Background: There are limited efficacious treatment options for severe osteoarthritis of the knee (OAK). The Low Molecular Weight Fraction of 5% human serum Albumin (LMWF-5A) is in development to treat severe OAK. This study evaluated the safety and efficacy of LMWF-5A for the signs and symptoms of OAK. Methods: This 12-week randomized, double-blind, controlled clinical trial was conducted at thirteen sites across the United States. Patients with symptomatic, severe OAK (Kellgren-Lawrence grade 4 disease) who were fully ambulatory and had no other conditions interfering with the study knee were randomized to a single 4 ml intra-articular injection of LMWF-5A or saline, randomized 6:1. The primary endpoint was Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responder rate (%), examined with a one-sided exact binomial test compared to a clinically meaningful response rate of 30%. Efficacy of LMWF-5A was also evaluated as controlled responder (%), defined as 20% improvements in both pain and function, compared to historical saline control from three previous trials. Safety was examined as the incidence and severity of adverse events (AEs). This trial was registered (clinicaltrials.gov identifier: NCT03182686). Results: In total, 168 patients were randomized; 144 subjects treated with LMWF-5A were analysed. Overall, 71% (95% CI: 63.4%–78.3%) of subjects treated with LMWF-5A met the OMERACT-OARSI responder criteria, exceeding the 30% threshold (p < 0.001). There were also significantly more responders at week 12 in the LMWF-5A arm than historical saline control (65% vs. 43%, p < 0.001). There were no drug-related serious AEs reported and no deaths or withdrawals due to adverse events. Conclusion: LMWF-5A provides relief for the signs and symptoms of severe osteoarthritis, and may be an alternative therapeutic treatment option for patients with severe osteoarthritis of the knee. Keywords: Safety, Efficacy, Osteoarthritis, Intra-articular injection * Correspondence: email@example.com Trauma Research Department, Swedish Medical Center, 501 E. Hampden Ave Rm 4-454, Englewood, CO 80113, USA Ampio Pharmaceuticals, Inc., 373 Inverness Parkway, Englewood, CO 80112, 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. Salottolo et al. Patient Safety in Surgery (2018) 12:11 Page 2 of 7 Background study was to confirm the efficacy of LMWF-5A in a Osteoarthritis (OA) is an incurable and progressive dis- population of patients with severe OAK (KL grade 4), order of the joints involving degradation of the intra- evaluating both the signs and symptoms of OAK. articular cartilage, joint lining, ligaments, and bone. OA affects up to 27 million adults in the US alone . The Methods incidence of developing osteoarthritis of the knee (OAK) Design and setting over a lifetime is approximately 45%, and this number is This was a randomized controlled trial to evaluate the expected to grow because OAK is associated with age, efficacy of a single injection of 4 ml LMWF-5A in obesity, and diabetes . The primary clinical symptoms patients with severe OAK (KL grade 4). Patients were ran- are pain and functional impairment leading to loss of domized 6:1 to LMWF-5A or saline. The trial was per- mobility . The severity of OAK is typically defined in formed in accordance with the principles of Good Clinical stages as noted by Kellgren-Lawrence (KL) grading: Grade Practice guidelines, in compliance with the CONSORT stan- 0 (normal knee; no osteophytes or joint space narrowing), dards, received institutional review board (IRB) approval Grade 1 (possible osteophytic lipping and doubtful nar- across all thirteen sites, and was registered prior to patient rowing of joint space), Grade 2 (definite osteophytes and recruitment (Clinicaltrials.gov identifier: NCT03182686). Pa- possible narrowing of joint space), Grade 3 (moderate tients were enrolled at thirteen sites within the United States multiple osteophytes, definite narrowing of joint space between June 19, 2017 and September 15, 2017 with follow- and some sclerosis, and possible deformity of the bone up and study completion through December 7, 2017. Up- ends) and Grade 4 (large osteophytes, marked narrowing dates to the study protocol that were made after the study of joint space, severe sclerosis, and definite deformity of commenced but prior to study completion, include: changes bone ends) . to secondary endpoints to include the endpoints listed Practice guidelines recommend the use of nonsteroidal below; Inclusion criteria of at least moderate functional anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 impairment (score > 1.5 Western Ontario and McMaster inhibitors, or acetaminophen for the pharmacologic Universities Arthritis (WOMAC®) function subscale) to en- management of pain in OAK (all KL grades) . Steroids sure patients presented with signs and symptoms of OAK. and hyaluronic acid injections have been approved for the treatment of OAK. However, they are not without contro- Test product versy due to varying evidence of efficacy [4, 5]. Further, The test product is LMWF-5A, which is the < 5 kilodalton these products received approval for clinical studies where (kDa) ultrafiltrate of 5% human serum albumin. The start- patients with KL grade 4 disease were excluded, and there ing material, commercial HSA, was subjected to centri- are no published studies examining their use exclusively fugation/ultrafiltration under sterile conditions. The in the KL grade 4 population. As such, there is an unmet ultrafiltrate, containing species with a molecular weight therapeutic need for patients with severe OAK who live less than 5000 Da, was separated. The ultrafiltrate contains with debilitating pain as well as functional and activity aspartyl-alanyl diketopiperazine (DA-DKP, approximately limitations. Patients with severe OAK routinely require a 50–200 μM) and the excipients (i.e. sodium caprylate and total knee replacement due to a lack of effective treatment sodium acetyltryptophanate). The ultrafiltrate was trans- options. Over 700,000 total knee replacements are per- ferred for aseptic filling to afford sterile drug product. DA- formed each year in the United States . This number is DKP has been shown to havemultipleanti-inflammatory expected to spiral to over 3.5 million procedures by 2030, and immune modulating effects [9–13], and is believed to in part because the aging patient population and increas- be one of the active ingredients in the pharmacological ef- ing obesity rates have resulted in increasing OA preva- fects of commercial HSA. lence and severity . LMWF-5A, the < 5 kilodalton (kDa) ultrafiltrate of 5% human serum albumin, is a novel non-steroidal, anti- Participants inflammatory biologic agent which has been shown to Eligible subjects had x-ray findings demonstrating KL effectively reduce pain in patients with severe OAK when grade 4 OAK, with at least moderate pain and functional administered as a single intra-articular (IA) injection [7, 8]. impairment (defined as a score of at least 1.5 on the 5- The molecular components and mechanisms of action of point Likert WOMAC osteoarthritis Index 3.1 pain and LMWF-5A have previously been described [9–13]. function subscales), with the ability to discontinue NSAID LMWF-5A is in development to provide relief for the use at screening for the duration of the study, be fully am- signs and symptoms of severe OAK. Prior trials evaluat- bulatory, have no known clinically significant liver abnor- ing LMWF-5A were conducted in a population with all mality, and between 40 to 85 years old. Subjects also had stages of symptomatic OAK (KL grades 2–4), and exam- to have minimal or no pain in the contralateral knee ined pain as the primary endpoint. The objective of this (pain < 1.5 on the 5-point Likert WOMAC pain subscale). Salottolo et al. Patient Safety in Surgery (2018) 12:11 Page 3 of 7 Exclusion criteria included: a history of allergic reac- function ≥20% and absolute change ≥0.5; iii) PGA ≥ 20% tions to albumin and its excipients; any human albumin and absolute change ≥0.5. treatment 3 months before randomization; concurrent Secondary efficacy endpoints included: a) controlled arthritic conditions or other conditions interfering with responder, defined as an improvement in both WOMAC the free use and evaluation of the index knee (e.g. chon- A pain and WOMAC C function of ≥20% and an abso- dromalacia, presence of tense effusions, acute fractures, lute change of 0.5 points; b) PGA responder, defined as history of aseptic necrosis or joint replacement in the a ≥ 20% improvement and absolute change ≥0.5 points affected knee, inflammatory or crystal arthropathies); in PGA. severe hip OA ipsilateral to the index knee; major sur- gery within 12 months prior to screening; pregnancy; any treatment targeting OAK started or changed 4 weeks Sample size and comparison groups before randomization; use of other IA-injected medica- Two comparators were used for evaluation of efficacy of tions at least 12 weeks (hyaluronic acid) or 4 weeks (ste- LMWF-5A. First, a 30% response to treatment was con- roids) prior to baseline; use of opioids, NSAIDs, topical sidered demonstration of a meaningful response to treat- treatments, significant anticoagulant therapy, immuno- ment of at least minimum efficacy. While the amount of suppressants, corticosteroids, or systemic treatments that improvement required may not be definitively established may interfere with study assessments. and is stated to be between 20%–40% based on best avail- able evidence , the 30% threshold was selected based on Randomization and blinding Initiative on Methods, Measurement, and Pain Assessment Randomization was developed and maintained by an in- in Clinical Trials (IMMPACT) recommendations demon- dependent statistician. Patients were randomized 6:1 to strating 30% represents moderate improvements in chronic receive a single 4 mL intra-articular injection of LMWF- pain intensity in pain trials . A 20–30% result is ex- 5A or saline (0.9% sodium chloride) into the knee joint pected in OA when evaluated by the OMERACT-OARSI space (inferior lateral to the patella). Study drugs were scenario D criteria . TheAmerican CollegeofRheuma- provided in vials labeled with double-panel labels blinded tology (ACR) also uses a 30% response to treatment in the for drug content. Lidocaine injection was not allowed pre- established ACR30 criteria, which evaluates six core do- ceding the administration of study drug. Acetaminophen mains including PGA and physical function . was allowed as pain analgesia during the study as 500 mg The hypotheses were tested as follows: H0: π ≤ π0versus tablets every 4 h, as required. The Sponsor, the investiga- HA:π > π0, where the null hypothesis was a 30% response tors, and all study staff having a role in the day-to-day to treatment (π0). A sample size of 146 patients in the conduct of the study remained blinded to treatment. LMWF-5A arm was calculated to have power greater than 90% when the anticipated proportion of responders under Assessments and endpoints the alternative hypothesis was 45%. The clinical effects of LMWF-5A was evaluated during Second, efficacy of LMWF-5A was evaluated versus a in-clinic visits at baseline, 6 and 12 weeks, and telephone historical saline-control, defined a priori as all patients contacts at 2 and 10 weeks, using the WOMAC osteo- with KL grade 4 disease who were randomized to saline arthritis Index 3.1 5-point Likert score and the Patient’s arm (n = 223) from three previous studies comparing Global Assessment of disease severity (PGA). Clinical LMWF-5A and saline when administered as a single in- benefit was evaluated using the Outcome Measures in jection . The current trial and all previous trials  Rheumatology (OMERACT) - Osteoarthritis Research were identical for selection criteria, treatment arms, Society International (OARSI) (OMERACT-OARSI) re- blinding, randomization (1:1), and safety and efficacy as- sponder criteria. The OMERACT-OARSI response uses sessments. While the study was powered to compare the WOMAC and PGA scales as assessed during the LMWF-5A to a clinically relevant threshold response, in-office visits and phone contacts. the comparison to historical saline was used to ensure a Safety was assessed by recording adverse events and meaningful and quantitative assessment of treatment ef- concomitant mediations (all follow-up contacts), physical fect. The Food and Drug Administration allows com- examination and vital signs (Baseline, Weeks 6 and 12), parison to historical control in its clinical trial guidance and laboratory tests (Screening and Week 12). document . There are currently no approved active The primary endpoint was OMERACT-OARSI response, controls (no IA-injected therapies approved in the severe defined using scenario D as follows: a) Large improvement KL grade 4 OAK population), and no available placebo in WOMAC A pain or in WOMAC C function ≥50% and controls. While saline has historically been used as a absolute change of ≥1 points, or b) moderate improve- control in IA trials, recently saline has demonstrated a ments in at least 2 of 3 response domains: i) WOMAC A pronounced therapeutic effect when administered as an pain ≥20% and absolute change ≥0.5; ii) WOMAC C IA injection into the knee [19–21]. Salottolo et al. Patient Safety in Surgery (2018) 12:11 Page 4 of 7 Statistical analysis causes severe discomfort, daily activities are significantly Statistical analyses were performed using SAS® software, impaired or prevented). Serious adverse events (SAEs) version 9.3 (SAS Institute, Cary, NC). Efficacy endpoints were defined as untoward medical occurrences resulting were analyzed in the intent-to-treat population (as random- in death, in-patient hospitalization, persistent or signifi- ized). For the primary effectiveness endpoints (WOMAC cant disability/incapacity, or were life-threatening. A, WOMAC C, and PGA), missing Week 12 values were imputed using the Worst Observation Carried Forward Results (WOCF) method, which is a more conservative approach Of 168 subjects, 144 subjects were randomized to LMWF- to imputation than the last observation carried forward 5A and 24 subjects were randomized to saline (Fig. 1). Pa- (LOCF) approach when patients are expected to improve tients were randomized across 13 sites, with no site effect over time, and is frequently used in analgesia drug trials. observed (p = 0.82). All 144 subjects treated with LMWF- All endpoints were defined a priori. 5A were included in the analysis. Missing data accounted The efficacy endpoints were tested in a hierarchical for 2.0% of all efficacy assessments, and 4.2% (n =7) of pa- manner, as the primary (OMERACT-OARSI responder), tients had WOCF values imputed for the primary endpoint and then secondary endpoints of controlled responder, at week 12. then PGA responder, then controlled responder com- Baseline data is shown in Table 1. Just over half of pared to historical saline. The primary and secondary subjects were female (52%), the average age was 63 years, efficacy endpoints were reported as proportions (%). A and the average baseline pain was 2.5 (0.6) on a 0–4 one-sided exact binomial test was used for comparison scale. There were no clinically meaningful imbalances of LMWF-5A to the 30% threshold (OMERACT re- between LMWF-5A, saline, and historical saline in demo- sponder, controlled responder, PGA responder); statis- graphics or baseline WOMAC subscores. tical significance was set at p value < 0.025. The Fisher’s exact test was used for comparison of LMWF-5A to his- torical saline for controlled responders; statistical signifi- Primary efficacy endpoint cance was set at p value < 0.05. Overall, 71% (95% CI: 63%–78%) of subjects treated with Adverse events (AEs) were examined in all patients LMWF-5A met the OMERACT-OARSI responder criteria, who were randomized. Missing or incomplete AE data which exceeded the 30% threshold for clinical benefit was assumed to be a severe, related AE. Adverse events (p < 0.001), Table 2. Responders experienced, on average were tabulated for incidence and severity; severity was a 53% decrease in pain as measured by WOMAC A defined as mild (symptom barely noticeable to the sub- and a 50% improvement in function as measured by ject), moderate (symptom is of sufficient severity to WOMAC C and a 45% improvement in quality of life make the subject uncomfortable), and severe (symptom as measured by PGA. Treatment with LMWF-5A resulted Fig. 1 CONSORT flowchart Salottolo et al. Patient Safety in Surgery (2018) 12:11 Page 5 of 7 Table 1 Demographics and baseline characteristics Mean (SD) LMWF-5A (n = 144) Saline (n = 24) Historical saline (n = 223) Female sex, % (n) 52.8 (76) 50.0 (12) 51.6 (113) Age, years 62.7 (9.6) 64.0 (6.3) 63.1 (8.6) BMI (lb/in2) 32.7 (6.4) 31.4 (6.3) 34.4 (7.9) Caucasian race 77.1 (111) 66.7 (16) 88.8 (198) Patient global assessment (PGA) 2.8 (0.8) 2.7 (0.8) 2.6 (0.8) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) WOMAC Pain 2.5 (0.6) 2.4 (0.4) 2.3 (0.6) WOMAC Stiffness 2.8 (0.7) 2.8 (0.6) 2.5 (0.7) WOMAC Function 2.6 (0.5) 2.5 (0.5) 2.4 (0.6) in a significant response using OMERACT-OARSI criteria Safety at all assessed time points (p < 0.001 for all, Table 2). Adverse events were reported for 49 (34.0%) LMWF-5A- treated patients (Table 3). Themostcommonlyoccurring AE was arthralgia, reported in 19 (13.2%) patients treated Secondary efficacy endpoints with LMWF-5A. The majority of AEs were of minor or The percent of subjects in the LMWF-5A arm that met moderate severity and unrelated to treatment. There were the controlled responder criteria was 65% (95% CI: 57%– no SAEs. AEs reported in this trial are in line with what 72%), which was significantly greater than the threshold of has been reported in previous trials of LMWF-5A of over 30% (p <0.001), Table 2. Further, the proportion of sub- 2000 patients (Table 3). In both trials the most commonly jects that met controlled responder at weeks 2, 6, 10, 12 occurring AE was arthralgia, which is considered a typical was significantly greater than the established threshold, at AE for IA injection trials in patients with OAK. all time points (p < 0.001, Table 2). The percent of subjects treated with LMWF-5A that Discussion were PGA responders was 66% (58%–74%), exceeding This trial was designed to follow on from the completed the 30% threshold (p < 0.001), Table 2. The proportion of single-injection LMWF-5A studies previously described  subjects that met PGA responder at weeks 2, 6, 10, 12 and confirmed the efficacy of an IA injection of LMWF-5A. was significantly greater than the established threshold, This trial explored the clinical impact of LMWF-5A on the at all time points (p < 0.001 for all, Table 2). signs and symptoms of severe OAK using the criteria devel- When compared to 223 historical saline controls, the oped by OMERACT-OARSI. Using these established cri- percent of subjects that met the controlled responder teria, 71% of patients treated with LMWF-5A responded to criteria at week 12 was significantly greater in the treatment, with clinically meaningful improvements in pain LMWF-5A arm than the historical control arm (65% vs. and function, supported by improvements in overall global 43%, p < 0.001). The percent of subjects meeting con- assessment of disease. There were no drug-related serious trolled responder criteria was also significantly greater for LMWF-5A vs. historical control at week 10 (62% vs. Table 3 Summary of Adverse Events (AEs) 47%, p = 0.007) and week 6 (58% vs. 43%, p = 0.005), but Endpoint LMWF-5A KL LMWF-5A KL Saline KL was similar at week 2 (54% vs. 49%, p = 0.33). grade 4 grade 2–4 grade 2–4 (n = 144) (n = 1076) (n = 931) One or more AE 49 (34.0%) 381 (35.4%) 386 (41.5%) Table 2 Summary of efficacy Responder rate, OMERACT- Controlled PGA responder One or more related AE 10 (6.9%) 11 (1.0%) 19 (2.0%) % (95% CI) OARSIResponder Responder AE by severity Week 2 66.0 (58.2–73.7) 54.2 (46.0–62.3) 66.0 (58.2–73.7) mild 25 (17.4%) 264 (24.5%) 253 (27.2%) Week 6 66.0 (58.2–73.7) 58.3 (50.3–66.4) 61.8 (53.9–69.7) moderate 22 (15.3%) 162 (15.1%) 190 (20.4%) Week 10 72.2 (64.9–79.5) 61.8 (53.9–69.7) 72.9 (65.7–80.2) severe 2 (1.4%) 35 (3.3%) 32 (3.4%) Week 12 70.8 (63.4–78.3) 64.6 (56.8–72.4) 66.0 (58.2–73.7) Serious AE (SAE) 0 (0%) 15 (1.4%) 20 (2.1%) CI confidence interval, OMERACT-OARSI Outcome Measures in Rheumatology AE leading to withdrawal 0 (0%) 0 (0%) 0 (0%) (OMERACT) - Osteoarthritis Research Society International (OARSI), PGA Patient Global AE resulting in death 0 (0%) 0 (0%) 0 (0%) Assessment. Efficacy endpoints were analyzed with one-sided exact binomial test compared to null hypothesis of 30% responder rate. P < 0.001 for all Subjects could have AEs in more than one severity category. KL, responder rates at all time points Kellgren Lawrence Salottolo et al. Patient Safety in Surgery (2018) 12:11 Page 6 of 7 AEs associated with treatment with LMWF-5A. The safety Availability of data and materials The datasets used and/or analysed during the current study are available and tolerability profile of LMWF-5A is consistent with pre- from the corresponding author on reasonable request. vious studies. To date, treatment with LMWF-5A has re- sulted in no reported drug-related SAEs. Authors’ contributions Ms. S is responsible for interpretation of data, and drafting the manuscript. Clinical trials that evaluate symptom-modifying effects Dr. C is responsible for data interpretation and critical revisions. Dr. B-O is of treatment often examine composite endpoints that responsible for interpretation of the data and drafting the manuscript. All incorporate the main symptoms of OAK (pain and func- authors provided final approval of the submitted manuscript. tional limitations). One of the most widely established com- Ethics approval and consent to participate posite endpoints is the OMERACT-OARSI responder  The study was approved from the Schulman Institutional Review Board with because it addresses clinically important and statistically documentation of informed consent. significant improvements. In prior trials that reported Competing interests OMERACT-OARSI responders, rates were reported to Dr. Bar-Or reports personal fees from Ampio Pharmaceuticals Inc., during the be 50–70% with active treatment across all severity of conduct of the study; In addition, Dr. Bar-Or has 120 issued patents and 80 OAK (KL grades 1–4) [22–27]. The favorable responder pending. Dr. Bar-Or is an employee of Ampio Pharmaceuticals, Inc. and serves as the chief Scientific officer of Ampio Pharmaceuticals and own rate of 71% observed in this study was in a subset with stocks and stock options in the company. Ampio is developing LMWF-5A for KL grade 4 OAK. Patients with severe disease have the treatment of OA of the knee. Mrs. Salottolo reports personal fees from been shown to have a lower response to treatment than Ampio Pharmaceuticals, Inc., and own stocks and stock options in the company. Dr. Cole reports conflicts outside the submitted work including: personal fees and patients with less severe OAK . other from Arthrex, other from Arthroscopy; other from Aesculap/B.Braun, other There are limitations. First, patients were randomized from American Journal of Orthopedics, other from American Orthopaedic Society to saline to maintain blinding, but since it is not a true for Sports Medicine, other from American Shoulder and Elbow Surgeons, personal fees and other from Arthrex, Inc., other from Arthroscopy Association of North placebo, [19–21] it was not used as the comparator or America, other from Athletico, other from Carticept, other from Cytori, other from powered to make inference about patients receiving DJ Orthopaedics, other from Elsevier Publishing, other from International Cartilage saline. This trial was designed using FDA guidance to Repair Society, other from Journal of Bone & Joint Surgery - American, other from Journal of Shoulder and Elbow Surgery, other from Journal of the American address the methodological issues in trial design where Academy of Orthopaedic Surgeons, other from Medipost, other from National there is the absence of a true available control, such as Institutes of Health (NIAMS & NICHD), other from Ossur, personal fees and other when there are no licensed or approved active comparators from Regentis, other from Saunders/Mosby-Elsevier, other from Smith & Nephew, other from Tornier, personal fees and other from Zimmer, other from in this distinct OAK population and where the previously Arthroscopy. used placebo control has been shown to be therapeutic. Second, imaging or biomarker data were not collected, and Publisher’sNote all outcomes were based on patient-reported outcome Springer Nature remains neutral with regard to jurisdictional claims in measures. Third, study participants were followed until published maps and institutional affiliations. week 12. An open label extension study is currently Author details being conducted to determine the clinical benefit of Trauma Research Department, Swedish Medical Center, 501 E. Hampden LMWF-5A through 52 weeks (Clinicaltrials.gov identi- Ave Rm 4-454, Englewood, CO 80113, USA. Department of Orthopedics, fier: NCT03349645). Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA. Ampio Pharmaceuticals, Inc., 373 Inverness Parkway, Englewood, CO 80112, USA. 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Patient Safety in Surgery – Springer Journals
Published: Jun 18, 2018
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