviewing (MI) communication approach [39–43]. The begin supplements on the 11th day of the diet to allow dietitians providing the intervention will be screened for them time to purchase the supplements after returning MI aptitudes prior to being hired, and they will receive Wahls et al. Trials (2018) 19:309 Page 9 of 16 Table 2 Vitamin D dosing based on blood level Table 2 Vitamin D dosing based on blood level (Continued) 2+ If vitamin D > 100 ng/ml and elevated calcium (Ca ) > 10.2 mg/dl the supplement every day and add or continue taking cod liver � Call study participant and have them stop vitamin D immediately, oil and multivitamin. increase water intake. � If taking 5000 IU or more they should add or continue taking 2+ a. If Ca level was 10.2–10.5: call your local physician, or urgent cod liver oil and multivitamin. Discuss with Dr. Wahls for care for guidance. further guidance on the appropriate vitamin D dose. The 2+ b. If Ca level was 10.6 or higher: go to the emergency room patient and primary care/neurology team will be notified for evaluation and probable intravenous fluids. by letter of the lab results and the vitamin D, cod liver oil � Stop or do not start taking the cod liver oil or the multivitamin and multivitamin recommendations. � When vitamin D < 80 ng/ml, resume vitamin D at a reduced � Send letter to participant and primary care/neurologist if dose and cod liver oil and multivitamin per local primary care participant is instructed to change vitamin D intake prescribed or neurology guidance by medical personnel � Call and notify the study participant’s primary care/neurology If visit 2 blood result: team about the high vitamin D level � Wait until visit 3 blood result. � Send letter to participant and primary care/neurologist If visit 3 or 4 blood result: � And participant is taking 5000 IU vitamin D, cod liver oil and 2+ If vitamin D > 100 ng/ml and normal calcium Ca 8.5–10.2 mg/dl a the multivitamin, discuss with Dr. Wahls for further guidance. � Study staff will call the participant and have them stop all An increase in the vitamin D dose will likely be recommended vitamin D supplements. Participant will follow up with their by Dr. Wahls and personalized results letters will be sent primary care doctor or neurologist. separately to the participant and their primary care/neurology � Stop or do not start taking cod liver oil but may continue team. multivitamin � When vitamin D < 80 ng/ml, may resume vitamin D at a reduced If vitamin D value 20 ng/ ml or less dose and cod liver oil and multivitamin per local primary care or If visit 1 or 2 blood result: neurology guidance � Refer participant back to primary care physician and neurologist, � Call and notify the study participant’s primary care/neurology recommending the primary care physician or neurologist team about the high vitamin D level prescribe vitamin D 50,000 IU once per week until vitamin D � Send letter to participant and primary care/neurologist level is greater than 40 ng/ml. Alternatively, the primary care physician may recommend 6000 to 10,000 IU vitamin D daily If vitamin D between 81 and 100 ng/ml if preferred over vitamin D . � Start or continue taking cod liver oil and multivitamin � Send letter to participant and primary care/neurologist � Reduce total vitamin D intake by 50% � Call and notify participant that vitamin D level is severely low ∘ The goal is half the dosage from all sources participant was and advise them that a letter is being sent to them and their taking at the time the blood measurement was made primary care/neurology team. ∘ If the vitamin D supplement dosage was in fractions; then, If visit 2, 3, or 4 round it down to the next available pill in the market. � Call participant to clarify if the participant is taking any vitamin D ∘ E.g., if the total taken is 7000; 1000 from MV, 1000 from supplements, cod liver oil or multivitamin and discuss with Dr. calcium/vitamin D supplement and 5000 IU vitamin D we 3 3 Wahls for further guidance. If already on vitamin D 5000 IU or want to halve the dose; then the total amount to take becomes a vitamin D supplement per their local medical team, the 3500. We will ask the participant to continue calcium/vitamin D participant may continue the vitamin D until they see their (1000 IU), switch to our MV (1000 IU), start cod liver oil (400 IU), primary care/neurology team for further guidance. Continue which totals 2400. The remaining vitamin D (3500–2400) is or add cod liver oil and multivitamin as scheduled. 1100 IU (round down to 1000 IU), so we prescribe a 1000-IU � Send letter to participant and primary care/neurologist pill once daily. The total vitamin D from vitamin D supplement (including cod liver oil and � Send letter to participant and primary care/neurologist 3 3 the multivitamin) recommended by the study team should not exceed If vitamin D 40 to 80 ng/ml 7000 IU/d (cod liver oil and multivitamin have approximately 1400 IU daily At visits 2, 3, and 4: combined) unless approved specifically by Dr. Wahls. � Start or continue taking cod liver oil and multivitamin which Abbreviation: MV Multivitamin contain about 1400 IU between the two supplements. Keep participant on current dose of vitamin D if in this range. training in this area prior to study initiation. The dietitian At all visits: will also receive ongoing consultative support throughout � Do not change vitamin D dose. E.g., if the participant is taking the study from an RD who is a member of the Motiv- 4000 IU from their personal physician, participant should stay on that dose. If they were taking 5000 IU from their personal ational Interviewing Network of Trainers (MINT). A physician they should stay on that dose. If participant is taking lesson plan was developed to guide the counseling session more than 5000 IU or less than 4000 IU, participant should for each in-person study visit. Participants will be asked to continue on that dose. � No need to start vitamin D supplement if not on any. consent to being audio recorded during in-person nutri- If vitamin D value less than 40 ng/ml but more than 20 ng/ml tion counseling sessions at visits 2 and 3. The visit 2 audio If visit 1 blood result: recordings will be reviewed by the MINT RD to verify � Wait until visit 2. fidelity to the study diet guidelines, which consist of At visit 2: � If not taking any vitamin D, begin 5000 IU daily. Participant will explaining the recommended and not recommended also begin or continue taking cod liver oil and multivitamin foods for the intervention diet and rationale for key diet- according to the supplement schedule. ary components. The MINT RD will review all visit 2 � If taking 4000 IU vitamin D or less daily, participant will be instructed to increase vitamin D to 5000 IU and add or audio recordings and 20% of visit 3 audio recordings using continue taking cod liver and multivitamin according to the the OnePass instrument [44] to assess use of the MI supplement schedule. approach. A mean OnePass score ≥4indicates average � If the participant is already taking 5000 IU but does not take the supplement regularly (i.e., daily) they will be instructed to take competence in MI. Wahls et al. Trials (2018) 19:309 Page 10 of 16 Table 3 Outcomes: change after 12-week intervention and Perceived fatigue will be assessed with the following 12 weeks of sustained intervention relative to observation period scales: Primary outcome measure: 1. The FSS [45]: a nine-item questionnaire measuring 1. Perceived fatigue assessed by FSS. the severity of perceived fatigue and its effect on Secondary outcome measures: daily activities. Scores range from 0 to 7, with 1. Perceived fatigue assessed by MFIS; higher scores indicating greater perceived fatigue 2. Perceived fatigue assessed by FSMCF; severity. Obtaining scores every 4 weeks will provide 3. Gait speed assessed by T25FW; more assessment points for the primary outcome 4. Distance walked assessed by 6MWT; measure and will improve the statistical power for hypothesis testing. 5. Speed of task completion in 9HPT; 2. Modified Fatigue Impact Scale (MFIS) [46], a 21- 6. Number of correct responses assessed by SDMT-O; item assessment of the effects of fatigue related to 7. Quality of life as measured by MSQOL-54; physical, cognitive, and psychosocial functioning. 8. Quality of life as measured by SF-36; 3. Fatigue Scale for Motor and Cognitive Functions 9. MSISv2 score; (FSMCF), a 20-item measure of cognitive and 10. Anxiety and depression as measured by HADS; motor fatigue for people with MS. 11. Physical activity (average daily steps and average minutes spent sedentary, light intensity physical activity, moderate Motor function (gait and hand) will be assessed with intensity physical activity and vigorous intensity physical the following tests: activity) and sleep (total sleep time, sleep efficiency) as measured by the accelerometer; 1. T25FW, a timed 25-ft walk to quantify mobility and 12. Sleep quality as measured by PSQI; leg function 13. Stress as measured by PSS-10; 2. 6MWT assesses distance walked in 6 minutes as a 14. Physical activity as assessed by IPAQ-L; submaximal test of aerobic capacity. 15. Cognitive performance as measured by PDQ; 3. 9HPT is a quantitative test of upper extremity 16. Change in mood as measured by the MHI. function (hand) in which patients are timed as they put nine pegs into holes in a block and then remove 17. Nutritional adequacy of the diet as measured by food frequency questionnaire (FFQ) and food records; them one at a time. The test is conducted twice with the nondominant hand and twice with the 18. Changes in blood biomarkers (insulin, glucose, hemoglobin A1c, lipids including HDL, vitamin K, vitamin D, calcium, dominant hand. vitamin B , folate, homocysteine, complete blood count with differential, Cardio IQ® [fatty acid levels]). Cognitive function will be assessed by: Abbreviations: 6MWT 6-Minute walk test, 9HPT 9-hole Pegboard Test, Cardio IQ® Omega-3 (EPA + DHA) Index, Omega-6/Omega-3 Ratio, EPA/Arachidonic Acid Ratio, Arachidonic Acid, EPA, and DHA, DHA Docosahexaenoic acid, EPA 1. SDMT-O is a screening tool for organic cerebral Eicosapentaenoic acid, FFQ Food Frequency Questionnaire, FSMCF Fatigue dysfunction. Scale for Motor and Cognitive Function, FSS Fatigue Severity Scale, HADS Hospital Anxiety and Depression Scale, HDL High Density Lipoprotein, IPAQ-L 2. Perceived Deficits Questionnaire (PDQ) is a self-report International Physical Activity Questionnaire–Long, MFIS Modified Fatigue measure of cognitive dysfunction specifically for MS. Impact Scale, MHI Mental Health Inventory, MSIS v2 Multiple Sclerosis Impact Scale version 2, MSQ Medical Symptoms Questionnaire, MSQOL54 Multiple Sclerosis Quality of Life 54, PDQ Perceived Deficits Questionnaire, PSQI QOL will be assessed by: Pittsburgh Sleep Quality Index, PSS 10 Perceived Stress Scale 10, SDMT-O Symbol Digit Modalities Test-Oral, SF-36 36-item Short Form Health Survey, SPMSQ Short Portable Mental Status Questionnaire, T25FW Timed 25-foot Walk 1. MSQOL54 [47] is a multidimensional health-related QOL measure that includes both generic and MS- Measures specific items. The SPMSQ will be used at screening to assess organic 2. SF-36 is a generic measure of health-related QOL. brain deficit. Personal information will be collected at visit 3. HADS [48] is an instrument used to assess mood 1. A medication audit, health history, vital signs, and blood and detect states of depression and anxiety. biomarkers (insulin, glucose, hemoglobin A1c, lipids in- 4. Mental Health Inventory (MHI) [49] provides an cluding high-density lipoprotein, vitamin K, vitamin D, assessment of anxiety, depression, behavioral calcium, vitamin B , folate, homocysteine, Cardio IQ® control, positive affect, and general distress. [Omega-3 (EPA + DHA) index, omega-6/omega-3 ratio, 5. Multiple Sclerosis Impact Scale version 2 (MSIS v2) EPA/arachidonic acid ratio, arachidonic acid, EPA, and is a 29-item self-report measure of the impact of DHA]) will be collected at each visit. Table 3 summarizes MS on day-to-day activities, including both physical the primary and secondary outcome measures. and psychosocial aspects. Wahls et al. Trials (2018) 19:309 Page 11 of 16 6. Perceived Stress Scale 10 (PSS-10) [50] measures massage, meditation, yoga, and Tai Chi derived from the degree to which situations in one’s life are the complementary health approaches section of perceived as stressful. National Health Interview Survey [57]. Side effects questionnaire to assess new or Physical activity and sleep will be assessed by: worsening symptoms that might be attributed to diet or supplement changes (see Additional file 2: 1. Accelerometers (GT9X Link; ActiGraph, Pensacola, Appendix 1). FL, USA) will be worn on the nondominant wrist  “Your Eating Experience” questionnaire, developed during the 7-day food-recording period (including by our research team to collect the following sleep time). Outcomes measured by accelerometer information: how often foods that are to be avoided will include daily steps, time spent in light-intensity were consumed during the past 4 weeks, what made activity, time spent in moderate-intensity activity, it difficult to avoid those foods, and the factors that time spent sedentary, sleep time, and sleep helped the participant follow the dietary guidelines efficiency. (see Additional file 3: Appendix 2). 2. International Physical Activity Questionnaire Long, (IPAQ-L) [51], a physical activity assessment. Assessments and visit schedule 3. Pittsburgh Sleep Quality Index (PSQI) [52], a Visit 1 – week 1 19-item self-report sleep quality assessment. Participants will fast for 12 hours prior to visit 1. Eligibility criteria will be checked, and the participant Diet quality will be assessed by: will be consented (Additional file 4: Appendix 3). Height and weight will be measured to confirm a BMI ≥ 19. If 1. Three-day weighed food records to assess nutrient participants qualify for the study, their vital signs will be intake. Nutrient intake will be calculated using the measured, and fasting blood will be drawn. Question- most current version of the Nutrition Data System naires including a medication audit and motor and for Research software (Nutrition Coordinating cognitive testing will be completed, as listed in Fig. 2, Center, University of Minnesota, Minneapolis, MN, and personal information such as duration of MS and USA). (Note: Initially, 7-day records were collected. handedness will be recorded. Participants will be Based on participant feedback, and confirmed with instructed on how to (1) keep a 3-day food record and use the Minnesota Nutrition Coordinating Center, a loaned food scale for weighing the amount of food eaten, consecutive 3-day records are in used in a standard (2) complete an FFQ, and (3) wear an accelerometer. manner to assess nutrient intake [53–55].) Participants will complete questionnaires, as listed in 2. Harvard Food Frequency Questionnaire (FFQ) is Fig. 2, via a secure Research Electronic Data Capture used to obtain information regarding the frequency (REDCap) system at home 1–3 days after the study visit. and portion size of food and beverages consumed Participants will wear an accelerometer for 7 continuous over the past year (visit 1) and the past 12 weeks days (24 h/d) following this visit and record the foods, (visits 2–4). beverages, and dietary supplements consumed between Thursday and Saturday following visit 1. The accelerom- Social support for eating will be assessed with: eter and dietary forms will be returned by mail. 1. A version of Social Support for Eating Habits Scale Visit 2 – week 12 [56], modified to include factors that are key to Participants will wear an accelerometer for the 7 days adherence by family members and friends, will prior to visit 2 and will record the foods, beverages, and assess social support for eating. These factors were dietary supplements consumed between Thursday and identified in qualitative interviews with participants Saturday prior to the visit. Participants will complete from our multimodal pilot study [4]. They include questionnaires (as outlined in Fig. 2)1–3 days prior to food purchasing, meal preparation, snack visit 2 using REDCap. Participants will fast for 12 hours availability, and modeling study diet adherence prior to visit 2. Vital signs, blood, motor and cognitive while in the presence of the study participant. tests, and questionnaires will be completed at visit 2 (see Fig. 2). Food records, FFQs, and accelerometer data, will To further monitor the health of participants, the be reviewed for completeness. Participants will be ran- following data variables will be collected: domized to one of the study diets. The study participant and their family member(s) or Health Practices Survey, a subset of questions asking adult companion will meet with an RD who will provide about use of complementary therapies, including individualized nutrition counseling on the participant’s Wahls et al. Trials (2018) 19:309 Page 12 of 16 assigned study diet. The family/adult companion will be participant will meet with the study dietitian, who will advised that, during our previous studies, we have ob- review the diet checklists and answer questions. For par- served that the study participants who have had their ticipants randomized to the modified Paleolithic diet, families adopt the study diet along with the study partic- the RD will encourage but not require the participant to ipants have had greater levels of success with adopting reintroduce nightshades to the diet. If the participant and sustaining the intervention diets. The family/adult elects to reintroduce nightshades, one nightshade food companion will be advised that they are expected to be will be introduced on 1 day using this process: consume supportive of eating study-compliant foods. one bite of the food and wait 3 hours; consume ½ cup Participants will view a brief video (< 20 min) that and wait 3 hours; consume 1 cup of food and wait 6 provides background information about the study diet to days. Symptoms will be recorded for a total of 7 days. If which they were randomized. Participants will receive an no symptoms have appeared by the end of 7 days, the intervention food guide developed by study staff that de- food may be added back to the diet, and another food scribes their study diet, as well as The Multiple Sclerosis can be tested. Diet Book [58] (low saturated fat diet) or The Wahls Participants will be given a fresh set of diet checklists Protocol [59] (modified Paleolithic diet), both of which to complete daily and a 3-day weighed food record contain sample menus and recipes to assist with meal booklet and FFQ to complete prior to their next study planning. Additional materials, such as grocery lists, will visit. A self-addressed, stamped envelope will be pro- be provided to assist with diet adoption. A diet checklist vided so that participants can return their diet checklists that offers guidance to the participant in the form of at weeks 28 and 32 for the study RD to review. An email prompts to eat the foods that are recommended and to will be sent to acknowledge receipt and provide assess- avoid those that are not recommended will be provided. ment comments. The RD will not make coaching calls The participants and their adult companions will be during this time, but study participants may contact the given a study-adherent meal and practice recording the RD to request support. Participants will be reminded to meal in the diet checklist to facilitate the learning of the continue their usual physical activity, medication, sup- principles of the assigned study diet and how to use the plement, and stress reduction regimens during the next daily diet checklist. 12 weeks unless their physician or physical therapist Participants will be given a set of diet checklists to directs them to make changes. complete daily and a 3-day weighed food record booklet as well as an FFQ to complete prior to their next study Visit 4 – week 36 visit. A self-addressed, stamped envelope will be pro- Participants will wear an accelerometer for the 7 days vided so that participants can return their diet checklists prior to visit 4 and will record the foods, beverages, and at weeks 16 and 20 for the study dietitian to review. dietary supplements consumed between Thursday and Upon receiving the week 20 checklist, the RD will send Saturday prior to the visit. Participants will again an email to acknowledge receipt and provide assessment complete some questionnaires (as outlined in Fig. 2) comments. Participants will be asked to continue their 1–3 days prior to visit 4 using REDCap. Participants usual physical activity, medication, and stress reduction will fast for 12 hours prior to visit 4. Vital signs, regimens during the next 24 weeks unless their phys- blood, motor and cognitive tests, and questionnaires ician or physical therapist recommends changes. will be completed at visit 4 (see Fig. 2). Food records, The study RD will continue to coach the participant FFQs, and accelerometer data will be reviewed for via coaching calls 2–3 days after visit 2 and then weekly completeness. Participants will view two videos from for 3 weeks. A final coaching call will be made after the principal investigator: a thank-you video and an receipt of the first 4-week diet checklist booklet. educational video about environmental factors that contribute to health. The participant will then meet Visit 3 – week 24 with the study RD, who will review the diet checklists Participants will wear an accelerometer for the 7 days and answer questions. prior to visit 3 and will record the foods, beverages, and dietary supplements consumed between Thursday and Saturday prior to the visit. Participants will again Risks and safety monitoring during intervention complete questionnaires (as outlined in Fig. 2)1–3 days Weight monitoring prior to visit 3 using REDCap [60]. Participants will fast If a participant’s BMI at visit 1 is < 19 kg/m , they are in- for 12 hours prior to visit 3. Vital signs, blood, motor eligible for the study. If BMI at visit 2 or 3 is < 18.5 kg/m , and cognitive tests, and questionnaires will be completed the participants will be asked to weigh themselves at home at visit 3 (see Fig. 2). Food records, FFQs, and acceler- 1 and 2 weeks after the study visit (in the morning after ometer data will be reviewed for completeness. The their first void wearing street clothing) and report that Wahls et al. Trials (2018) 19:309 Page 13 of 16 information to the study coordinator/study team. If the monitoring board composed of two UI faculty physicians BMI remains < 18.5 kg/m for 2 consecutive weeks: will receive all adverse events sheets. A data monitoring committee has not been constituted. Guidelines for stop- 1. The intervention dietitian will conduct a special ping participation due to adverse events, patient decision telephone coaching call to discuss strategies for to withdraw, or treatment medical provider recommenda- increasing their calorie intake. The dietitian will tion have been established. Coaching and contact with make a second telephone call 1 week after the first study dietitian and motivational interviewing. Subjects call to provide continued support. Additional calls who elect or are obligated to discontinue the study diet will be based on participant need and dietitian will be asked to complete the study forms and the motor assessment. The participant will be instructed to assessments through 36 weeks. continue weighing themselves weekly and reporting that information to the study team. Data management 2. The participant will be advised to follow up with Study data will be collected and managed using REDCap their personal physician regarding the weight loss. [60] tools hosted at UI. REDCap is a secure, web-based ap- plication designed to support data capture for research If the BMI increases to 19 kg/m , the weekly weight studies, and it provides (1) an intuitive interface for vali- monitoring will be discontinued. If a participant’sBMI at dated data entry, (2) audit trails for tracking data manipula- study visit 2 is 18.5–19 kg/m , the participant may be at tion and export procedures, (3) automated export risk for additional weight loss, so the dietitian will alert procedures for seamless data downloads to common them of this possibility and briefly discuss strategies to statistical packages, and (4) procedures for importing prevent weight loss. data from external sources. Study participants will log The study team will report to the Data and Safety into REDCap using a secure web-based portal to an- Monitoring Board (DSMB) the number of participants swer study questionnaires from home. Study staff will currently being monitored for low BMI and the correct- use REDCap for manual entry of laboratory and other ive actions taken by study staff. The DSMB will review data and interviewer-administered questionnaires. the BMIs of all participants quarterly along with any cor- rective action taken by study staff. The DSMB is consti- Power and sample size justification tuted and managed by the NMSS and will review the Table 4 displays the mean minimum clinically important adverse events, significant adverse events, and laboratory difference that can be detected for primary and second- values greater than 10% outside the reference range. In ary outcomes to be assessed in the study. The table also addition to the quarterly reports provided to the includes the SD and correlation between observations DSMB, trial auditing procedures will also include a over time, with 34 patients in each group after attrition, closed report from the study statistician with more and an alpha value of 0.05. The minimum differences details related to diet assignment and adverse events. and SDs are derived from the preliminary studies The data management application also provides data ma- and peer-reviewed published MS longitudinal studies. nipulation and user activity audit trails. A medical Forty-five patients will be recruited in each group, Table 4 Power and sample size justification Variable Within Study Groups Between Study Groups at Last Visit MMCD SD Correlation MMCD SD Group A SD Group B Power is ≥0.85 for the primary outcome FSS-9 1.2–2.0 1.1–1.4 0.6 0.7 [35] 0.9 1.1 Power is ≥0.90 for secondary outcomes MSQOL-54 PHC 11.5 16.0 0.6 17.0 17.0 19.0 MHC 12.0 17.0 0.5 18.0 18.0 19.0 6 min walk test 35 50.0 0.5 45.0 45.0 50.0 Timed 25 ft walk 2.9 4.0 0.5 4.0 4.0 4.3 9 hole peg test 5.5 8.0 0.5 8.0 8.1 8.3 PASAT 4.2 6.0 0.5 5.8 6.0 6.3 Abbreviations: FSS Fatigue Severity Scale, MSQOL-54 Multiple Sclerosis Quality of Life 54, PHC MSQOL-54 physical health composite score, MHC MSQOL-54 mentalhealth composite score, PASAT Paced Auditory Serial Addition Test, MMCD Minimun Mean Clinical Difference Power and sample size calculations based on PASAT. Per NMSS, SDMT-O replaces the PASAT measure in this study Wahls et al. Trials (2018) 19:309 Page 14 of 16 assuming a 25% attrition rate, to attain the 34 patients comparison of two study diets is a better approach than a needed in each group. crossover design for this population. Maintaining differences between the dietary groups may be challenging because participants may want to Data analysis modify their eating patterns to make them similar to the All analyses will be completed by a masked statistician diet to which they are not assigned. That is, participants who will not have access to study diet assignment. Data in the low saturated fat diet group may wish to eliminate analysis will include both intention-to-treat and gluten and dairy, and those in the modified Paleolithic per-protocol analytic methods. Data for this study will diet group may elect to greatly restrict saturated fat in- be analyzed using SAS® 9.4 software (SAS Institute, Cary, take. To minimize this, the dietary intervention guide NC, USA). Statistical significance will be set at α ≤ 0.05. for the low saturated fat diet encourages consumption of Descriptive statistics will be calculated for all variables at gluten-containing grains, and the modified Paleolithic all data collection times. Outliers will be checked for diet encourages consumption of foods containing satu- accuracy and possible entry errors. Respondents who rated fat. Additionally, physical symptoms related to drop out of the study will be compared with those who consumption of gluten or a reluctance to eat saturated complete the study so that differences in baseline charac- fat are included in the inclusion/exclusion criteria. teristics that may affect the study results will be detected. Both study groups are likely to experience reductions in Patterns of missing data (missing at random, not missing MS-related symptoms. Differences within and between at random) will be investigated [61]. The analytic methods groups will be assessed for clinical significance, supported will account for the type of missing data. The distributions by statistical analyses. Because the primary outcome meas- of continuous variables will be evaluated for normality ure is a self-reported measure and not an objectively mea- and homogeneity of variance. Appropriate transforma- sured laboratory or imaging result, the NMSS requested tions will be applied as needed, and/or statistical analyses two modifications in the study design. First, a 12-week ob- for nonnormal data will be performed. Collinearity among servation period was added, during which participants fixed effect variables will be examined. continue to eat their usual diet, so that each participant Repeated-measures analyses will use generalized linear can be her or his own control in the repeated-measures mixed models methods to test for within-group and analyses. Second, an accelerometer measure was added to between-group changes in both primary and secondary the study to provide an objective assessment of the change outcomes. Intraclass correlations for repeated measures in physical activity, sleep duration, and sleep quality. within patients will be included in the model structure for Given the anecdotal reports regarding improvement in analyses. Mixed models for both continuous and categor- MS symptoms with dietary changes, results from this ical outcomes will have both random and fixed effects. study will contribute to understanding of the optimal Fixed effects will include characteristics such age, sex, dietary approach for reducing MS-related fatigue. Find- intervention group, time indicators, and group-by-time in- ings of the study as well as any challenges observed will teractions. Intercepts and slopes may be considered as be submitted to journals for publication. Published random effects. papers will be listed on the Wahls research lab website (https://wahls.lab.uiowa.edu/publications). Discussion Clinical studies of diet in MS are needed because there is Trial status uncertainty about the optimal dietary approach to redu- Recruitment commenced August 24, 2016. We have cing MS-related fatigue. Randomized trials that include consented 58 participants to date. assignment to a control or standard care group are the preferred design; however, previous studies including diet- Additional files ary approaches to reduce MS-related symptoms suggest increased participant adherence when a study diet is of- Additional file 1: SPIRIT Checklist. (DOC 121 kb) fered to all participants because dropout is high among Additional file 2: Appendix 1. Side Effects Survey. (PDF 47 kb) nondiet control group participants. Crossover study Additional file 3: Appendix 2. Your Eating Experience Questionnaire. (PDF 56 kb) designs have also been used to test dietary hypotheses. Additional file 4: Appendix 3. Study Consent. (PDF 259 kb) However, we have observed MS symptom reductions among participants following a modified Paleolithic diet and marked increases in MS-related symptoms among Abbreviations 6MWT: 6-Minute walk test; 9HPT: 9-Hole Pegboard Test; ADA: American those who returned to eating gluten-containing grains or Diabetes Association; BMI: Body mass index; Cardio IQ®: Omega-3 (EPA + casein-containing dairy products. Therefore, to most ef- DHA) index, omega-6/omega-3 ratio, EPA/arachidonic acid ratio, arachidonic fectively and ethically study such dietary approaches, the acid, EPA, and DHA; DHA: Docosahexaenoic acid; DSMB: Data and Safety Wahls et al. Trials (2018) 19:309 Page 15 of 16 Monitoring Board; EPA: Eicosapentaenoic acid; FFQ: Food Frequency multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Questionnaire; FSMCF: Fatigue Scale for Motor and Cognitive Function; Psychiatry. 2002;72(2):179–83. FSS: Fatigue Severity Scale; HADS: Hospital Anxiety and Depression Scale; 8. Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, HDL: High-density lipoprotein; IPAQ-L: International Physical Activity French Modafinil Study Group. Modafinil for fatigue in MS: a randomized Questionnaire–Long; IRB: Institutional review board; MFIS: Modified Fatigue placebo-controlled double-blind study. Neurology. 2005;64(7):1139–43. Impact Scale; MHI: Mental Health Inventory; MI: Motivational Interviewing; https://doi.org/10.1212/01.WNL.0000158272.27070.6A. MINT: Motivational Interviewing Network of Trainers; MRI: Magnetic 9. Naldi L, Conti A, Cazzaniga S, Patrizi A, Pazzaglia M, Lanzoni A, et al.; resonance imaging; MS: Multiple sclerosis; MSIS v2: Multiple Sclerosis Impact Psoriasis Emilia Romagna Study Group. Diet and physical exercise in Scale version 2; MSQ: Medical Symptoms Questionnaire; MSQOL54: Multiple psoriasis: a randomized controlled trial. Br J Dermatol. 2014;170(3):634–642. Sclerosis Quality of Life 54; NMSS: National Multiple Sclerosis Society; doi: https://doi.org/10.1111/bjd.12735. PDQ: Perceived Deficits Questionnaire; PSQI: Pittsburgh Sleep Quality Index; 10. Sedlacek SM, Playdon MC, Wolfe P, Μginley JN, Wisthoff MR, Daeninck EA, PSS 10: Perceived Stress Scale 10; QOL: Quality of life; RD: Registered Jiang W, Zhu Z, Thompson HJ. Effect of a low fat versus a low carbohydrate dietitian; REDCap: Research Electronic Data Capture; RRMS: Relapsing- weight loss dietary intervention on biomarkers of long term survival in remitting multiple sclerosis; SDMT-O: Symbol Digit Modalities Test–Oral; breast cancer patients (‘CHOICE’): study protocol. BMC Cancer. 2011;11:287. SF36: 36-Item Short Form Health Survey; SPMSQ: Short Portable Mental https://doi.org/10.1186/1471-2407-11-287. Status Questionnaire; T25FW: Timed 25-foot walk; UI: University of Iowa 11. Self S, Prentice R, Iverson D, Henderson M, Thompson D, Byar D, et al. Statistical design of the Women’s Health Trial. Control Clin Trials. 1988;9(2): Funding 119–36. Funding for this trial was provided by the National Multiple Sclerosis Society. 12. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3:59. 13. Lauer K. Environmental risk factors in multiple sclerosis. Expert Rev Authors’ contributions Neurother. 2010;10(3):421–40. https://doi.org/10.1586/ern.10.7. TW designed the study, secured study funding, and drafted the manuscript. 14. Swank RL, Grimsgaard A. Multiple sclerosis: the lipid relationship. Am J Clin MOS drafted the manuscript. ZA drafted the manuscript. LR designed the Nutr. 1988;48(6):1387–93. study and helped draft the manuscript. WD designed the study. LC designed 15. Swank RL, Lerstad O, Strom A, Backer J. Multiple sclerosis in rural Norway its the study. KS contributed to the study design. CAC contributed to the study geographic and occupational incidence in relation to nutrition. N Engl J design. NL contributed to the study design. LS designed the study and Med. 1952;246(19):722–8. helped draft the manuscript. All authors commented on the final manuscript 16. Swank RL. Treatment of multiple sclerosis with low-fat diet. AMA Arch draft, and all authors read and approved the final manuscript. Neurol Psychiatry. 1953;69(1):91–103. 17. Swank RL. Treatment of multiple sclerosis with low-fat diet; results of five and Ethics approval and consent to participate one-half years’ experience. AMA Arch Neurol Psychiatry. 1955;73(6):631–44. Ethical approval was obtained from the University of Iowa Institutional 18. Swank RL. Treatment of multiple sclerosis with low-fat diet: result of seven Review Board (IRB identifier 201604705). Informed consent will be obtained years’ experience. 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Am Heart J. 2001;142(6):1041–6. https://doi.org/10.1067/mhj.2001.118740. 52. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213. 53. National Cancer Institute. Food Record at a Glance: Dietary Assessment Primer 2018. https://dietassessmentprimer.cancer.gov/profiles/record/. 54. Harttig U, Haubrock J, Knuppel S, Boeing H. The MSM program: web-based statistics package for estimating usual dietary intake using the Multiple http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Trials Springer Journals

Dietary approaches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls Elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: study protocol for a randomized controlled trial

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Abstract

Background: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS) and contributes to diminishing quality of life. Although currently available interventions have had limited success in relieving MS- related fatigue, clinically significant reductions in perceived fatigue severity have been reported in a multimodal intervention pilot study that included a Paleolithic diet in addition to stress reduction, exercise, and electrical muscle stimulation. An optimal dietary approach to reducing MS-related fatigue has not been identified. To establish the specific effects of diet on MS symptoms, this study focuses on diet only instead of the previously tested multimodal intervention by comparing the effectiveness of two dietary patterns for the treatment of MS- related fatigue. The purpose of this study is to determine the impact of a modified Paleolithic and low saturated fat diet on perceived fatigue (primary outcome), cognitive and motor symptoms, and quality of life in persons with relapsing-remitting multiple sclerosis (RRMS). Methods/design: This 36-week randomized clinical trial consists of three 12-week periods during which assessments of perceived fatigue, quality of life, motor and cognitive function, physical activity and sleep, diet quality, and social support for eating will be collected. The three 12-week periods will consist of the following: 1. Observation: Participants continue eating their usual diet. 2. Intervention: Participants will be randomized to a modified Paleolithic or low saturated fat diet for the intervention period. Participants will receive support from a registered dietitian (RD) through in-person coaching, telephone calls, and emails. 3. Follow-up: Participants will continue the study diet for an additional 12 weeks with minimal RD support to assess the ability of the participants to sustain the study diet on their own. (Continued on next page) * Correspondence: terry-wahls@uiowa.edu University of Iowa, Iowa City, Iowa, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wahls et al. Trials (2018) 19:309 Page 2 of 16 (Continued from previous page) Discussion: Because fatigue is one of the most common and disabling symptoms of MS, effective management and reduction of MS-related fatigue has the potential to increase quality of life in this population. The results of this study will add to the evidence base for providing dietary recommendations to treat MS-related fatigue and other symptoms associated with this disease. Trial registration: ClinicalTrials.gov, NCT02914964. Registered on 24 August 2016. Keywords: Multiple sclerosis, Fatigue, Diet, Accelerometer, Quality of life, Intervention, Swank diet, Wahls elimination diet Background physical and mental performance [16–21]. The Swank Fatigue is one of the most common and disabling symptoms study found that the number of relapses and progression of multiple sclerosis (MS), diminishing quality of life (QOL) of disability was associated strongly with dietary satu- and contributing to early exit from the workforce [1, 2]. rated fat consumption [17–22]. The 50-year follow-up is MS-related fatigue is most commonly managed through a strength of the Swank study, but the absence of a con- multiple interventions, including disease-modifying drugs trol group and lack of brain imaging are limitations. and stimulants, exercise, energy conservation, and stress Consumption of vegetables has also been associated management techniques [3]. Although exercise augmented with favorable health outcomes related to MS. Notably, by electrical muscle stimulation can be modestly effective in the mean daily serving of vegetables is associated with reducing perceived fatigue [4, 5], studies investigating the ef- lower risk of developing obesity [23], which is a risk fac- ficacy of pharmaceutical therapies have shown conflicting tor for and a common comorbid diagnosis of those with results [6–8]. Because drug treatment has not been effective, MS. Increased consumption of vegetables is associated dietary interventions are being explored. Statistically and with lower Expanded Disability Status Scale scores [24], clinically significant reductions in perceived fatigue severity insulin sensitivity, blood pressure, body weight, and body in persons with progressive multiple sclerosis (pwPMS) have mass index (BMI). Considering these observations, re- been reported with use of a multimodal intervention searchers in a more recent randomized controlled trial consisting of a modified Paleolithic diet, stress reduction, used a vegetarian version of the Swank diet [25], also exercise, and electrical muscle stimulation [4, 5]. known as the McDougall diet. Measures included the Interventions considering the whole diet (vs. Fatigue Severity Scale (FSS), 36-item Short Form Health supplement-based, single-nutrient focus) have been Survey (SF-36) quality-of-life scores, lipids, weight, BMI, used in treating or preventing diseases, including psoriasis and brain magnetic resonance imaging (MRI) scans at [9], cancer [10, 11], and neurological diseases [12]. Emer- baseline and at 1 year [26]. Favorable reductions in ging data support the notion that environmental rather weight, BMI, and total cholesterol were observed, but no than genetic factors are likely the predominant causes of statistically significant differences in MRI findings or MS [13]. Given that food consumed is a major component SF-36 quality-of-life scores were reported [26]. of the environment, it is conceivable that improving the Anotherdietofinteresttothe MS communityisa quality of the diet may have a significant impact on the Paleolithic diet [27]. Dr. Loren Cordain’s recommendations development of MS. The relationship between the quality for a modern version of the Paleolithic diet stresses the of the diet and MS-related symptoms such as fatigue is consumption of meats, vegetables, and fruits; excludes unknown. In this study, we will compare two dietary grains, legumes, and dairy [27, 28]; and excludes night- patterns for the treatment of MS-related fatigue: the shade vegetables (potatoes, tomatoes, peppers, and egg- modified Paleolithic diet (Wahls elimination diet) and plants) [29] for persons with rheumatoid arthritis. Recently a low saturated fat diet (Swank diet). tested for its impact on various biomarkers in healthy One early dietary intervention for individuals with MS individuals, the Paleolithic diet was associated with im- was based on the observation that high levels of satu- provements in blood pressure, BMI [30], total cholesterol, rated fat in the diet were associated with increased risk insulin sensitivity, fasting insulin, and arterial distensibility for MS in Norway [14, 15]. Dr. Roy Swank theorized that [31]. In a study of patients with type 2 diabetes, the a diet high in saturated fats causes more rapid disease Paleolithic diet was shown to be more satiating per calorie progression. Dr. Swank followed 144 patients with mild than the American Diabetes Association (ADA) diet, which to more severe disability for 34 years. These individuals encourages increased intake of vegetables, dietary fiber, had agreed to consume a diet containing < 20 g of satu- whole-grain bread and cereal products, fruits, and berries rated fat per day and report their dietary adherence. The and decreased intake of total fat with more unsaturated fat patients’ clinical outcomes were monitored, including [32]. In a crossover study comparing the Paleolithic diet Wahls et al. Trials (2018) 19:309 Page 3 of 16 with the ADA diet, the Paleolithic diet was superior to the saturated fat diet (Swank diet) on perceived fatigue, ADA diet with respect to improving blood pressure, lipid cognitive and motor symptoms, and quality of life in profile, and glycemic control [33]. Finally, in a randomized persons with RRMS, a milder form of disease that often controlled study of obese persons with metabolic syn- transitions to a more progressive and severe form of MS. drome, comparison of the Paleolithic diet with the control We hypothesize that participants following the modified diet, which was an isoenergetic diet based on Dutch dietary Paleolithic diet will have a clinically greater reduction in guidelines, the Paleolithic diet was associated with greater FSS score than participants following the low saturated improvements in blood pressure, fasting levels of lipids, fat diet. and weight loss than the control diet [34]. A modified version of the Paleolithic diet was shown to Research hypothesis 1a reduce perceived fatigue in pwPMS (either secondary or After 12 weeks of the diet intervention, relative to the primary progressive multiple sclerosis [SPMS or PPMS, re- observation period, at least 15% of participants in the spectively]) [4, 5] as part of a multimodal intervention low saturated fat diet group will demonstrate decreased (modified Paleolithic diet, targeted vitamin supplementa- perceived fatigue (assessed by FSS score), 30% will have tion, stress-reducing practices, exercise, and electrical improvement in QOL mental health and physical health muscle stimulation). The study diet stressed the consump- scores (mean score increase of > 5 points), 50% will tion of more vegetables, with a target of 6 to 9 cups of demonstrate improved cognition (> 5% improvement in vegetables and fruit per day, and recommended somewhat mean Symbol Digit Modalities Test–Oral [SDMT-O] less meat than Paleolithic diets tested in the previously score), and 30% will demonstrate improved motor func- mentioned studies. At enrollment, study participants were tion (> 5% improvement in mean distance of 6 Minute consuming less than 1.5 servings of vegetables per day but Walk Test [6MWT]). In the modified Paleolithic diet raised this to an average of 8 servings per day by month 12 group, ≥ 60% of the participants will demonstrate de- [5]. The dietary component of the multimodal intervention creased perceived fatigue, 70% will have improvement in was significantly associated with favorable changes in QOL mental health and physical health score, 70% will mood and cognition between baseline and 12 months, demonstrate improved cognition, and 55% will demon- whereas the nondietary components were not [25]. It is strate improved motor function. unknown whether the dietary component of the multi- modal intervention also significantly contributed to the ob- Research hypothesis 1b served reduction in perceived fatigue [4, 5]; however, After 12 weeks of the diet intervention, participants in several participants anecdotally reported that deviations the low saturated fat diet group will not have clinically from the study diet resulted in a sharp worsening of their or statistically significant reductions in fatigue or im- fatigue and noted that the fatigue resolved with stricter provements in QOL measures or motor and cognitive adherence to the study diet. Data from another pilot ran- function relative to the observation period, whereas par- domized controlled trial also showed significant reductions ticipants in the modified Paleolithic diet group will have in perceived fatigue (as assessed by FSS) in individuals with clinically and statistically significantly reduced fatigue relapsing-remitting multiple sclerosis (RRMS) following a and improved QOL measures and motor and cognitive modified Paleolithic diet intervention [35]. function as measured by changes in mean scores of the To establish the specific effects of diet on MS symp- aforementioned measures. toms such as fatigue, this study focuses on diet only in- stead of the previously tested multimodal intervention. Research hypothesis 2a The modified Paleolithic diet continues to stress a high By 12 weeks after initiation of diet, participants in the intake of vegetables but also eliminates foods to which modified Paleolithic diet group will have a clinically some individuals may be sensitive: eggs and nightshade greater reduction, relative to the observation period, of vegetables [29]. To enhance adherence and reduce the perceived fatigue (assessed by FSS) than those in the low rate of dropout, which occurred early in the intervention saturated fat diet group. among participants in a nondiet control group [35], con- trol participants will be assigned a second diet, a low sat- Research hypothesis 2b urated fat (Swank) diet, which is also popular among the By 12 weeks after initiation of diet, participants in the MS community and has research to support its efficacy. modified Paleolithic diet group will have clinically greater improvement, relative to the observation period, Methods/design with respect to both motor function (gait, assessed by Aims of study the timed 25-ft walk test [T25FW] and by the 6MWT; In this study, we will compare the impact of the modi- hand, assessed by 9-hole peg test (9HPT); physical activ- fied Paleolithic diet (Wahls elimination diet) and a low ity outcomes, measured by accelerometer [e.g., increased Wahls et al. Trials (2018) 19:309 Page 4 of 16 daily steps, increased time spent in light-intensity activity, group assignment. The medical monitor will be blinded increased time spent in moderate-intensity activity, re- to group assignment. Unblinding of assessors and med- duced time spent sedentary]; sleep quantity, as measured ical monitors will not be permitted. To ensure that the by accelerometer) and cognitive function (assessed by the proposed study is conducted without bias toward either SDMT-O) than those in the low saturated fat diet group. of the study diets, Dr. Wahls will not have access to study participants or raw study data and will not be Research hypothesis 2c involved in data analysis. By 12 weeks after the initiation of diet, participants in the modified Paleolithic diet group will have clinically Eligibility criteria greater improvement, relative to the observation period, Adults with RRMS who can ambulate 25 ft with either with respect to quality of life (assessed by Multiple no support or unilateral support, living within approxi- Sclerosis Quality of Life 54 [MSQOL54] instrument) and mately a 500-mile radius of Iowa City, meeting eligibility mood (assessed by Hospital Anxiety and Depression criteria, and providing written informed consent will be Scale [HADS]) than those in the low saturated fat diet invited to participate. The inclusion criteria are outlined group. below: Research hypothesis 3 1. a. Willing to allow their neurologist to sign a letter After 24 weeks of the diet intervention, changes in the confirming MS diagnosis and criteria used to measures identified in hypotheses 1a and 1b observed at confirm diagnosis 12 weeks will be sustained in ≥ 80% of the participants b. Definitive diagnosis of RRMS based on the in both diet groups. revised 2010 McDonald criteria [36], confirmed by the treating neurologist Study Design 2. FSS score ≥ 4 obtained within 12 weeks of This 36-week randomized parallel group clinical trial scheduling their first study visit (Screened consists of three 12-week periods during which assess- participants with FSS ≥ 3 and < 4 will be contacted ments of perceived fatigue, quality of life, motor and again in 6 months to retake FSS to determine if cognitive function, physical activity and sleep, diet qual- they qualify, if participants desire.) ity, and social support for eating will be collected. The 3. Ability to shop for and prepare, or availability of 12-week periods will consist of: someone in the family to shop for and prepare, home-cooked meals according to the study diet 1. Observation: Participants continue eating their usual guidelines diet. 4. Willing to keep detailed food records of all 2. Intervention: Participants will be randomized to consumed foods and beverages either the modified Paleolithic or low saturated fat 5. Aged between 18 and 70 years at time of diet for the intervention period. Participants will enrollment into the study receive support by a registered dietitian (RD) 6. Willing to eat a diet that includes more vegetables through coaching telephone calls and emails. and excludes many comfort foods such as those 3. Follow-up: Participants will continue the study diet made with white flour for an additional 12 weeks with minimal RD 7. Willing to eat a diet that eliminates red meat ( support to assess the ability of the participant to beef, pork, lamb, veal), limits saturated fats (butter, sustain the study diet on their own. coconut oil, margarine, and hydrogenated oils found in processed foods) to 15 g per day, and Study evaluations will be done to compare the effects of includes unsaturated fats (e.g., vegetable oils, nuts, the two study diets on perceived fatigue (primary outcome fatty fish) to 20–50 g (4–10 teaspoons) per day if measured by FSS) and secondary outcomes (cognitive assigned to the low saturated fat diet but willing to function, motor function, QOL). The protocol was pre- eat saturated fats > 20 g per day if assigned to the pared according to the Standard Protocol Items: Recom- modified Paleolithic diet mendations for Interventional Trials (SPIRIT) guidelines 8. Not pregnant or planning to become pregnant in (see Figs. 1 and 2 and Additional file 1: SPIRIT Checklist). the next 12 months 9. Able to walk 25 ft without support or with only Study setting unilateral support (i.e., cane in one hand) Data collection will be completed at the University of 10. Have not been told by a physician or other health Iowa (UI) Preventive Intervention Center in Iowa City, care professional that they have celiac disease IA, USA, by trained research assistants blinded to the 11. Willing and able to eat gluten-containing grains Wahls et al. Trials (2018) 19:309 Page 5 of 16 Fig. 1 Dietary Approaches to Treat Multiple Sclerosis-Related Fatigue Study flowchart. MS Multiple sclerosis RRMS Relapsing-remitting multiple sclerosis 12. Lives within approximately a 500-mile radius of continue, with screening scheduled at least Iowa City, which includes Illinois, Indiana, Iowa, 12 weeks after the last relapse start date, if Kansas, Michigan, Minnesota, Missouri, Nebraska, relapse happened after consenting; participation Ohio, South Dakota, and Wisconsin will be continued.) 3. Undergoing treatment for cancer by radiation or The exclusion criteria are outlined below: chemotherapy within the prior 12 months other than for skin cancer (They will be contacted after 1. Taking insulin or warfarin the 12 months if participants desire.) 2. Having a relapse during the prior 12 weeks 4. Being diagnosed with kidney stones, heart failure, before consenting (The screening process will angina, or liver cirrhosis Wahls et al. Trials (2018) 19:309 Page 6 of 16 Fig. 2 (See legend on next page.) Wahls et al. Trials (2018) 19:309 Page 7 of 16 (See figure on previous page.) Fig. 2 Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT): the schedule of enrollment, interventions, and assessments. SPMSQ Short Portable Mental Status Questionnaire, FSS Fatigue Severity Scale, 9HPT 9-Hole Peg Test, T25FW Timed 25-foot walk, SDMT-O Symbol Digit Modalities Test–Oral, 6MWT 6-Minute walk test, MSQ Medical Symptoms Questionnaire, MFIS Modified Fatigue Impact Scale, MSQOL54 Multiple Sclerosis Quality of Life 54, FSMCF Fatigue Scale for Motor and Cognitive Function, MSIS v2 Multiple Sclerosis Impact Scale version 2, HADS Hospital Anxiety and Depression Scale, PSQI, PSS 10 Perceived Stress Scale 10, IPAQ-L International Physical Activity Questionnaire–Long, SF36 36-Item Short Form Health Survey, PDQ Perceived Deficits Questionnaire, MHI Mental Health Inventory, FFQ Food Frequency Questionnaire 5. Having a psychiatric disease, such as schizophrenia, Committee on Multiple Sclerosis (NARCOMS), the UI that makes study adherence more difficult Hospitals neurology clinic, the Iowa City VA neurology (Participants with depression and anxiety diagnoses clinic, the Swank Foundation, terrywahls.com, and other are allowed.) organizations to recruit study participants. 6. Having a diagnosis of an eating disorder such as anorexia, bulimia, binge eating, or orthorexia Randomization 7. Having BMI < 19 kg/m Participants will be randomized to the modified Paleolithic 8. Having a moderate to severe mental impairment as or low saturated fat diet on the basis of the screening FSS measured by the Short Portable Mental Status score that qualified them for the study. Two randomization Questionnaire (SPMSQ) [37] tables based on computer software will be used, one for 9. Participating in another research study investigating moderate perceived fatigue (a score ≥4 and < 5.5) and the MS or other medications, diet, supplements, other for high perceived fatigue (≥ 5.5), so that similar exercise, or other treatments mean FSS scores are achieved for each diet group. The 10. Having had gastric bypass surgery with their randomization tables are accessible (password-protected) treating physician believing it is medically unsafe to only by intervention dietitians. participate in this study 11. Having been told by a physician or other health Intervention care provider they have celiac disease Study diets 12. Have adverse physical reaction to eating gluten- The study diets are summarized in Table 1. containing products 13. Living outside a 500-mile radius of Iowa City Study diet 1 The modified Paleolithic diet stresses more 14. Not able or willing to comply with the study vegetables than other Paleolithic diets that have been protocol studied previously, and it limits meat to 6–12 oz per day. Like other Paleolithic diets, it excludes all grain, Exclusion criteria for continuation into the intervention legumes, and dairy (except for clarified butter or ghee) phase of the study are as follows: and additionally excludes eggs. Nightshade vegetables/ spices will be excluded during the first 12 weeks on the 1. Inability to obtain blood at visit 1 or 2 diet and then reintroduced during the second 12 weeks 2. Not providing a sufficiently detailed visit 1 food on the diet, if the participant desires, to safely test toler- record ance to nightshades while under study team observation. 3. Not mailing back visit 1 study materials by study Specific guidance will be provided to participants about day 28 how to reintroduce nightshades into the diet. 4. Not responding to queries for clarification of food record details within 7 days of the second attempt Study diet 2 The low saturated fat diet restricts satu- to contact rated fat to ≤ 15 g per day and limits unsaturated fat to 20–50 g (4–10 teaspoons) per day. (This diet is pro- Recruitment moted by the Swank MS Foundation [38] and includes Participants will be recruited from within a 500-mile ra- more emphasis on vegetables and whole grains than the dius of Iowa City. The North Central Multiple Sclerosis original Swank Diet.) Society Region, which serves Iowa and Nebraska, has over 8000 members. The research team will work with Dietary supplements the support groups of the National Multiple Sclerosis All study participants will follow the supplement regi- Society (NMSS) in communities within a 2-hour driving men outlined in Table 1, with the exception of vitamin distance of Iowa City to advertise the study to their D (amount prescribed will vary on the basis of vitamin members. Additionally, the study team will work with D level measured in the blood at visit 1 and subsequent regional MS centers, the North American Research visits as outlined in Table 2; target range, 40–80 ng/ml). Wahls et al. Trials (2018) 19:309 Page 8 of 16 Table 1 Study diets Modified Paleolithic (Wahls Elimination Diet) Low Saturated Fat (Swank Diet) Recommended � 2–3 cups (6 cups raw) leafy greens/day � 2 cups vegetables/day � 2–3 cups sulfur rich vegetables/day � 2 cups fruit/day (fresh preferred) � 2–3 cups colorful fruits/vegetables/day � 2 cups fat-free dairy/day � 6–12 oz. meat, fish, poultry or game/day � 4 servings grain and cereal/day (whole preferred) � Approved fats (Extra virgin olive oil, coconut � 4 oz. + skinless chicken/turkey breast, white fish oil/butter, ghee, avocado, flax, hemp, walnut, or shellfish/day sesame and sunflower oil, tahini, rendered � 4–10 tsp. (20–50 g) unsaturated fat/day animal fats and bacon grease) Encouraged or Limited � 12 oz. organ meat/week � Maximum 3 egg yolks/week � 16 oz. omega-3 fish/week � Maximum 3 cups caffeinated beverages/day � 1 serving seaweed, algae, nutritional yeast/day � Maximum 1 alcoholic beverage/day � 1 serving fermented food/day � Maximum 15 g saturated fat/day � Maximum 4 oz. nuts and seeds/day (soaked preferred) � Maximum 50 g unsaturated fat/day � Maximum 2 tbsp. flax, hemp and/or walnut oil/day � Flax and chia seeds to achieve 2 soft bowel movements/day � Maximum 1 alcoholic beverage/day (women) � Maximum 2 alcoholic beverages/day (men) � Maximum 1 tsp. approved sweetener/day (honey, molasses, maple syrup, stevia or sugar) Not Recommended � Dairy products (cow, goat, mare, soy milk, rice milk) � Red meat (beef, pork, lamb, veal, liver, kidney, � Grains with gluten heart, tongue) � Gluten-free grains � Chicken or turkey dark meat � Eggs � Rabbit, venison, elk, squab, pheasant � Legumes (beans, peas, soy, lentils, peanuts) � Dairy products with > 1 g saturated fat per serving � Nonallowed sweeteners; approved sweeteners > 1 tsp. � Foods containing hydrogenated fat or > 1 g saturated per day fat per serving such as desserts, snacks, candies, etc. � Nightshade vegetables/spices during first 12 weeks on diet � Butter, margarine, shortening, coconut oil and other s � White fruits/vegetables (apple, pear, white potato) aturated and hydrogenated fats � Vegetable oils (corn, soy, canola, palm kernel, cottonseed, grapeseed), partially hydrogenated � Monosodium glutamate � Irradiated, deep fried, or microwaved food Supplements � 1 tsp. cod liver oil � 1 tsp. cod liver oil � 1000 μg methyl B � 1000 μg methyl B 12 12 � 1000 μg methylfolate � 1000 μg methylfolate a a � 5000 IU vitamin D � 5000 IU vitamin D 3 3 � 1 multivitamin/mineral tablet for men aged 50+ � 1 multivitamin/mineral tablet for men aged 50+ without iron without iron Dose adjusted based on serum vitamin D After review of participant’s dietary supplement intake, home from visit 2. They will introduce one new sup- study staff will ask participants to discontinue plement every third day to allow time to identify any over-the-counter dietary supplements containing the potential adverse reactions. If side effects are noted, study supplement ingredients (fish oil, vitamin D, vita- the participant will be told to stop the supplement min B , folate, and/or multivitamins) and use study and contact study staff. supplements instead. Participants will be instructed to continue taking all other dietary supplements they have Nutrition counseling been using and not to begin any new supplements until Following randomization, participants will receive two after study completion. If the participant is asked to dis- in-person and five phone nutrition counseling sessions continue a supplement recommended by their physician with the intervention RD. Personalized emails with feed- or neurologist, the research team will send a letter to the back will be sent after participants return the diet check- treating physician, detailing which supplements have lists every 4 weeks. Participants may contact the been discontinued and which supplements have been intervention RD at any time to receive additional support. initiated as part of the study protocol. A final in-person counseling session will be conducted at Study staff will provide participants with a list of sup- visit 4. Nutrition counseling will be based on the plements to purchase and will reimburse participants for Self-Determination Theory and use the Motivational all study supplements. Participants will be instructed to Interviewing (MI) communication approach [39–43]. The begin supplements on the 11th day of the diet to allow dietitians providing the intervention will be screened for them time to purchase the supplements after returning MI aptitudes prior to being hired, and they will receive Wahls et al. Trials (2018) 19:309 Page 9 of 16 Table 2 Vitamin D dosing based on blood level Table 2 Vitamin D dosing based on blood level (Continued) 2+ If vitamin D > 100 ng/ml and elevated calcium (Ca ) > 10.2 mg/dl the supplement every day and add or continue taking cod liver � Call study participant and have them stop vitamin D immediately, oil and multivitamin. increase water intake. � If taking 5000 IU or more they should add or continue taking 2+ a. If Ca level was 10.2–10.5: call your local physician, or urgent cod liver oil and multivitamin. Discuss with Dr. Wahls for care for guidance. further guidance on the appropriate vitamin D dose. The 2+ b. If Ca level was 10.6 or higher: go to the emergency room patient and primary care/neurology team will be notified for evaluation and probable intravenous fluids. by letter of the lab results and the vitamin D, cod liver oil � Stop or do not start taking the cod liver oil or the multivitamin and multivitamin recommendations. � When vitamin D < 80 ng/ml, resume vitamin D at a reduced � Send letter to participant and primary care/neurologist if dose and cod liver oil and multivitamin per local primary care participant is instructed to change vitamin D intake prescribed or neurology guidance by medical personnel � Call and notify the study participant’s primary care/neurology If visit 2 blood result: team about the high vitamin D level � Wait until visit 3 blood result. � Send letter to participant and primary care/neurologist If visit 3 or 4 blood result: � And participant is taking 5000 IU vitamin D, cod liver oil and 2+ If vitamin D > 100 ng/ml and normal calcium Ca 8.5–10.2 mg/dl a the multivitamin, discuss with Dr. Wahls for further guidance. � Study staff will call the participant and have them stop all An increase in the vitamin D dose will likely be recommended vitamin D supplements. Participant will follow up with their by Dr. Wahls and personalized results letters will be sent primary care doctor or neurologist. separately to the participant and their primary care/neurology � Stop or do not start taking cod liver oil but may continue team. multivitamin � When vitamin D < 80 ng/ml, may resume vitamin D at a reduced If vitamin D value 20 ng/ ml or less dose and cod liver oil and multivitamin per local primary care or If visit 1 or 2 blood result: neurology guidance � Refer participant back to primary care physician and neurologist, � Call and notify the study participant’s primary care/neurology recommending the primary care physician or neurologist team about the high vitamin D level prescribe vitamin D 50,000 IU once per week until vitamin D � Send letter to participant and primary care/neurologist level is greater than 40 ng/ml. Alternatively, the primary care physician may recommend 6000 to 10,000 IU vitamin D daily If vitamin D between 81 and 100 ng/ml if preferred over vitamin D . � Start or continue taking cod liver oil and multivitamin � Send letter to participant and primary care/neurologist � Reduce total vitamin D intake by 50% � Call and notify participant that vitamin D level is severely low ∘ The goal is half the dosage from all sources participant was and advise them that a letter is being sent to them and their taking at the time the blood measurement was made primary care/neurology team. ∘ If the vitamin D supplement dosage was in fractions; then, If visit 2, 3, or 4 round it down to the next available pill in the market. � Call participant to clarify if the participant is taking any vitamin D ∘ E.g., if the total taken is 7000; 1000 from MV, 1000 from supplements, cod liver oil or multivitamin and discuss with Dr. calcium/vitamin D supplement and 5000 IU vitamin D we 3 3 Wahls for further guidance. If already on vitamin D 5000 IU or want to halve the dose; then the total amount to take becomes a vitamin D supplement per their local medical team, the 3500. We will ask the participant to continue calcium/vitamin D participant may continue the vitamin D until they see their (1000 IU), switch to our MV (1000 IU), start cod liver oil (400 IU), primary care/neurology team for further guidance. Continue which totals 2400. The remaining vitamin D (3500–2400) is or add cod liver oil and multivitamin as scheduled. 1100 IU (round down to 1000 IU), so we prescribe a 1000-IU � Send letter to participant and primary care/neurologist pill once daily. The total vitamin D from vitamin D supplement (including cod liver oil and � Send letter to participant and primary care/neurologist 3 3 the multivitamin) recommended by the study team should not exceed If vitamin D 40 to 80 ng/ml 7000 IU/d (cod liver oil and multivitamin have approximately 1400 IU daily At visits 2, 3, and 4: combined) unless approved specifically by Dr. Wahls. � Start or continue taking cod liver oil and multivitamin which Abbreviation: MV Multivitamin contain about 1400 IU between the two supplements. Keep participant on current dose of vitamin D if in this range. training in this area prior to study initiation. The dietitian At all visits: will also receive ongoing consultative support throughout � Do not change vitamin D dose. E.g., if the participant is taking the study from an RD who is a member of the Motiv- 4000 IU from their personal physician, participant should stay on that dose. If they were taking 5000 IU from their personal ational Interviewing Network of Trainers (MINT). A physician they should stay on that dose. If participant is taking lesson plan was developed to guide the counseling session more than 5000 IU or less than 4000 IU, participant should for each in-person study visit. Participants will be asked to continue on that dose. � No need to start vitamin D supplement if not on any. consent to being audio recorded during in-person nutri- If vitamin D value less than 40 ng/ml but more than 20 ng/ml tion counseling sessions at visits 2 and 3. The visit 2 audio If visit 1 blood result: recordings will be reviewed by the MINT RD to verify � Wait until visit 2. fidelity to the study diet guidelines, which consist of At visit 2: � If not taking any vitamin D, begin 5000 IU daily. Participant will explaining the recommended and not recommended also begin or continue taking cod liver oil and multivitamin foods for the intervention diet and rationale for key diet- according to the supplement schedule. ary components. The MINT RD will review all visit 2 � If taking 4000 IU vitamin D or less daily, participant will be instructed to increase vitamin D to 5000 IU and add or audio recordings and 20% of visit 3 audio recordings using continue taking cod liver and multivitamin according to the the OnePass instrument [44] to assess use of the MI supplement schedule. approach. A mean OnePass score ≥4indicates average � If the participant is already taking 5000 IU but does not take the supplement regularly (i.e., daily) they will be instructed to take competence in MI. Wahls et al. Trials (2018) 19:309 Page 10 of 16 Table 3 Outcomes: change after 12-week intervention and Perceived fatigue will be assessed with the following 12 weeks of sustained intervention relative to observation period scales: Primary outcome measure: 1. The FSS [45]: a nine-item questionnaire measuring 1. Perceived fatigue assessed by FSS. the severity of perceived fatigue and its effect on Secondary outcome measures: daily activities. Scores range from 0 to 7, with 1. Perceived fatigue assessed by MFIS; higher scores indicating greater perceived fatigue 2. Perceived fatigue assessed by FSMCF; severity. Obtaining scores every 4 weeks will provide 3. Gait speed assessed by T25FW; more assessment points for the primary outcome 4. Distance walked assessed by 6MWT; measure and will improve the statistical power for hypothesis testing. 5. Speed of task completion in 9HPT; 2. Modified Fatigue Impact Scale (MFIS) [46], a 21- 6. Number of correct responses assessed by SDMT-O; item assessment of the effects of fatigue related to 7. Quality of life as measured by MSQOL-54; physical, cognitive, and psychosocial functioning. 8. Quality of life as measured by SF-36; 3. Fatigue Scale for Motor and Cognitive Functions 9. MSISv2 score; (FSMCF), a 20-item measure of cognitive and 10. Anxiety and depression as measured by HADS; motor fatigue for people with MS. 11. Physical activity (average daily steps and average minutes spent sedentary, light intensity physical activity, moderate Motor function (gait and hand) will be assessed with intensity physical activity and vigorous intensity physical the following tests: activity) and sleep (total sleep time, sleep efficiency) as measured by the accelerometer; 1. T25FW, a timed 25-ft walk to quantify mobility and 12. Sleep quality as measured by PSQI; leg function 13. Stress as measured by PSS-10; 2. 6MWT assesses distance walked in 6 minutes as a 14. Physical activity as assessed by IPAQ-L; submaximal test of aerobic capacity. 15. Cognitive performance as measured by PDQ; 3. 9HPT is a quantitative test of upper extremity 16. Change in mood as measured by the MHI. function (hand) in which patients are timed as they put nine pegs into holes in a block and then remove 17. Nutritional adequacy of the diet as measured by food frequency questionnaire (FFQ) and food records; them one at a time. The test is conducted twice with the nondominant hand and twice with the 18. Changes in blood biomarkers (insulin, glucose, hemoglobin A1c, lipids including HDL, vitamin K, vitamin D, calcium, dominant hand. vitamin B , folate, homocysteine, complete blood count with differential, Cardio IQ® [fatty acid levels]). Cognitive function will be assessed by: Abbreviations: 6MWT 6-Minute walk test, 9HPT 9-hole Pegboard Test, Cardio IQ® Omega-3 (EPA + DHA) Index, Omega-6/Omega-3 Ratio, EPA/Arachidonic Acid Ratio, Arachidonic Acid, EPA, and DHA, DHA Docosahexaenoic acid, EPA 1. SDMT-O is a screening tool for organic cerebral Eicosapentaenoic acid, FFQ Food Frequency Questionnaire, FSMCF Fatigue dysfunction. Scale for Motor and Cognitive Function, FSS Fatigue Severity Scale, HADS Hospital Anxiety and Depression Scale, HDL High Density Lipoprotein, IPAQ-L 2. Perceived Deficits Questionnaire (PDQ) is a self-report International Physical Activity Questionnaire–Long, MFIS Modified Fatigue measure of cognitive dysfunction specifically for MS. Impact Scale, MHI Mental Health Inventory, MSIS v2 Multiple Sclerosis Impact Scale version 2, MSQ Medical Symptoms Questionnaire, MSQOL54 Multiple Sclerosis Quality of Life 54, PDQ Perceived Deficits Questionnaire, PSQI QOL will be assessed by: Pittsburgh Sleep Quality Index, PSS 10 Perceived Stress Scale 10, SDMT-O Symbol Digit Modalities Test-Oral, SF-36 36-item Short Form Health Survey, SPMSQ Short Portable Mental Status Questionnaire, T25FW Timed 25-foot Walk 1. MSQOL54 [47] is a multidimensional health-related QOL measure that includes both generic and MS- Measures specific items. The SPMSQ will be used at screening to assess organic 2. SF-36 is a generic measure of health-related QOL. brain deficit. Personal information will be collected at visit 3. HADS [48] is an instrument used to assess mood 1. A medication audit, health history, vital signs, and blood and detect states of depression and anxiety. biomarkers (insulin, glucose, hemoglobin A1c, lipids in- 4. Mental Health Inventory (MHI) [49] provides an cluding high-density lipoprotein, vitamin K, vitamin D, assessment of anxiety, depression, behavioral calcium, vitamin B , folate, homocysteine, Cardio IQ® control, positive affect, and general distress. [Omega-3 (EPA + DHA) index, omega-6/omega-3 ratio, 5. Multiple Sclerosis Impact Scale version 2 (MSIS v2) EPA/arachidonic acid ratio, arachidonic acid, EPA, and is a 29-item self-report measure of the impact of DHA]) will be collected at each visit. Table 3 summarizes MS on day-to-day activities, including both physical the primary and secondary outcome measures. and psychosocial aspects. Wahls et al. Trials (2018) 19:309 Page 11 of 16 6. Perceived Stress Scale 10 (PSS-10) [50] measures massage, meditation, yoga, and Tai Chi derived from the degree to which situations in one’s life are the complementary health approaches section of perceived as stressful. National Health Interview Survey [57]. Side effects questionnaire to assess new or Physical activity and sleep will be assessed by: worsening symptoms that might be attributed to diet or supplement changes (see Additional file 2: 1. Accelerometers (GT9X Link; ActiGraph, Pensacola, Appendix 1). FL, USA) will be worn on the nondominant wrist  “Your Eating Experience” questionnaire, developed during the 7-day food-recording period (including by our research team to collect the following sleep time). Outcomes measured by accelerometer information: how often foods that are to be avoided will include daily steps, time spent in light-intensity were consumed during the past 4 weeks, what made activity, time spent in moderate-intensity activity, it difficult to avoid those foods, and the factors that time spent sedentary, sleep time, and sleep helped the participant follow the dietary guidelines efficiency. (see Additional file 3: Appendix 2). 2. International Physical Activity Questionnaire Long, (IPAQ-L) [51], a physical activity assessment. Assessments and visit schedule 3. Pittsburgh Sleep Quality Index (PSQI) [52], a Visit 1 – week 1 19-item self-report sleep quality assessment. Participants will fast for 12 hours prior to visit 1. Eligibility criteria will be checked, and the participant Diet quality will be assessed by: will be consented (Additional file 4: Appendix 3). Height and weight will be measured to confirm a BMI ≥ 19. If 1. Three-day weighed food records to assess nutrient participants qualify for the study, their vital signs will be intake. Nutrient intake will be calculated using the measured, and fasting blood will be drawn. Question- most current version of the Nutrition Data System naires including a medication audit and motor and for Research software (Nutrition Coordinating cognitive testing will be completed, as listed in Fig. 2, Center, University of Minnesota, Minneapolis, MN, and personal information such as duration of MS and USA). (Note: Initially, 7-day records were collected. handedness will be recorded. Participants will be Based on participant feedback, and confirmed with instructed on how to (1) keep a 3-day food record and use the Minnesota Nutrition Coordinating Center, a loaned food scale for weighing the amount of food eaten, consecutive 3-day records are in used in a standard (2) complete an FFQ, and (3) wear an accelerometer. manner to assess nutrient intake [53–55].) Participants will complete questionnaires, as listed in 2. Harvard Food Frequency Questionnaire (FFQ) is Fig. 2, via a secure Research Electronic Data Capture used to obtain information regarding the frequency (REDCap) system at home 1–3 days after the study visit. and portion size of food and beverages consumed Participants will wear an accelerometer for 7 continuous over the past year (visit 1) and the past 12 weeks days (24 h/d) following this visit and record the foods, (visits 2–4). beverages, and dietary supplements consumed between Thursday and Saturday following visit 1. The accelerom- Social support for eating will be assessed with: eter and dietary forms will be returned by mail. 1. A version of Social Support for Eating Habits Scale Visit 2 – week 12 [56], modified to include factors that are key to Participants will wear an accelerometer for the 7 days adherence by family members and friends, will prior to visit 2 and will record the foods, beverages, and assess social support for eating. These factors were dietary supplements consumed between Thursday and identified in qualitative interviews with participants Saturday prior to the visit. Participants will complete from our multimodal pilot study [4]. They include questionnaires (as outlined in Fig. 2)1–3 days prior to food purchasing, meal preparation, snack visit 2 using REDCap. Participants will fast for 12 hours availability, and modeling study diet adherence prior to visit 2. Vital signs, blood, motor and cognitive while in the presence of the study participant. tests, and questionnaires will be completed at visit 2 (see Fig. 2). Food records, FFQs, and accelerometer data, will To further monitor the health of participants, the be reviewed for completeness. Participants will be ran- following data variables will be collected: domized to one of the study diets. The study participant and their family member(s) or Health Practices Survey, a subset of questions asking adult companion will meet with an RD who will provide about use of complementary therapies, including individualized nutrition counseling on the participant’s Wahls et al. Trials (2018) 19:309 Page 12 of 16 assigned study diet. The family/adult companion will be participant will meet with the study dietitian, who will advised that, during our previous studies, we have ob- review the diet checklists and answer questions. For par- served that the study participants who have had their ticipants randomized to the modified Paleolithic diet, families adopt the study diet along with the study partic- the RD will encourage but not require the participant to ipants have had greater levels of success with adopting reintroduce nightshades to the diet. If the participant and sustaining the intervention diets. The family/adult elects to reintroduce nightshades, one nightshade food companion will be advised that they are expected to be will be introduced on 1 day using this process: consume supportive of eating study-compliant foods. one bite of the food and wait 3 hours; consume ½ cup Participants will view a brief video (< 20 min) that and wait 3 hours; consume 1 cup of food and wait 6 provides background information about the study diet to days. Symptoms will be recorded for a total of 7 days. If which they were randomized. Participants will receive an no symptoms have appeared by the end of 7 days, the intervention food guide developed by study staff that de- food may be added back to the diet, and another food scribes their study diet, as well as The Multiple Sclerosis can be tested. Diet Book [58] (low saturated fat diet) or The Wahls Participants will be given a fresh set of diet checklists Protocol [59] (modified Paleolithic diet), both of which to complete daily and a 3-day weighed food record contain sample menus and recipes to assist with meal booklet and FFQ to complete prior to their next study planning. Additional materials, such as grocery lists, will visit. A self-addressed, stamped envelope will be pro- be provided to assist with diet adoption. A diet checklist vided so that participants can return their diet checklists that offers guidance to the participant in the form of at weeks 28 and 32 for the study RD to review. An email prompts to eat the foods that are recommended and to will be sent to acknowledge receipt and provide assess- avoid those that are not recommended will be provided. ment comments. The RD will not make coaching calls The participants and their adult companions will be during this time, but study participants may contact the given a study-adherent meal and practice recording the RD to request support. Participants will be reminded to meal in the diet checklist to facilitate the learning of the continue their usual physical activity, medication, sup- principles of the assigned study diet and how to use the plement, and stress reduction regimens during the next daily diet checklist. 12 weeks unless their physician or physical therapist Participants will be given a set of diet checklists to directs them to make changes. complete daily and a 3-day weighed food record booklet as well as an FFQ to complete prior to their next study Visit 4 – week 36 visit. A self-addressed, stamped envelope will be pro- Participants will wear an accelerometer for the 7 days vided so that participants can return their diet checklists prior to visit 4 and will record the foods, beverages, and at weeks 16 and 20 for the study dietitian to review. dietary supplements consumed between Thursday and Upon receiving the week 20 checklist, the RD will send Saturday prior to the visit. Participants will again an email to acknowledge receipt and provide assessment complete some questionnaires (as outlined in Fig. 2) comments. Participants will be asked to continue their 1–3 days prior to visit 4 using REDCap. Participants usual physical activity, medication, and stress reduction will fast for 12 hours prior to visit 4. Vital signs, regimens during the next 24 weeks unless their phys- blood, motor and cognitive tests, and questionnaires ician or physical therapist recommends changes. will be completed at visit 4 (see Fig. 2). Food records, The study RD will continue to coach the participant FFQs, and accelerometer data will be reviewed for via coaching calls 2–3 days after visit 2 and then weekly completeness. Participants will view two videos from for 3 weeks. A final coaching call will be made after the principal investigator: a thank-you video and an receipt of the first 4-week diet checklist booklet. educational video about environmental factors that contribute to health. The participant will then meet Visit 3 – week 24 with the study RD, who will review the diet checklists Participants will wear an accelerometer for the 7 days and answer questions. prior to visit 3 and will record the foods, beverages, and dietary supplements consumed between Thursday and Saturday prior to the visit. Participants will again Risks and safety monitoring during intervention complete questionnaires (as outlined in Fig. 2)1–3 days Weight monitoring prior to visit 3 using REDCap [60]. Participants will fast If a participant’s BMI at visit 1 is < 19 kg/m , they are in- for 12 hours prior to visit 3. Vital signs, blood, motor eligible for the study. If BMI at visit 2 or 3 is < 18.5 kg/m , and cognitive tests, and questionnaires will be completed the participants will be asked to weigh themselves at home at visit 3 (see Fig. 2). Food records, FFQs, and acceler- 1 and 2 weeks after the study visit (in the morning after ometer data will be reviewed for completeness. The their first void wearing street clothing) and report that Wahls et al. Trials (2018) 19:309 Page 13 of 16 information to the study coordinator/study team. If the monitoring board composed of two UI faculty physicians BMI remains < 18.5 kg/m for 2 consecutive weeks: will receive all adverse events sheets. A data monitoring committee has not been constituted. Guidelines for stop- 1. The intervention dietitian will conduct a special ping participation due to adverse events, patient decision telephone coaching call to discuss strategies for to withdraw, or treatment medical provider recommenda- increasing their calorie intake. The dietitian will tion have been established. Coaching and contact with make a second telephone call 1 week after the first study dietitian and motivational interviewing. Subjects call to provide continued support. Additional calls who elect or are obligated to discontinue the study diet will be based on participant need and dietitian will be asked to complete the study forms and the motor assessment. The participant will be instructed to assessments through 36 weeks. continue weighing themselves weekly and reporting that information to the study team. Data management 2. The participant will be advised to follow up with Study data will be collected and managed using REDCap their personal physician regarding the weight loss. [60] tools hosted at UI. REDCap is a secure, web-based ap- plication designed to support data capture for research If the BMI increases to 19 kg/m , the weekly weight studies, and it provides (1) an intuitive interface for vali- monitoring will be discontinued. If a participant’sBMI at dated data entry, (2) audit trails for tracking data manipula- study visit 2 is 18.5–19 kg/m , the participant may be at tion and export procedures, (3) automated export risk for additional weight loss, so the dietitian will alert procedures for seamless data downloads to common them of this possibility and briefly discuss strategies to statistical packages, and (4) procedures for importing prevent weight loss. data from external sources. Study participants will log The study team will report to the Data and Safety into REDCap using a secure web-based portal to an- Monitoring Board (DSMB) the number of participants swer study questionnaires from home. Study staff will currently being monitored for low BMI and the correct- use REDCap for manual entry of laboratory and other ive actions taken by study staff. The DSMB will review data and interviewer-administered questionnaires. the BMIs of all participants quarterly along with any cor- rective action taken by study staff. The DSMB is consti- Power and sample size justification tuted and managed by the NMSS and will review the Table 4 displays the mean minimum clinically important adverse events, significant adverse events, and laboratory difference that can be detected for primary and second- values greater than 10% outside the reference range. In ary outcomes to be assessed in the study. The table also addition to the quarterly reports provided to the includes the SD and correlation between observations DSMB, trial auditing procedures will also include a over time, with 34 patients in each group after attrition, closed report from the study statistician with more and an alpha value of 0.05. The minimum differences details related to diet assignment and adverse events. and SDs are derived from the preliminary studies The data management application also provides data ma- and peer-reviewed published MS longitudinal studies. nipulation and user activity audit trails. A medical Forty-five patients will be recruited in each group, Table 4 Power and sample size justification Variable Within Study Groups Between Study Groups at Last Visit MMCD SD Correlation MMCD SD Group A SD Group B Power is ≥0.85 for the primary outcome FSS-9 1.2–2.0 1.1–1.4 0.6 0.7 [35] 0.9 1.1 Power is ≥0.90 for secondary outcomes MSQOL-54 PHC 11.5 16.0 0.6 17.0 17.0 19.0 MHC 12.0 17.0 0.5 18.0 18.0 19.0 6 min walk test 35 50.0 0.5 45.0 45.0 50.0 Timed 25 ft walk 2.9 4.0 0.5 4.0 4.0 4.3 9 hole peg test 5.5 8.0 0.5 8.0 8.1 8.3 PASAT 4.2 6.0 0.5 5.8 6.0 6.3 Abbreviations: FSS Fatigue Severity Scale, MSQOL-54 Multiple Sclerosis Quality of Life 54, PHC MSQOL-54 physical health composite score, MHC MSQOL-54 mentalhealth composite score, PASAT Paced Auditory Serial Addition Test, MMCD Minimun Mean Clinical Difference Power and sample size calculations based on PASAT. Per NMSS, SDMT-O replaces the PASAT measure in this study Wahls et al. Trials (2018) 19:309 Page 14 of 16 assuming a 25% attrition rate, to attain the 34 patients comparison of two study diets is a better approach than a needed in each group. crossover design for this population. Maintaining differences between the dietary groups may be challenging because participants may want to Data analysis modify their eating patterns to make them similar to the All analyses will be completed by a masked statistician diet to which they are not assigned. That is, participants who will not have access to study diet assignment. Data in the low saturated fat diet group may wish to eliminate analysis will include both intention-to-treat and gluten and dairy, and those in the modified Paleolithic per-protocol analytic methods. Data for this study will diet group may elect to greatly restrict saturated fat in- be analyzed using SAS® 9.4 software (SAS Institute, Cary, take. To minimize this, the dietary intervention guide NC, USA). Statistical significance will be set at α ≤ 0.05. for the low saturated fat diet encourages consumption of Descriptive statistics will be calculated for all variables at gluten-containing grains, and the modified Paleolithic all data collection times. Outliers will be checked for diet encourages consumption of foods containing satu- accuracy and possible entry errors. Respondents who rated fat. Additionally, physical symptoms related to drop out of the study will be compared with those who consumption of gluten or a reluctance to eat saturated complete the study so that differences in baseline charac- fat are included in the inclusion/exclusion criteria. teristics that may affect the study results will be detected. Both study groups are likely to experience reductions in Patterns of missing data (missing at random, not missing MS-related symptoms. Differences within and between at random) will be investigated [61]. The analytic methods groups will be assessed for clinical significance, supported will account for the type of missing data. The distributions by statistical analyses. Because the primary outcome meas- of continuous variables will be evaluated for normality ure is a self-reported measure and not an objectively mea- and homogeneity of variance. Appropriate transforma- sured laboratory or imaging result, the NMSS requested tions will be applied as needed, and/or statistical analyses two modifications in the study design. First, a 12-week ob- for nonnormal data will be performed. Collinearity among servation period was added, during which participants fixed effect variables will be examined. continue to eat their usual diet, so that each participant Repeated-measures analyses will use generalized linear can be her or his own control in the repeated-measures mixed models methods to test for within-group and analyses. Second, an accelerometer measure was added to between-group changes in both primary and secondary the study to provide an objective assessment of the change outcomes. Intraclass correlations for repeated measures in physical activity, sleep duration, and sleep quality. within patients will be included in the model structure for Given the anecdotal reports regarding improvement in analyses. Mixed models for both continuous and categor- MS symptoms with dietary changes, results from this ical outcomes will have both random and fixed effects. study will contribute to understanding of the optimal Fixed effects will include characteristics such age, sex, dietary approach for reducing MS-related fatigue. Find- intervention group, time indicators, and group-by-time in- ings of the study as well as any challenges observed will teractions. Intercepts and slopes may be considered as be submitted to journals for publication. Published random effects. papers will be listed on the Wahls research lab website (https://wahls.lab.uiowa.edu/publications). Discussion Clinical studies of diet in MS are needed because there is Trial status uncertainty about the optimal dietary approach to redu- Recruitment commenced August 24, 2016. We have cing MS-related fatigue. Randomized trials that include consented 58 participants to date. assignment to a control or standard care group are the preferred design; however, previous studies including diet- Additional files ary approaches to reduce MS-related symptoms suggest increased participant adherence when a study diet is of- Additional file 1: SPIRIT Checklist. (DOC 121 kb) fered to all participants because dropout is high among Additional file 2: Appendix 1. Side Effects Survey. (PDF 47 kb) nondiet control group participants. Crossover study Additional file 3: Appendix 2. Your Eating Experience Questionnaire. (PDF 56 kb) designs have also been used to test dietary hypotheses. Additional file 4: Appendix 3. Study Consent. (PDF 259 kb) However, we have observed MS symptom reductions among participants following a modified Paleolithic diet and marked increases in MS-related symptoms among Abbreviations 6MWT: 6-Minute walk test; 9HPT: 9-Hole Pegboard Test; ADA: American those who returned to eating gluten-containing grains or Diabetes Association; BMI: Body mass index; Cardio IQ®: Omega-3 (EPA + casein-containing dairy products. Therefore, to most ef- DHA) index, omega-6/omega-3 ratio, EPA/arachidonic acid ratio, arachidonic fectively and ethically study such dietary approaches, the acid, EPA, and DHA; DHA: Docosahexaenoic acid; DSMB: Data and Safety Wahls et al. Trials (2018) 19:309 Page 15 of 16 Monitoring Board; EPA: Eicosapentaenoic acid; FFQ: Food Frequency multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Questionnaire; FSMCF: Fatigue Scale for Motor and Cognitive Function; Psychiatry. 2002;72(2):179–83. FSS: Fatigue Severity Scale; HADS: Hospital Anxiety and Depression Scale; 8. Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, HDL: High-density lipoprotein; IPAQ-L: International Physical Activity French Modafinil Study Group. Modafinil for fatigue in MS: a randomized Questionnaire–Long; IRB: Institutional review board; MFIS: Modified Fatigue placebo-controlled double-blind study. Neurology. 2005;64(7):1139–43. Impact Scale; MHI: Mental Health Inventory; MI: Motivational Interviewing; https://doi.org/10.1212/01.WNL.0000158272.27070.6A. MINT: Motivational Interviewing Network of Trainers; MRI: Magnetic 9. Naldi L, Conti A, Cazzaniga S, Patrizi A, Pazzaglia M, Lanzoni A, et al.; resonance imaging; MS: Multiple sclerosis; MSIS v2: Multiple Sclerosis Impact Psoriasis Emilia Romagna Study Group. Diet and physical exercise in Scale version 2; MSQ: Medical Symptoms Questionnaire; MSQOL54: Multiple psoriasis: a randomized controlled trial. Br J Dermatol. 2014;170(3):634–642. Sclerosis Quality of Life 54; NMSS: National Multiple Sclerosis Society; doi: https://doi.org/10.1111/bjd.12735. PDQ: Perceived Deficits Questionnaire; PSQI: Pittsburgh Sleep Quality Index; 10. Sedlacek SM, Playdon MC, Wolfe P, Μginley JN, Wisthoff MR, Daeninck EA, PSS 10: Perceived Stress Scale 10; QOL: Quality of life; RD: Registered Jiang W, Zhu Z, Thompson HJ. Effect of a low fat versus a low carbohydrate dietitian; REDCap: Research Electronic Data Capture; RRMS: Relapsing- weight loss dietary intervention on biomarkers of long term survival in remitting multiple sclerosis; SDMT-O: Symbol Digit Modalities Test–Oral; breast cancer patients (‘CHOICE’): study protocol. BMC Cancer. 2011;11:287. SF36: 36-Item Short Form Health Survey; SPMSQ: Short Portable Mental https://doi.org/10.1186/1471-2407-11-287. Status Questionnaire; T25FW: Timed 25-foot walk; UI: University of Iowa 11. Self S, Prentice R, Iverson D, Henderson M, Thompson D, Byar D, et al. Statistical design of the Women’s Health Trial. Control Clin Trials. 1988;9(2): Funding 119–36. Funding for this trial was provided by the National Multiple Sclerosis Society. 12. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3:59. 13. Lauer K. Environmental risk factors in multiple sclerosis. Expert Rev Authors’ contributions Neurother. 2010;10(3):421–40. https://doi.org/10.1586/ern.10.7. TW designed the study, secured study funding, and drafted the manuscript. 14. Swank RL, Grimsgaard A. Multiple sclerosis: the lipid relationship. Am J Clin MOS drafted the manuscript. ZA drafted the manuscript. LR designed the Nutr. 1988;48(6):1387–93. study and helped draft the manuscript. WD designed the study. LC designed 15. Swank RL, Lerstad O, Strom A, Backer J. Multiple sclerosis in rural Norway its the study. KS contributed to the study design. CAC contributed to the study geographic and occupational incidence in relation to nutrition. N Engl J design. NL contributed to the study design. LS designed the study and Med. 1952;246(19):722–8. helped draft the manuscript. All authors commented on the final manuscript 16. Swank RL. Treatment of multiple sclerosis with low-fat diet. AMA Arch draft, and all authors read and approved the final manuscript. Neurol Psychiatry. 1953;69(1):91–103. 17. Swank RL. Treatment of multiple sclerosis with low-fat diet; results of five and Ethics approval and consent to participate one-half years’ experience. AMA Arch Neurol Psychiatry. 1955;73(6):631–44. Ethical approval was obtained from the University of Iowa Institutional 18. Swank RL. Treatment of multiple sclerosis with low-fat diet: result of seven Review Board (IRB identifier 201604705). Informed consent will be obtained years’ experience. 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