Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study

Lugo et al. Nutrition Journal (2016) 15:14 DOI 10.1186/s12937-016-0130-8 RESEARCH Open Access Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study James P. Lugo1, Zainulabedin M. Saiyed1 and Nancy E. Lane2* Abstract Background: Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis (OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin sulfate (GC). Methods: One hundred ninety one volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G & 1200 mg C), or placebo for a 180-day period. The primary endpoint was the change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis were performed for all endpoints using analysis of covariance and mixed model repeated measures, while incremental area under the curve was calculated by the intent-to-treat method. Results: At day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04). Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo). Safety outcomes did not differ among the groups. Conclusion: UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional studies that elucidate the mechanism for this supplement’s actions are warranted. Trial registration: CTRI/2013/05/003663; CTRI/2013/02/003348. Keywords: Knee function, Osteoarthritis, T regulatory cell, Undenatured type II collagen * Correspondence: 2 Center for Musculoskeletal Health, University of California Davis Health System, 4625 2nd Avenue, Suite 2006, Sacramento, CA 95817, USA Full list of author information is available at the end of the article © 2016 Lugo et al. 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. Lugo et al. Nutrition Journal (2016) 15:14 Introduction Osteoarthritis, which entails the destruction of joint cartilage and remodeling of the adjacent bone, is the most common form of arthritis affecting more than 25 million Americans [1]. Current therapies for OA include various over the counter analgesics, a number of nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections of corticosteroids or hyaluronic acid, plus tramadol and other opioid analgesics to relieve severe pain [2, 3]. While these therapies can alleviate symptoms in the near term, their ultimate impact on the pathophysiologic progression of OA is limited [4]. Previous studies reported UC-II to be efficacious for the treatment of arthritis [5, 6]. More recently, a statistically significant improvement in knee joint function over placebo was also reported in a clinical study comprising a group of healthy individuals, supplemented with UC-II, and who developed transient knee joint pain upon strenuous exercise [7]. These same individuals also took longer to experience pain after 120 days of supplementation. Based on these observations, the current study was designed to evaluate the efficacy of UC-II in knee OA subjects compared to placebo and to GC, which is a widely available supplement that is used for reducing joint pain. Materials and methods Investigational products The study product UC-II® (Lot 1204004) was derived from chicken sternum. It was manufactured under current good manufacturing practice (cGMP) conditions using a patented process that preserved its native structure (Chick Cart Inc., Fort Smith, AR). Both glucosamine hydrochloride (GH) and chondroitin sulfate (CS) were purchased through Wilke Resources (Lenexa, KS). The Wellable group (Shishi City, Fujian) manufactured GH under cGMP and according to United States Pharmacopeia 26 specifications. Sioux Pharm (Sioux Center, IA) manufactured bovine-derived CS under cGMP. UC-II and GC were encapsulated in opaque, size “00” capsules with sufficient amounts of excipients (microcrystalline cellulose and silicon dioxide) such that they were sensory identical to placebo. InterHealth Nutraceuticals provided all study materials. All American Pharmaceutical (Billings, MT) verified the amount of active ingredients in the study capsules. Study materials were kept in a secure cabinet with access restricted to the site coordinator, the dispensing pharmacist, and the principal investigator. Study design The objective of this randomized, double-blind, placebocontrolled clinical study was to evaluate the ability of UC-II to improve knee symptoms in OA subjects, as Page 2 of 15 measured by overall WOMAC score, compared to placebo and to GC. The trial was conducted at 13 centers in southern India. Because of a limitation in synovial fluid sampling procedures at multiple clinical sites, the study was conducted under two separate study protocols. Study protocols were approved by each center’s Institutional Ethics Committee (IEC), and listed on the clinical trial registry of India as study protocols 003663 and 003348. Enrollment, randomization, and follow-up visits were identical for both protocols, and were carried out at days 1 (baseline), 7, 30, 60, 90, 120, 150 and 180 (Table 1). All investigators attended the same investigator meetings, used identical intake and data reporting forms, and were trained and monitored by the same group of clinical research associates. Efficacy measurements were assessed at all visits and included WOMAC, VAS, and LFI indices. The knee flexion range of motion (ROM) test was performed at each visit. Subject diaries and study product were provided at all visits, except day 180 and were collected at all follow-up visits. Subjects were instructed to record daily the consumption of study product, use of rescue medication, as well as concomitant medications in the subject dairy for the entire duration of the study. Blood and urine were collected at screening and day 1 (...truncated)