Safety and Efficacy of High Versus Standard Starting Doses of Insulin Glargine in Overweight and Obese Chinese Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic Medications (Beyond VII): Study Protocol for a Randomized Controlled Trial

Safety and Efficacy of High Versus Standard Starting Doses of Insulin Glargine in Overweight and... Adv Ther (2018) 35:864–874 https://doi.org/10.1007/s12325-018-0717-x STUDY PROTOCOL Safety and Efficacy of High Versus Standard Starting Doses of Insulin Glargine in Overweight and Obese Chinese Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic Medications (Beyond VII): Study Protocol for a Randomized Controlled Trial . . . . Linong Ji Zhengnan Gao Bimin Shi Rongwen Bian . . . Fuzai Yin Wuyan Pang Hong Gao Nan Cui Received: March 15, 2018 / Published online: June 5, 2018 The Author(s) 2018 treatment satisfaction and compliance as well ABSTRACT require fewer steps to titrate. Considering that overweight and obese patients usually require Background: Treatment with basal insulin in higher insulin doses because of insulin resis- Chinese populations is currently sub-optimal, tance, a higher initial dose of the basal insulin is with delayed initiation of insulin treatment and feasible in overweight and obese patients with inadequate dose titration. Increasing the initial type 2 diabetes. However, safety is an important dose of insulin may be a practicable and effec- issue needing to be considered for higher initial tive solution to the problem of titration. A dose treatment. The aim of this study is to assess higher initial dose will be helpful for patients to the safety and efficacy of higher (0.3 U/kg) achieve the blood glucose target and improve compared with standard (0.2 U/kg) starting doses of basal insulin in overweight and obese Enhanced Digital Features To view enhanced digital Chinese patients with type 2 diabetes who have features for this article go to https://doi.org/10.6084/ failed to achieve glycaemic control using oral m9.figshare.6269984. antidiabetic drugs (OADs). L. Ji (&) F. Yin Department of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, The Peking University People’s Hospital, 11 Xizhimen First Hospital of Qinhuangdao, 258 Wenhua Road, South Street, Xicheng District, Beijing 100044, Qinhuangdao 066000, Hebei, China China W. Pang e-mail: jiln@bjmu.edu.cn Department of Endocrinology and Metabolism, Z. Gao Huaihe Hospital of Henan University, 115 Ximen Department of Endocrinology and Metabolism, Street, Kaifeng 475000, Henan, China Dalian Municipal Central Hospital Affiliated of Dalian Medical University, 826 Xi’nan Road, Dalian H. Gao  N. Cui 116033, Liaoning, China Sanofi China, 19 Floor, Tower III, Jing’An Kerry Centre, 1228 Middle Yan’an Road, Shanghai 200040, B. Shi China Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China R. Bian Department of Endocrinology and Metabolism, Jiangsu Province Institute of Geriatrics, 30 Luojia Road, Nanjing 210024, Jiangsu, China Adv Ther (2018) 35:864–874 865 Methods: This is a phase IV, randomized, non- OAD Oral antidiabetic drug inferiority, open-label trial that will be con- ORBIT Observational Registry of Basal Insulin ducted at approximately 50 centers in China. Treatment Eight hundred eighty overweight and obese PPG Postprandial plasma glucose adult Chinese patients with type 2 diabetes will SAE Serious adverse event be randomized to receive higher (0.3 U/kg) or SMBG Self-monitored blood glucose standard (0.2 U/kg) starting doses of basal SPIRIT Standard protocol items for clinical insulin glargine (100 U/ml) during a 16-week trials period. The primary endpoint is whether a T2DM Type 2 diabetes mellitus higher initial dose of basal insulin (0.3 U/kg) is TC Total cholesterol non-inferior to a standard initial dose (0.2 U/kg) TG Triglyceride based on the percentage of patients with at least UKPDS UK Prospective Diabetes Study one episode of hypoglycaemia (B 3.9 mmol/l or severe) over 16 weeks. Secondary endpoints include evaluation of glycosylated haemoglobin INTRODUCTION A1c (HbA1c), fasting blood glucose, postpran- dial blood glucose, insulin dose and safety. The incidence of type 2 diabetes mellitus Discussion: This study is the first randomized- (T2DM) in China has increased rapidly over the controlled study to evaluate the safety and past 2 decades [1, 2]. By 2040, an estimated 642 efficacy of basal insulin treatment with a higher million people worldwide will live with diabetes starting dose versus standard starting dose in and 150.7 million are in China [3]. A study overweight and obese Chinese patients with reported by the International Diabetes Federa- type 2 diabetes. Results of this study could tion (IDF) and the Chinese Diabetes Society generate evidence to support the feasibility of a (CDS) in 2010 found that 13% of all medical higher starting dose of basal insulin in diabetes expenditures in China (US$ 25 billion per management of overweight and obese Chinese annum) was directly caused by diabetes [4]. patients, therefore providing an easy approach Therefore, unless improvements are made in to improve diabetes management. both the prevention and treatment of diabetes Trial Registration: ClinicalTrials.gov identifier, in China, the economic and healthcare burden NCT02836704. Registered on July 7th 2016. will continue to rise. Funding: Sanofi China. One way to reduce the healthcare and eco- nomic burden of diabetes patients is to achieve Keywords: Basal insulin; BMI; Insulin glargine; and maintain good glycaemic control, thus Obesity; Type 2 diabetes reducing the risk of diabetes-related complica- tions. Like the American Diabetes Association Abbreviations standards of medical care in diabetes [5], Cur- DCCT Diabetes control and complications rent Chinese treatment guidelines [6] recom- trial mend a stepwise approach to diabetes DPP-4 Dipeptidyl peptidase-4 management, with patients initially receiving DTSQ Diabetes treatment satisfaction lifestyle intervention and therapy with oral questionnaire antidiabetic drugs (OADs). As T2DM is a pro- EQ-5D European quality of Life -5 gressive disease, with a gradual decrease in the Dimensions number of functional insulin-producing b-cells, FBG Fasting blood glucose patients often require basal insulin treatment if FPG Fasting plasma glucose glycaemic control cannot be maintained by HbA1c Glycated haemoglobin OADs. HDL-c High-density lipoprotein cholesterol Insulin glargine is a long-acting basal insulin IMP Investigational medicinal product analogue that is widely used in the glycaemic LDL-c Low-density lipoprotein cholesterol control of type 2 diabetes patients [7, 8]. NPH Neutral protamine hagedorn 866 Adv Ther (2018) 35:864–874 Adequate starting doses of insulin and an HbA1c in insulin-naı¨ve Japanese diabetes appropriate titration algorithm are important to patients. Furthermore, patients who did not achieve optimal glycaemic control. The treat to receive insulin titration had a significantly target trial demonstrated that titrating the lower chance of achieving HbA1c targets [12]. insulin glargine dose using a fasting plasma Considering the current healthcare system glucose (FPG) target of B 6.1 mmol/l resulted barriers in China, inadequate glucose control in good glycaemic control (58% of individuals will continue to exist for a long time and the achieved HbA1c \ 7%) and a low incidence of challenge of insulin titration in Chinese dia- nocturnal hypoglycaemia [9]. betes patients requires long-term patient edu- Although a number of clinical studies have cation. It has been suggested that initiating demonstrated the benefits of sufficient insulin insulin at higher starting doses may be of ben- dosing on glycaemic management, the current efit. Inadequate titration of insulin can lead to practice in China remains sub-optimal in both an insufficient total dose of insulin, which may the time to initiation of insulin treatment and cause sub-optimal glycaemic control and a low the subsequent titration of insulin in patients rate of patients achieving glycaemic control with inadequate glycaemic control. A study of targets. Therefore, initiating treatment with a almost 240,000 patients with T2DM throughout higher dose of insulin may represent a treat- China found that among those treated with ment approach that will partially compensate OADs and/or insulin, less than 1/3 of patients for the current insufficiency in dose titration. achieved the glycaemic target of HbA1c \ 7% However, hypoglycaemia is another concern for [10]. Similarly, the First Basal Insulin Evaluation most physicians and patients when they are (FINE) study assessed real-world insulin prac- considering using a higher initial dose of insu- tices in T2DM patients from 2006 to 2008 across lin. Currently, standard basal insulin is recom- 11 countries in Asia and found that initiation of mended by the American Diabetes Association insulin therapy was delayed by approximately (ADA) and American Association of Clinical 9 years in these patients, despite their high Endocrinologists (AACE), starting with HbA1c levels [11]. Furthermore, there was an 0.1–0.2 U/kg per day depending on the degree overall lack of insulin titration in Asian patients of hyperglycaemia [5, 13]. In China, the rec- with the average insulin dose only increasing by ommended standard starting dose is 0.2 U/kg approximately 0.03 U/kg after 6 months’ treat- per day [6]. ment and only 33.7% of patients achieved their The AACE guidelines recommend a higher HbA1c targets [11]. A more recent Observational initial dose of basal insulin (0.2–0.3 U/kg) for Registry of Basal Insulin Treatment (ORBIT) diabetes patients with HbA1c [ 8% [13]. In study, conducted from 2011 to 2013 across 209 addition, considering the impact of body hospitals in China, found that more than one- weight on insulin resistance, a BMI-based insu- third of patients with uncontrolled diabetes at lin dose regimen has recently been described follow-up visits did not receive insulin titration, [14]; the BMI-based higher dose of initial insulin and the average increase in basal insulin dose at demonstrated equal safety efficacy and safety 6 months was only 0.03 U/kg. The ORBIT compared with a standard starting dose of investigators suggested that Chinese type 2 insulin. Furthermore, several interventional diabetes patients tend to have a delayed insulin studies conducted in China have shown that initiation and efforts to improve insulin uti- the final insulin dosing after 16 weeks of treat- lization are urgently needed to achieve and ment is as high as 0.3–0.5 U/kg in order to maintain glycaemic control [8]. Similar chal- achieve glycaemic control [15, 16]. Taking into lenges with sub-optimal insulin titration in real- account these factors, this study will initiate world practice have been demonstrated in other insulin therapy at a dose of 0.3 U/kg in over- Asian countries. In a sub-analysis of the Add-on weight and obese Chinese diabetes patients Lantus to Oral Hypoglycemic Agents (ALOHA) with inadequate glycaemic control on OADs. study, Odawara et al. found that an appropriate Few data are available regarding the use of a starting dose was essential to achieving target higher starting dose of insulin, especially Adv Ther (2018) 35:864–874 867 regarding potential hypoglycaemia risk. This is Study Objectives the first study that will be conducted in Chinese diabetes patients that investigates the safety of The primary objective is to determine whether a initiating insulin treatment at a higher dose. It higher initial dose of basal insulin glargine will enroll patients who are overweight or obese (0.3 U/kg) is non-inferior to a standard initial as these patients will most likely require a dose (0.2 U/kg) based on the percentage of higher dose of insulin. This study will therefore patients with at least one episode of hypogly- assess the safety and efficacy of a higher starting caemia (B 3.9 mmol/l or severe) during the dose of 0.3 U/kg basal insulin compared with 16 weeks of treatment. the standard starting dose of 0.2 U/kg in over- Secondary study objectives include evaluation weight or obese diabetes patients in China. The of the percentage of patients achieving HbA1c study will also assess whether a higher starting \ 7% at week 16 and the percentage and accu- dose has a positive effect on current sub-optimal mulated percentage of patients achieving FPG titration practices and insufficient insulin targets (\ 5.6,\ 6.1 and\ 7.0 mmol/l) from dosage in China. baseline to week 16. Changes in HbA1c, FPG, postprandial plasma glucose (PPG) and insulin dose (units per day and U/kg) from baseline to METHODS AND DESIGN week 16 will also be evaluated. The safety profile will be assessed, including adverse events and the Setting incidences of overall hypoglycaemia, nocturnal hypoglycaemia and severe hypoglycaemia This is a phase IV, randomized, non-inferiority, throughout the treatment period. Patient and open-label trial that will be conducted in 880 physician satisfaction and adherence will also be diabetes patients at approximately 50 study assessed, including the drop-out rate and per- centers in China. The aim is to assess the safety centage of patients able to comply with insulin and efficacy of a higher (0.3 U/kg) compared treatment and titration. with standard (0.2 U/kg) starting dose of basal A planned sub-group analysis will evaluate insulin in overweight and obese Chinese the safety and efficacy (including the glycaemic patients with type T2DM who have failed to control rate and changes in HbA1c, FPG and achieve glycaemic control using OADs. The PPG), stratified by patient age, duration of standard starting dose of 0.2 U/Kg was chosen as T2DM, baseline OAD treatment and baseline this is the current recommended initial dose of levels of HbA1c, FPG and PPG. basal insulin [11, 17]. The comparator starting dose of 0.3 U/kg was chosen on the basis of Patients patients’ characteristics of uncontrolled blood glucose levels [13], the previous research expe- Participants aged between 18 and 70 years with rience of the BMI-based starting dose of insulin a confirmed diagnosis of T2DM for at least glargine in non-Chinese populations [14] and 2 years who have received continuous treat- data from Chinese studies indicating that the ment with two to three OADs (including met- final dose of insulin required to achieve gly- formin C 1.5 g/day or at the maximum caemic control can be 0.3–0.5 U/kg after tolerated dose) for [ 3 months and have an 16 weeks of treatment [15, 16]. HbA1c level between 7.5% and 11% with fast- All procedures performed in studies involv- ing blood glucose (FBG) level of [ 9 mmol/l ing human participants will be in accordance and BMI between 25 and 40 kg/m are eligible with the ethical standards of the institutional for this study. Moreover, patients must agree to and/or national research committee and with perform self-monitoring of blood glucose the 1964 Helsinki Declaration, as revised in (SMBG) using the sponsor-provided blood glu- 2013. Informed consent will be obtained from cose meter. Patients with diabetes other than all individual participants included in the confirmed type 2 diabetes are excluded. In studies. 868 Adv Ther (2018) 35:864–874 addition, patients are excluded if they are trea- not obtained approval for being combined with ted with insulin or thiazolidinediones or GLP-1 insulin, it must be stopped at randomization. receptors agonists during the 3 months prior to Patient will be trained in the use of the blood screening, received pharmacological treatments glucose meter and insulin injections. During for weight loss during the 3 months prior to the run-in period, if a patient has FBG levels screening, have a history of diabetic ketoacido- [ 16.7 mmol/l, which is later confirmed by the sis or hyperosmolar nonketotic coma, have a fasting plasma glucose (FPG), they should dis- history of hypoglycaemia unawareness or continue the run-in process, should be appro- unexplained hypoglycaemia in the past priately treated in accordance with routine 6 months, are pregnant or breast feeding, or are clinical practice and are therefore excluded not using an acceptable method of birth from the study. control. Randomization Study Design Following successful completion of the run-in period, the patient is randomized to receive either a standard dose or higher dose basal Screening Period insulin injection. Randomization is based on a Following written informed consent, patients computer-generated code stratified by baseline will enter a 2-week screening phase (Fig. 1). sulfonylurea or glinide use, and allocation is During this phase, the patient will continue on performed via a centralized interactive voice their current stable doses of OADs and lifestyle response system or interactive web response interventions. system. Patients are randomized in a 1:1 ratio to receive either a standard initial dose (0.2 U/kg) Run-In Period or a higher initial dose (0.3 U/kg) of insulin At the end of the screening period, patients will glargine (100 U/ml, Lantus , Sanofi). enter a 3-day run-in period. During this run-in period, 3 days prior to randomization, patients Treatment Period will cease sulfonylurea or glinide treatment, but The study medication is provided as a pre-filled continue other OAD agents at the same dosage Lantus SoloSTAR insulin pen containing 3 ml of and frequency. If the DPP-4 inhibitor used has Fig. 1 Study design algorithm. FPG fasting blood glucose; BMI body mass index; Gla insulin glargine; OAD oral anti- diabetic drug; SU sulfonylurea Adv Ther (2018) 35:864–874 869 100 U/ml insulin glargine. After randomization Table 1 Titration algorithm for insulin glargine to either standard or higher initial doses, Median fasting blood Insulin glargine dose patients will be injected once a day at the same glucose (FPG), mmol/l adjustment, units time, usually at bedtime, for a period of C 5.6 and \ 6.7 0–2 (at the discretion of the 16 weeks. The starting daily dose will be 0.2 U/ kg of body weight (standard initial dose arm) or investigator/physician) 0.3 U/kg of body weight (higher initial dose C 6.7 and \ 7.8 2 arm). A forced dose titration will be conducted C 7.8 and \ 10.0 4 at each subsequent visit to keep the FBG level between 4.4 mmol/l and 5.6 mmol/l C 10 6 (80–100 mg/dl). Titration will be based on the \ 4.4 - 2 FBG levels of 3 consecutive days (see insulin titration). During this treatment period, patients in dose titration should be according to the lower both arms will continue their non-sulfonylurea value. If there are two FBG values missing (only and non-glinide OAD therapy at the same one available), the dose adjustment should be dosage and frequency prior to study enrolment. postponed to the next visit. Patients may withdraw from treatment with the medication if they decide to do so, at any time Definitions of Hypoglycaemia and for any reason, or this may be the investi- gator’s decision. Hypoglycaemia is categorized as follows: con- firmed hypoglycaemia is defined as a measured Self-Monitored Blood Glucose Test (SMBG) blood glucose level B 3.9 mmol/l with or with- The 4-point (before breakfast and 2 h after the out clinical symptoms of hypoglycaemia; noc- start of breakfast, lunch and dinner) SMBG turnal hypoglycaemia is defined as should be performed and recorded by patients hypoglycaemia (blood glucose on their own at the last day of the run-in period level B 3.9 mmol/l) that occurs during sleep and at least 3 consecutive days within the week (0:00–5:59 a.m.) and responds to ingestion of prior to visit 13 (week 16) or in case of prema- carbohydrates; severe hypoglycaemia is defined ture discontinuation. During the treatment as an event with clinical symptoms resulting period, SMBG, at least for FBG, should be per- from hypoglycaemia in which the study subject formed and recorded at least on 3 consecutive requires assistance for the administration of days within the week prior to each visit. carbohydrate, glucagon or other treatments and Meanwhile, all SMBG values whenever the a measured blood glucose level \ 2 mmol/l or patient experiences symptoms possibly related prompt recovery following oral carbohydrate, to hypoglycaemia will also be recorded. intravenous glucose or glucagon administration. Insulin Titration The titration will be done at each visit by a Data Collection physician. A forced dose titration will be con- ducted at each subsequent visit to keep the FBG Participants have mandatory clinic visits during level between 4.4 mmol/l and 5.6 mmol/l the screening, run-in, randomization periods (80–100 mg/dl). The physician will look at the and then at weeks 2, 6, 12 and 16 post-ran- FBG values of the last 3 consecutive days to domization during the treatment period adjust insulin doses. The FBG value used for the (Fig. 2). Telephone follow-up is conducted at titration is the median of the three values, weeks 1, 3, 4, 5, 8 and 10 post-randomization except if one is below 4.4 mmol/l; in this case, and 1 week after the end of the study treatment this lowest value will be used (Table 1). If there schedule. FBG levels are assessed at run-in and is one FBG value missing (only two available), weeks 2, 6, 12 and 16 post-randomization. 870 Adv Ther (2018) 35:864–874 Fig. 2 SPIRIT figure. *Sampling before the visit to obtain (week 16) should be performed at the subject’s last visit, the result on the day of the visit. (1) Patients will self- except for HbA1c, which should be evaluated only at or monitor their blood glucose (BG) values immediately after week 12. TC total cholesterol, HDL-c high-density before breakfast and 2 h after breakfast, lunch and dinner. lipoprotein cholesterol, LDL-c low-density lipoprotein Note: Telephone counselling will be available at any time cholesterol, TG triglyceride, FPG fasting plasma glucose, as required; blood glucose measurements obtained by IMP investigational medicinal product, BG blood glucose, SMBG will be performed regardless of whether there was a FBG fasting blood glucose, DTSQ diabetes treatment clinical or telephone visit. If treated subjects withdraw satisfaction questionnaire, EQ-5D European quality of life- from the study prematurely, all final assessment evaluations 5 dimensions, AE adverse event, SAE serious adverse event HbA1c is assessed at randomization and by the protocol for that patient. All adverse week 16 post-randomization. Patient-reported events will be managed and reported in com- outcomes (Diabetes Treatment Satisfaction pliance with the applicable regulations and Questionnaire, DTSQ) and European Quality of included in the final clinical study report. Life-5 Dimensions (EQ-5D) are recorded during the run-in period and at week 16 post- Sample Size Calculation randomization. Adverse events will be collected throughout The study sample size was calculated using a the study from the signature of the informed formula to test the non-inferiority of the consent form to the end of the study as defined Adv Ther (2018) 35:864–874 871 difference between two sample proportions DISCUSSION [18]. In brief, based on an estimated non-infe- riority margin of 10% (absolute value) and a The Beyond VII study is currently recruiting one-sided alpha of 0.025 with an estimated patients. The results of this study will be clini- control group incidence of hypoglycaemia of cally important given that diabetes treatment in 32.65% [19], 440 patients in each group are Asia is currently sub-optimal [11, 20], with required to achieve a power of 85%, assuming a delays in the initiation of insulin treatment and 10% dropout rate. subsequent inadequate dose titration, leading to increased levels of diabetic micro- and Statistical Analysis macrovascular complications. In China, delayed initiation of insulin treatment and inadequate dose titration are also observed and Analysis is based on a modified intent-to-treat thought to be predominantly due to a lack of (ITT) population of all randomized patients medical resources and difficulties in maintain- who have received at least one dose of insulin ing long-term follow-up of patients [8, 11]. glargine and have at least one post-treatment Ineffective blood glucose monitoring is also a efficacy measurement. Analyses will be repeated barrier to dose titration [11, 20, 21]. Therefore, in the per protocol population of all patients in starting basal insulin treatment at a higher dose the ITT population who have not had a major may offer a practical solution to this issue as protocol violation. Safety analyses will be con- long as it does not lead to a significant increase ducted in all patients who are randomized and in adverse events. receive at least one dose of insulin glargine. The primary objective of the Beyond VII For analysis of the primary endpoint, the study is therefore to assess whether the safety of number and percentage of patients with con- commencing basal insulin at a higher dose firmed or severe hypoglycaemia will be tabu- (0.3 U/kg) is non-inferior to that of the current lated by treatment arm. Analyses will be standard of care (0.2 U/kg) in overweight and performed to obtain a crude estimate of the obese T2DM patients uncontrolled with OADs; difference between groups in the percentage of this will be based on the percentage of patients patients with confirmed or severe hypogly- with at least one episode of hypoglycaemia caemia with 95% CIs for the difference deter- (3.9 mmol/l or severe) during the 16 weeks of mined using the normal approximation to the treatment. binomial. Non-inferiority is established when In treating diabetes, there is a balance the confidence interval lies entirely to the left of between efficacy and safety, namely a trade-off 10%. For the analysis of secondary endpoints, between improved glycaemic control and a risk the percentages of patients achieving HbA1c of hypoglycaemic episodes, and this has resul- and FPG targets will be analyzed using the same ted in a fear of hypoglycaemia being one of the method as that used for the primary endpoint. most common barriers for doctors initiating Changes in endpoints from baseline to post- and titrating basal insulin [22, 23]. It is there- baseline visits will be estimated using a mixed fore important that the potential safety impact model, taking end-of-treatment measurements of any new treatment paradigm in diabetes is as the dependent variable, treatment as a fixed assessed and compared with the current stan- effect, baseline measurements as a covariate and dard of care. To this end, the Beyond VII trial is patient/visit as a repeated measure indicator. designed and powered to focus on the safety of The results will be used to test whether there are a 0.3 U/kg dose of basal insulin in obese and any differences in the change from baseline by overweight patients. The safety measurement is both treatments, and between the two treat- the number of patients with at least one episode ment arms, and 95% CIs will be estimated. of hypoglycaemia during treatment, which is Other continuous variables will be summarized both a clinically meaningful assessment and an using descriptive statistics. endpoint that has been used as a safety outcome 872 Adv Ther (2018) 35:864–874 measure in recent clinical trials [24]. Hypogly- obese to ensure the safety of the patients; fur- caemia is a recognized adverse event of all forms ther studies in more generalized populations of insulin treatment, although basal insulin is may be conducted in the future on the basis of associated with fewer episodes of hypogly- the Beyond VII results. caemia than postprandial insulin treatment Despite these study design limitations, if the [10, 25]. results of Beyond VII demonstrate that a higher In this study, the higher starting dose of starting dose of basal insulin appears efficacious 0.3 U/kg was chosen on the basis of interven- and does not increase the rate of hypoglycaemic tional studies conducted in China that reported events, it may provide a viable treatment option final doses of insulin glargine of between 0.3 in countries where poor insulin titration has and 0.5 U/kg [15, 16]. In addition, the AACE been demonstrated. If a higher starting dose guidelines recommend a higher initial dose of also reduces the need for titration in these basal insulin between 0.2 and 0.3 U/kg for patients, there is the potential to maintain patients with HbA1c [ 8% [13]. Franco et al. better glycaemic control over the longer term [14] also support the efficacy and safety of BMI- and therefore reduce the prevalence of diabetes- based higher initial dosing of insulin. In addi- related complications. This, in turn, will help tion, this study has been designed in accor- relieve some of the expected future increases in dance with the current Consolidated Standards the healthcare burden of diabetes in China. of Reporting Clinical Trials (CONSORT) guide- In summary, the Beyond VII will test the lines and SPIRIT 2013 statement [26, 27], which hypothesis that a higher versus standard start- provide guidance on best practice in relation to ing dose of basal insulin has comparable safety clinical trial design and reporting. to standard dose insulin and can help overcome Considering that commencing insulin glar- suboptimal insulin titration in overweight and gine treatment at 0.3 U/kg is not currently a obese Chinese people with T2DM. The titration regular clinical practice in the real-world set- of insulin is complex, and the addition of data ting, the Beyond VII study is designed as an from a clinical study that reviews the safety of interventional and ‘‘treat-to-target’’ study that commencing patients on a high-dose insulin seeks to demonstrate the viability and safety of regimen will be welcomed by the clinical com- commencing a patient cohort at a higher munity. In addition, results from the BEYOND (0.3 U/kg) insulin glargine dose under compar- VII study will provide treating clinicians with a ative glycaemic control versus 0.2 U/kg. The framework in which patients on high-dose average endpoint dose of insulin glargine for insulin regimens can be managed. Chinese patients in clinical trials is 0.3–0.5 U/kg [15, 16]. Based on this fact, we hypothesize that Trial Status in the real-world setting where a lack of, or inadequate, titration of insulin is common, This study is currently recruiting participants. most patients with an initial dose of 0.3 U/kg would achieve a better outcome than patients with an initial dose of 0.2 U/kg. The limitation ACKNOWLEDGEMENTS of this trial is that the study population is overweight and obese patients. Current evi- We thank all patients and investigators of the dence suggests that BMI is an appropriate Beyond VII Study. selection criterion for increasing the starting dose [13]; however, this trial population may be Funding. This study and the article process- narrower than the real-world population, which ing charges for this manuscript was sponsored could benefit from increased doses of insulin at by Sanofi China. All authors had full access to initiation. Given the limited clinical trial data regarding the use of high-dose insulin, it was all of the data in this study and take complete responsibility for the integrity of the data and considered appropriate to restrict the patient cohort to individuals who are overweight or accuracy of the data analysis. Adv Ther (2018) 35:864–874 873 Medical Writing Assistance. Medical writ- accordance with the Helsinki Declaration of 1964, ing services were provided by Hongmei Xu of as revised in 2013. All patients meeting the inclu- Nucleus Global and were funded by Sanofi in sion criteria will have the study explained to them accordance with Good Publication Practice in detail andwillthensignaninformedpatient (GPP3) guidelines (http://ismpp.org/gpp3). consent to participate in the study. Authorship. All named authors meet the Data Availability. Data sharing is not International Committee of Medical Journal applicable to this article as no data sets were Editors (ICMJE) criteria for authorship for this generated or analyzed during the current study. manuscript, take responsibility for the integrity Open Access. This article is distributed of the work as a whole and have given final under the terms of the Creative Commons approval to the version to be published. Attribution-NonCommercial 4.0 International Author Contributions. Linong Ji contributed License (http://creativecommons.org/licenses/ to the conception and design of the study, devel- by-nc/4.0/), which permits any noncommer- oped the study protocol, will be responsible for the cial use, distribution, and reproduction in any recruitment and the follow-up of the patients medium, provided you give appropriate credit enrolled, and will also contribute to the analysis to the original author(s) and the source, provide and interpretation of data. Zhengnan Gao, Bimin a link to the Creative Commons license, and Shi, Rongwen Bian, Fuzai Yin, and Wuyan Pang indicate if changes were made. contributed to the design of the study and will be responsible for the recruitment and the follow-up of the patients enrolled. Hong Gao contributed to REFERENCES the conception and design of the study and the development of the study protocol. NC con- 1. Wang L, Gao P, Zhang M, et al. Prevalence and tributed to the review and revision of the study ethnic pattern of diabetes and prediabetes in China protocol. All authors read and approved the final in 2013. JAMA. 2017;317:2515–23. manuscript. 2. Xu Y, Wang L, He J, et al. Prevalence and control of Disclosures. Linong Ji reported receiving diabetes in Chinese adults. JAMA. 2013;310:948–59. consulting and lecture fees from Eli Lilly, Bris- 3. International Diabetes Federation. Diabetes Atlas, tol-Myers Squibb, Novartis, Novo Nordisk, 7th ed. 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Owens DR, Traylor L, Dain MP, et al. Efficacy and to-target trial: randomized addition of glargine or safety of basal insulin glargine 12 and 24 weeks human NPH insulin to oral therapy of type 2 dia- after initiation in persons with type 2 diabetes: a betic patients. Diabetes Care. 2003;26:3080–6. pooled analysis of data from treatment arms of 15 treat-to-target randomised controlled trials. Dia- 10. Ji LN, Lu JM, Guo XH, et al. Glycemic control betes Res Clin Pract. 2014;106:264–74. among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables. BMC 20. Kadowaki T, Ohtani T, Naito Y, et al. Potential Public Health. 2013;13:602. formula for the calculation of starting and incre- mental insulin glargine doses: ALOHA subanalysis. 11. Tsai ST, Pathan F, Ji L, et al. First insulinization with PLoS One. 2012;7:e41358. basal insulin in patients with type 2 diabetes in a real-world setting in Asia. J Diabetes. 21. Ji L, Newman J, Lu J, et al. 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A prospective study to nocturnal hypoglycemia and better post-dinner optimize insulin treatment by switching to insulin glucose control with bedtime insulin glargine glargine in type 2 diabetic patients previously compared with bedtime NPH insulin during insulin uncontrolled on premixed insulin: the optimiza- combination therapy in type 2 diabetes. HOE tion study. Curr Med Res Opin. 2012;28:533–41. 901/3002 Study Group. Diabetes Care. 2000;23:1130–6. 16. Zhang B, Zhao J, Yang W, et al. Glycemic control and safety in Chinese patients with type 2 diabetes 26. Piaggio G, Elbourne DR, Altman DG, et al. Report- mellitus who switched from premixed insulin to ing of noninferiority and equivalence randomized insulin glargine plus oral antidiabetics: a large, trials: an extension of the CONSORT statement. prospective, observational study. Diabetes Metab JAMA. 2006;295:1152–60. Res Rev. 2017;33:e2863. 27. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 17. Garg SK, Admane K, Freemantle N, et al. 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Safety and Efficacy of High Versus Standard Starting Doses of Insulin Glargine in Overweight and Obese Chinese Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic Medications (Beyond VII): Study Protocol for a Randomized Controlled Trial

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Medicine & Public Health; Internal Medicine; Oncology; Cardiology; Rheumatology; Endocrinology; Pharmacology/Toxicology
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Adv Ther (2018) 35:864–874 https://doi.org/10.1007/s12325-018-0717-x STUDY PROTOCOL Safety and Efficacy of High Versus Standard Starting Doses of Insulin Glargine in Overweight and Obese Chinese Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic Medications (Beyond VII): Study Protocol for a Randomized Controlled Trial . . . . Linong Ji Zhengnan Gao Bimin Shi Rongwen Bian . . . Fuzai Yin Wuyan Pang Hong Gao Nan Cui Received: March 15, 2018 / Published online: June 5, 2018 The Author(s) 2018 treatment satisfaction and compliance as well ABSTRACT require fewer steps to titrate. Considering that overweight and obese patients usually require Background: Treatment with basal insulin in higher insulin doses because of insulin resis- Chinese populations is currently sub-optimal, tance, a higher initial dose of the basal insulin is with delayed initiation of insulin treatment and feasible in overweight and obese patients with inadequate dose titration. Increasing the initial type 2 diabetes. However, safety is an important dose of insulin may be a practicable and effec- issue needing to be considered for higher initial tive solution to the problem of titration. A dose treatment. The aim of this study is to assess higher initial dose will be helpful for patients to the safety and efficacy of higher (0.3 U/kg) achieve the blood glucose target and improve compared with standard (0.2 U/kg) starting doses of basal insulin in overweight and obese Enhanced Digital Features To view enhanced digital Chinese patients with type 2 diabetes who have features for this article go to https://doi.org/10.6084/ failed to achieve glycaemic control using oral m9.figshare.6269984. antidiabetic drugs (OADs). L. Ji (&) F. Yin Department of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, The Peking University People’s Hospital, 11 Xizhimen First Hospital of Qinhuangdao, 258 Wenhua Road, South Street, Xicheng District, Beijing 100044, Qinhuangdao 066000, Hebei, China China W. Pang e-mail: jiln@bjmu.edu.cn Department of Endocrinology and Metabolism, Z. Gao Huaihe Hospital of Henan University, 115 Ximen Department of Endocrinology and Metabolism, Street, Kaifeng 475000, Henan, China Dalian Municipal Central Hospital Affiliated of Dalian Medical University, 826 Xi’nan Road, Dalian H. Gao  N. Cui 116033, Liaoning, China Sanofi China, 19 Floor, Tower III, Jing’An Kerry Centre, 1228 Middle Yan’an Road, Shanghai 200040, B. Shi China Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China R. Bian Department of Endocrinology and Metabolism, Jiangsu Province Institute of Geriatrics, 30 Luojia Road, Nanjing 210024, Jiangsu, China Adv Ther (2018) 35:864–874 865 Methods: This is a phase IV, randomized, non- OAD Oral antidiabetic drug inferiority, open-label trial that will be con- ORBIT Observational Registry of Basal Insulin ducted at approximately 50 centers in China. Treatment Eight hundred eighty overweight and obese PPG Postprandial plasma glucose adult Chinese patients with type 2 diabetes will SAE Serious adverse event be randomized to receive higher (0.3 U/kg) or SMBG Self-monitored blood glucose standard (0.2 U/kg) starting doses of basal SPIRIT Standard protocol items for clinical insulin glargine (100 U/ml) during a 16-week trials period. The primary endpoint is whether a T2DM Type 2 diabetes mellitus higher initial dose of basal insulin (0.3 U/kg) is TC Total cholesterol non-inferior to a standard initial dose (0.2 U/kg) TG Triglyceride based on the percentage of patients with at least UKPDS UK Prospective Diabetes Study one episode of hypoglycaemia (B 3.9 mmol/l or severe) over 16 weeks. Secondary endpoints include evaluation of glycosylated haemoglobin INTRODUCTION A1c (HbA1c), fasting blood glucose, postpran- dial blood glucose, insulin dose and safety. The incidence of type 2 diabetes mellitus Discussion: This study is the first randomized- (T2DM) in China has increased rapidly over the controlled study to evaluate the safety and past 2 decades [1, 2]. By 2040, an estimated 642 efficacy of basal insulin treatment with a higher million people worldwide will live with diabetes starting dose versus standard starting dose in and 150.7 million are in China [3]. A study overweight and obese Chinese patients with reported by the International Diabetes Federa- type 2 diabetes. Results of this study could tion (IDF) and the Chinese Diabetes Society generate evidence to support the feasibility of a (CDS) in 2010 found that 13% of all medical higher starting dose of basal insulin in diabetes expenditures in China (US$ 25 billion per management of overweight and obese Chinese annum) was directly caused by diabetes [4]. patients, therefore providing an easy approach Therefore, unless improvements are made in to improve diabetes management. both the prevention and treatment of diabetes Trial Registration: ClinicalTrials.gov identifier, in China, the economic and healthcare burden NCT02836704. Registered on July 7th 2016. will continue to rise. Funding: Sanofi China. One way to reduce the healthcare and eco- nomic burden of diabetes patients is to achieve Keywords: Basal insulin; BMI; Insulin glargine; and maintain good glycaemic control, thus Obesity; Type 2 diabetes reducing the risk of diabetes-related complica- tions. Like the American Diabetes Association Abbreviations standards of medical care in diabetes [5], Cur- DCCT Diabetes control and complications rent Chinese treatment guidelines [6] recom- trial mend a stepwise approach to diabetes DPP-4 Dipeptidyl peptidase-4 management, with patients initially receiving DTSQ Diabetes treatment satisfaction lifestyle intervention and therapy with oral questionnaire antidiabetic drugs (OADs). As T2DM is a pro- EQ-5D European quality of Life -5 gressive disease, with a gradual decrease in the Dimensions number of functional insulin-producing b-cells, FBG Fasting blood glucose patients often require basal insulin treatment if FPG Fasting plasma glucose glycaemic control cannot be maintained by HbA1c Glycated haemoglobin OADs. HDL-c High-density lipoprotein cholesterol Insulin glargine is a long-acting basal insulin IMP Investigational medicinal product analogue that is widely used in the glycaemic LDL-c Low-density lipoprotein cholesterol control of type 2 diabetes patients [7, 8]. NPH Neutral protamine hagedorn 866 Adv Ther (2018) 35:864–874 Adequate starting doses of insulin and an HbA1c in insulin-naı¨ve Japanese diabetes appropriate titration algorithm are important to patients. Furthermore, patients who did not achieve optimal glycaemic control. The treat to receive insulin titration had a significantly target trial demonstrated that titrating the lower chance of achieving HbA1c targets [12]. insulin glargine dose using a fasting plasma Considering the current healthcare system glucose (FPG) target of B 6.1 mmol/l resulted barriers in China, inadequate glucose control in good glycaemic control (58% of individuals will continue to exist for a long time and the achieved HbA1c \ 7%) and a low incidence of challenge of insulin titration in Chinese dia- nocturnal hypoglycaemia [9]. betes patients requires long-term patient edu- Although a number of clinical studies have cation. It has been suggested that initiating demonstrated the benefits of sufficient insulin insulin at higher starting doses may be of ben- dosing on glycaemic management, the current efit. Inadequate titration of insulin can lead to practice in China remains sub-optimal in both an insufficient total dose of insulin, which may the time to initiation of insulin treatment and cause sub-optimal glycaemic control and a low the subsequent titration of insulin in patients rate of patients achieving glycaemic control with inadequate glycaemic control. A study of targets. Therefore, initiating treatment with a almost 240,000 patients with T2DM throughout higher dose of insulin may represent a treat- China found that among those treated with ment approach that will partially compensate OADs and/or insulin, less than 1/3 of patients for the current insufficiency in dose titration. achieved the glycaemic target of HbA1c \ 7% However, hypoglycaemia is another concern for [10]. Similarly, the First Basal Insulin Evaluation most physicians and patients when they are (FINE) study assessed real-world insulin prac- considering using a higher initial dose of insu- tices in T2DM patients from 2006 to 2008 across lin. Currently, standard basal insulin is recom- 11 countries in Asia and found that initiation of mended by the American Diabetes Association insulin therapy was delayed by approximately (ADA) and American Association of Clinical 9 years in these patients, despite their high Endocrinologists (AACE), starting with HbA1c levels [11]. Furthermore, there was an 0.1–0.2 U/kg per day depending on the degree overall lack of insulin titration in Asian patients of hyperglycaemia [5, 13]. In China, the rec- with the average insulin dose only increasing by ommended standard starting dose is 0.2 U/kg approximately 0.03 U/kg after 6 months’ treat- per day [6]. ment and only 33.7% of patients achieved their The AACE guidelines recommend a higher HbA1c targets [11]. A more recent Observational initial dose of basal insulin (0.2–0.3 U/kg) for Registry of Basal Insulin Treatment (ORBIT) diabetes patients with HbA1c [ 8% [13]. In study, conducted from 2011 to 2013 across 209 addition, considering the impact of body hospitals in China, found that more than one- weight on insulin resistance, a BMI-based insu- third of patients with uncontrolled diabetes at lin dose regimen has recently been described follow-up visits did not receive insulin titration, [14]; the BMI-based higher dose of initial insulin and the average increase in basal insulin dose at demonstrated equal safety efficacy and safety 6 months was only 0.03 U/kg. The ORBIT compared with a standard starting dose of investigators suggested that Chinese type 2 insulin. Furthermore, several interventional diabetes patients tend to have a delayed insulin studies conducted in China have shown that initiation and efforts to improve insulin uti- the final insulin dosing after 16 weeks of treat- lization are urgently needed to achieve and ment is as high as 0.3–0.5 U/kg in order to maintain glycaemic control [8]. Similar chal- achieve glycaemic control [15, 16]. Taking into lenges with sub-optimal insulin titration in real- account these factors, this study will initiate world practice have been demonstrated in other insulin therapy at a dose of 0.3 U/kg in over- Asian countries. In a sub-analysis of the Add-on weight and obese Chinese diabetes patients Lantus to Oral Hypoglycemic Agents (ALOHA) with inadequate glycaemic control on OADs. study, Odawara et al. found that an appropriate Few data are available regarding the use of a starting dose was essential to achieving target higher starting dose of insulin, especially Adv Ther (2018) 35:864–874 867 regarding potential hypoglycaemia risk. This is Study Objectives the first study that will be conducted in Chinese diabetes patients that investigates the safety of The primary objective is to determine whether a initiating insulin treatment at a higher dose. It higher initial dose of basal insulin glargine will enroll patients who are overweight or obese (0.3 U/kg) is non-inferior to a standard initial as these patients will most likely require a dose (0.2 U/kg) based on the percentage of higher dose of insulin. This study will therefore patients with at least one episode of hypogly- assess the safety and efficacy of a higher starting caemia (B 3.9 mmol/l or severe) during the dose of 0.3 U/kg basal insulin compared with 16 weeks of treatment. the standard starting dose of 0.2 U/kg in over- Secondary study objectives include evaluation weight or obese diabetes patients in China. The of the percentage of patients achieving HbA1c study will also assess whether a higher starting \ 7% at week 16 and the percentage and accu- dose has a positive effect on current sub-optimal mulated percentage of patients achieving FPG titration practices and insufficient insulin targets (\ 5.6,\ 6.1 and\ 7.0 mmol/l) from dosage in China. baseline to week 16. Changes in HbA1c, FPG, postprandial plasma glucose (PPG) and insulin dose (units per day and U/kg) from baseline to METHODS AND DESIGN week 16 will also be evaluated. The safety profile will be assessed, including adverse events and the Setting incidences of overall hypoglycaemia, nocturnal hypoglycaemia and severe hypoglycaemia This is a phase IV, randomized, non-inferiority, throughout the treatment period. Patient and open-label trial that will be conducted in 880 physician satisfaction and adherence will also be diabetes patients at approximately 50 study assessed, including the drop-out rate and per- centers in China. The aim is to assess the safety centage of patients able to comply with insulin and efficacy of a higher (0.3 U/kg) compared treatment and titration. with standard (0.2 U/kg) starting dose of basal A planned sub-group analysis will evaluate insulin in overweight and obese Chinese the safety and efficacy (including the glycaemic patients with type T2DM who have failed to control rate and changes in HbA1c, FPG and achieve glycaemic control using OADs. The PPG), stratified by patient age, duration of standard starting dose of 0.2 U/Kg was chosen as T2DM, baseline OAD treatment and baseline this is the current recommended initial dose of levels of HbA1c, FPG and PPG. basal insulin [11, 17]. The comparator starting dose of 0.3 U/kg was chosen on the basis of Patients patients’ characteristics of uncontrolled blood glucose levels [13], the previous research expe- Participants aged between 18 and 70 years with rience of the BMI-based starting dose of insulin a confirmed diagnosis of T2DM for at least glargine in non-Chinese populations [14] and 2 years who have received continuous treat- data from Chinese studies indicating that the ment with two to three OADs (including met- final dose of insulin required to achieve gly- formin C 1.5 g/day or at the maximum caemic control can be 0.3–0.5 U/kg after tolerated dose) for [ 3 months and have an 16 weeks of treatment [15, 16]. HbA1c level between 7.5% and 11% with fast- All procedures performed in studies involv- ing blood glucose (FBG) level of [ 9 mmol/l ing human participants will be in accordance and BMI between 25 and 40 kg/m are eligible with the ethical standards of the institutional for this study. Moreover, patients must agree to and/or national research committee and with perform self-monitoring of blood glucose the 1964 Helsinki Declaration, as revised in (SMBG) using the sponsor-provided blood glu- 2013. Informed consent will be obtained from cose meter. Patients with diabetes other than all individual participants included in the confirmed type 2 diabetes are excluded. In studies. 868 Adv Ther (2018) 35:864–874 addition, patients are excluded if they are trea- not obtained approval for being combined with ted with insulin or thiazolidinediones or GLP-1 insulin, it must be stopped at randomization. receptors agonists during the 3 months prior to Patient will be trained in the use of the blood screening, received pharmacological treatments glucose meter and insulin injections. During for weight loss during the 3 months prior to the run-in period, if a patient has FBG levels screening, have a history of diabetic ketoacido- [ 16.7 mmol/l, which is later confirmed by the sis or hyperosmolar nonketotic coma, have a fasting plasma glucose (FPG), they should dis- history of hypoglycaemia unawareness or continue the run-in process, should be appro- unexplained hypoglycaemia in the past priately treated in accordance with routine 6 months, are pregnant or breast feeding, or are clinical practice and are therefore excluded not using an acceptable method of birth from the study. control. Randomization Study Design Following successful completion of the run-in period, the patient is randomized to receive either a standard dose or higher dose basal Screening Period insulin injection. Randomization is based on a Following written informed consent, patients computer-generated code stratified by baseline will enter a 2-week screening phase (Fig. 1). sulfonylurea or glinide use, and allocation is During this phase, the patient will continue on performed via a centralized interactive voice their current stable doses of OADs and lifestyle response system or interactive web response interventions. system. Patients are randomized in a 1:1 ratio to receive either a standard initial dose (0.2 U/kg) Run-In Period or a higher initial dose (0.3 U/kg) of insulin At the end of the screening period, patients will glargine (100 U/ml, Lantus , Sanofi). enter a 3-day run-in period. During this run-in period, 3 days prior to randomization, patients Treatment Period will cease sulfonylurea or glinide treatment, but The study medication is provided as a pre-filled continue other OAD agents at the same dosage Lantus SoloSTAR insulin pen containing 3 ml of and frequency. If the DPP-4 inhibitor used has Fig. 1 Study design algorithm. FPG fasting blood glucose; BMI body mass index; Gla insulin glargine; OAD oral anti- diabetic drug; SU sulfonylurea Adv Ther (2018) 35:864–874 869 100 U/ml insulin glargine. After randomization Table 1 Titration algorithm for insulin glargine to either standard or higher initial doses, Median fasting blood Insulin glargine dose patients will be injected once a day at the same glucose (FPG), mmol/l adjustment, units time, usually at bedtime, for a period of C 5.6 and \ 6.7 0–2 (at the discretion of the 16 weeks. The starting daily dose will be 0.2 U/ kg of body weight (standard initial dose arm) or investigator/physician) 0.3 U/kg of body weight (higher initial dose C 6.7 and \ 7.8 2 arm). A forced dose titration will be conducted C 7.8 and \ 10.0 4 at each subsequent visit to keep the FBG level between 4.4 mmol/l and 5.6 mmol/l C 10 6 (80–100 mg/dl). Titration will be based on the \ 4.4 - 2 FBG levels of 3 consecutive days (see insulin titration). During this treatment period, patients in dose titration should be according to the lower both arms will continue their non-sulfonylurea value. If there are two FBG values missing (only and non-glinide OAD therapy at the same one available), the dose adjustment should be dosage and frequency prior to study enrolment. postponed to the next visit. Patients may withdraw from treatment with the medication if they decide to do so, at any time Definitions of Hypoglycaemia and for any reason, or this may be the investi- gator’s decision. Hypoglycaemia is categorized as follows: con- firmed hypoglycaemia is defined as a measured Self-Monitored Blood Glucose Test (SMBG) blood glucose level B 3.9 mmol/l with or with- The 4-point (before breakfast and 2 h after the out clinical symptoms of hypoglycaemia; noc- start of breakfast, lunch and dinner) SMBG turnal hypoglycaemia is defined as should be performed and recorded by patients hypoglycaemia (blood glucose on their own at the last day of the run-in period level B 3.9 mmol/l) that occurs during sleep and at least 3 consecutive days within the week (0:00–5:59 a.m.) and responds to ingestion of prior to visit 13 (week 16) or in case of prema- carbohydrates; severe hypoglycaemia is defined ture discontinuation. During the treatment as an event with clinical symptoms resulting period, SMBG, at least for FBG, should be per- from hypoglycaemia in which the study subject formed and recorded at least on 3 consecutive requires assistance for the administration of days within the week prior to each visit. carbohydrate, glucagon or other treatments and Meanwhile, all SMBG values whenever the a measured blood glucose level \ 2 mmol/l or patient experiences symptoms possibly related prompt recovery following oral carbohydrate, to hypoglycaemia will also be recorded. intravenous glucose or glucagon administration. Insulin Titration The titration will be done at each visit by a Data Collection physician. A forced dose titration will be con- ducted at each subsequent visit to keep the FBG Participants have mandatory clinic visits during level between 4.4 mmol/l and 5.6 mmol/l the screening, run-in, randomization periods (80–100 mg/dl). The physician will look at the and then at weeks 2, 6, 12 and 16 post-ran- FBG values of the last 3 consecutive days to domization during the treatment period adjust insulin doses. The FBG value used for the (Fig. 2). Telephone follow-up is conducted at titration is the median of the three values, weeks 1, 3, 4, 5, 8 and 10 post-randomization except if one is below 4.4 mmol/l; in this case, and 1 week after the end of the study treatment this lowest value will be used (Table 1). If there schedule. FBG levels are assessed at run-in and is one FBG value missing (only two available), weeks 2, 6, 12 and 16 post-randomization. 870 Adv Ther (2018) 35:864–874 Fig. 2 SPIRIT figure. *Sampling before the visit to obtain (week 16) should be performed at the subject’s last visit, the result on the day of the visit. (1) Patients will self- except for HbA1c, which should be evaluated only at or monitor their blood glucose (BG) values immediately after week 12. TC total cholesterol, HDL-c high-density before breakfast and 2 h after breakfast, lunch and dinner. lipoprotein cholesterol, LDL-c low-density lipoprotein Note: Telephone counselling will be available at any time cholesterol, TG triglyceride, FPG fasting plasma glucose, as required; blood glucose measurements obtained by IMP investigational medicinal product, BG blood glucose, SMBG will be performed regardless of whether there was a FBG fasting blood glucose, DTSQ diabetes treatment clinical or telephone visit. If treated subjects withdraw satisfaction questionnaire, EQ-5D European quality of life- from the study prematurely, all final assessment evaluations 5 dimensions, AE adverse event, SAE serious adverse event HbA1c is assessed at randomization and by the protocol for that patient. All adverse week 16 post-randomization. Patient-reported events will be managed and reported in com- outcomes (Diabetes Treatment Satisfaction pliance with the applicable regulations and Questionnaire, DTSQ) and European Quality of included in the final clinical study report. Life-5 Dimensions (EQ-5D) are recorded during the run-in period and at week 16 post- Sample Size Calculation randomization. Adverse events will be collected throughout The study sample size was calculated using a the study from the signature of the informed formula to test the non-inferiority of the consent form to the end of the study as defined Adv Ther (2018) 35:864–874 871 difference between two sample proportions DISCUSSION [18]. In brief, based on an estimated non-infe- riority margin of 10% (absolute value) and a The Beyond VII study is currently recruiting one-sided alpha of 0.025 with an estimated patients. The results of this study will be clini- control group incidence of hypoglycaemia of cally important given that diabetes treatment in 32.65% [19], 440 patients in each group are Asia is currently sub-optimal [11, 20], with required to achieve a power of 85%, assuming a delays in the initiation of insulin treatment and 10% dropout rate. subsequent inadequate dose titration, leading to increased levels of diabetic micro- and Statistical Analysis macrovascular complications. In China, delayed initiation of insulin treatment and inadequate dose titration are also observed and Analysis is based on a modified intent-to-treat thought to be predominantly due to a lack of (ITT) population of all randomized patients medical resources and difficulties in maintain- who have received at least one dose of insulin ing long-term follow-up of patients [8, 11]. glargine and have at least one post-treatment Ineffective blood glucose monitoring is also a efficacy measurement. Analyses will be repeated barrier to dose titration [11, 20, 21]. Therefore, in the per protocol population of all patients in starting basal insulin treatment at a higher dose the ITT population who have not had a major may offer a practical solution to this issue as protocol violation. Safety analyses will be con- long as it does not lead to a significant increase ducted in all patients who are randomized and in adverse events. receive at least one dose of insulin glargine. The primary objective of the Beyond VII For analysis of the primary endpoint, the study is therefore to assess whether the safety of number and percentage of patients with con- commencing basal insulin at a higher dose firmed or severe hypoglycaemia will be tabu- (0.3 U/kg) is non-inferior to that of the current lated by treatment arm. Analyses will be standard of care (0.2 U/kg) in overweight and performed to obtain a crude estimate of the obese T2DM patients uncontrolled with OADs; difference between groups in the percentage of this will be based on the percentage of patients patients with confirmed or severe hypogly- with at least one episode of hypoglycaemia caemia with 95% CIs for the difference deter- (3.9 mmol/l or severe) during the 16 weeks of mined using the normal approximation to the treatment. binomial. Non-inferiority is established when In treating diabetes, there is a balance the confidence interval lies entirely to the left of between efficacy and safety, namely a trade-off 10%. For the analysis of secondary endpoints, between improved glycaemic control and a risk the percentages of patients achieving HbA1c of hypoglycaemic episodes, and this has resul- and FPG targets will be analyzed using the same ted in a fear of hypoglycaemia being one of the method as that used for the primary endpoint. most common barriers for doctors initiating Changes in endpoints from baseline to post- and titrating basal insulin [22, 23]. It is there- baseline visits will be estimated using a mixed fore important that the potential safety impact model, taking end-of-treatment measurements of any new treatment paradigm in diabetes is as the dependent variable, treatment as a fixed assessed and compared with the current stan- effect, baseline measurements as a covariate and dard of care. To this end, the Beyond VII trial is patient/visit as a repeated measure indicator. designed and powered to focus on the safety of The results will be used to test whether there are a 0.3 U/kg dose of basal insulin in obese and any differences in the change from baseline by overweight patients. The safety measurement is both treatments, and between the two treat- the number of patients with at least one episode ment arms, and 95% CIs will be estimated. of hypoglycaemia during treatment, which is Other continuous variables will be summarized both a clinically meaningful assessment and an using descriptive statistics. endpoint that has been used as a safety outcome 872 Adv Ther (2018) 35:864–874 measure in recent clinical trials [24]. Hypogly- obese to ensure the safety of the patients; fur- caemia is a recognized adverse event of all forms ther studies in more generalized populations of insulin treatment, although basal insulin is may be conducted in the future on the basis of associated with fewer episodes of hypogly- the Beyond VII results. caemia than postprandial insulin treatment Despite these study design limitations, if the [10, 25]. results of Beyond VII demonstrate that a higher In this study, the higher starting dose of starting dose of basal insulin appears efficacious 0.3 U/kg was chosen on the basis of interven- and does not increase the rate of hypoglycaemic tional studies conducted in China that reported events, it may provide a viable treatment option final doses of insulin glargine of between 0.3 in countries where poor insulin titration has and 0.5 U/kg [15, 16]. In addition, the AACE been demonstrated. If a higher starting dose guidelines recommend a higher initial dose of also reduces the need for titration in these basal insulin between 0.2 and 0.3 U/kg for patients, there is the potential to maintain patients with HbA1c [ 8% [13]. Franco et al. better glycaemic control over the longer term [14] also support the efficacy and safety of BMI- and therefore reduce the prevalence of diabetes- based higher initial dosing of insulin. In addi- related complications. This, in turn, will help tion, this study has been designed in accor- relieve some of the expected future increases in dance with the current Consolidated Standards the healthcare burden of diabetes in China. of Reporting Clinical Trials (CONSORT) guide- In summary, the Beyond VII will test the lines and SPIRIT 2013 statement [26, 27], which hypothesis that a higher versus standard start- provide guidance on best practice in relation to ing dose of basal insulin has comparable safety clinical trial design and reporting. to standard dose insulin and can help overcome Considering that commencing insulin glar- suboptimal insulin titration in overweight and gine treatment at 0.3 U/kg is not currently a obese Chinese people with T2DM. The titration regular clinical practice in the real-world set- of insulin is complex, and the addition of data ting, the Beyond VII study is designed as an from a clinical study that reviews the safety of interventional and ‘‘treat-to-target’’ study that commencing patients on a high-dose insulin seeks to demonstrate the viability and safety of regimen will be welcomed by the clinical com- commencing a patient cohort at a higher munity. In addition, results from the BEYOND (0.3 U/kg) insulin glargine dose under compar- VII study will provide treating clinicians with a ative glycaemic control versus 0.2 U/kg. The framework in which patients on high-dose average endpoint dose of insulin glargine for insulin regimens can be managed. Chinese patients in clinical trials is 0.3–0.5 U/kg [15, 16]. Based on this fact, we hypothesize that Trial Status in the real-world setting where a lack of, or inadequate, titration of insulin is common, This study is currently recruiting participants. most patients with an initial dose of 0.3 U/kg would achieve a better outcome than patients with an initial dose of 0.2 U/kg. The limitation ACKNOWLEDGEMENTS of this trial is that the study population is overweight and obese patients. Current evi- We thank all patients and investigators of the dence suggests that BMI is an appropriate Beyond VII Study. selection criterion for increasing the starting dose [13]; however, this trial population may be Funding. This study and the article process- narrower than the real-world population, which ing charges for this manuscript was sponsored could benefit from increased doses of insulin at by Sanofi China. All authors had full access to initiation. Given the limited clinical trial data regarding the use of high-dose insulin, it was all of the data in this study and take complete responsibility for the integrity of the data and considered appropriate to restrict the patient cohort to individuals who are overweight or accuracy of the data analysis. Adv Ther (2018) 35:864–874 873 Medical Writing Assistance. Medical writ- accordance with the Helsinki Declaration of 1964, ing services were provided by Hongmei Xu of as revised in 2013. All patients meeting the inclu- Nucleus Global and were funded by Sanofi in sion criteria will have the study explained to them accordance with Good Publication Practice in detail andwillthensignaninformedpatient (GPP3) guidelines (http://ismpp.org/gpp3). consent to participate in the study. Authorship. All named authors meet the Data Availability. Data sharing is not International Committee of Medical Journal applicable to this article as no data sets were Editors (ICMJE) criteria for authorship for this generated or analyzed during the current study. manuscript, take responsibility for the integrity Open Access. This article is distributed of the work as a whole and have given final under the terms of the Creative Commons approval to the version to be published. Attribution-NonCommercial 4.0 International Author Contributions. Linong Ji contributed License (http://creativecommons.org/licenses/ to the conception and design of the study, devel- by-nc/4.0/), which permits any noncommer- oped the study protocol, will be responsible for the cial use, distribution, and reproduction in any recruitment and the follow-up of the patients medium, provided you give appropriate credit enrolled, and will also contribute to the analysis to the original author(s) and the source, provide and interpretation of data. Zhengnan Gao, Bimin a link to the Creative Commons license, and Shi, Rongwen Bian, Fuzai Yin, and Wuyan Pang indicate if changes were made. contributed to the design of the study and will be responsible for the recruitment and the follow-up of the patients enrolled. Hong Gao contributed to REFERENCES the conception and design of the study and the development of the study protocol. NC con- 1. Wang L, Gao P, Zhang M, et al. Prevalence and tributed to the review and revision of the study ethnic pattern of diabetes and prediabetes in China protocol. All authors read and approved the final in 2013. JAMA. 2017;317:2515–23. manuscript. 2. Xu Y, Wang L, He J, et al. Prevalence and control of Disclosures. Linong Ji reported receiving diabetes in Chinese adults. JAMA. 2013;310:948–59. consulting and lecture fees from Eli Lilly, Bris- 3. International Diabetes Federation. Diabetes Atlas, tol-Myers Squibb, Novartis, Novo Nordisk, 7th ed. 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Advances in TherapySpringer Journals

Published: Jun 5, 2018

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