Efficacy and Safety of Intra-Articular Hyaluronic Acid Injection (NRD101 / SUVENYL®) in Patients With Knee Osteoarthritis: a Multicenter, Randomized, Double-blind, Parallel, Active Control, Non-Inferiority Clinical Study

Abstract

Background

Intra-articular injection of hyaluronic acid (HA) has favorable effects on pain relief and knee function along with the low incidence of serious adverse reactions. Although various HA products are available for the treatment of knee osteoarthritis, it is still controversial whether differences in HA products have any clinically significant difference in efficacy and safety. In light of the above, the efficacy and safety of intra-articular injection of biological fermentation–derived high-molecular-weight HA (NRD101) was investigated in a double-blind comparative manner in Chinese patients with knee osteoarthritis.

Method

A multicenter, prospective, randomized, double-blind, parallel, active control, non-inferiority study was conducted in Chinese patients with knee osteoarthritis. Patients were randomized to receive five consecutive weekly injections of either NRD101 or Artz (a non-crosslinked low-molecular-weight HA derived from combs of roosters) followed by 4 weeks follow-up. The primary efficacy endpoint was the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) NRS pain subscale score at Week 5. Secondary efficacy endpoints included WOMAC stiffness and physical function subscale score, local pain, range of joint motion, and overall improvement.

Results

Among 267 randomized patients, 259 patients completed the study. The change from baseline in WOMAC NRS pain subscale score at Week 5 was −2.98 ± 0.193 in the NRD101 group and −2.66 ± 0.194 in the Artz group, and the trial met the non-inferiority criteria. Efficacy in the NRD101 group tended to be consistently higher than in the Artz group for most items of WOMAC. Several subgroup analyses also showed differences between the two groups, tending to favor NRD101. Adverse events were seen in 26.0% (34/131) of patients in the NRD101 group and 38.3% (51/133) in the Artz group.

Conclusions

NRD101 improved knee pain in Chinese patients with osteoarthritis after five consecutive weekly injections. NRD101 tended to be somewhat more effective than Artz. No new safety concerns were identified.

Trial registration: JapicCTI, JapicCTI-173531. Registered 10 March 2017, https://www.clinicaltrials.jp/cti-user/trial/Search.jsp

Introduction

Knee osteoarthritis is a degenerative disease of the knee joint involving progressive damage to the cartilage and joint against the background of genetic alterations, menopause-related estrogen deficiency, and aging (1). Pain in the damaged joints can severely interfere with activities of daily living. Knee osteoarthritis is one of the leading causes for reduced quality of life (2). In countries with aging populations, the numbers of patients with knee osteoarthritis are increasing (3). It has also been shown that older Chinese, especially women, have a higher prevalence of knee osteoarthritis than does the US white population (4). Knee osteoarthritis is becoming a major public health problem in China due mainly to the rapidly aging population(5).

Hyaluronic acid (HA) is commonly regarded as one of the most important components of the synovial fluid, and the concentration and the molecular weight of hyaluronic acid in the synovial fluid decrease as osteoarthritis progresses (6). The main purpose of intra-articular HA injections (IA-HA) is to restore the elasticity and viscosity of the synovial fluid to protect against the degradation of cartilage. The modality of IA-HA has received favorable clinical attention because of its beneficial effects on pain relief and knee function and the low incidence of serious adverse reactions (7, 8).

Various HA products are now available for clinical use, each with differing molecular weights (ranging from 500 to 6000 kDa), molecular structure (crosslinked or non-crosslinked), process of manufacturing (animal-derived or biological fermentation–derived), and so on (9). NRD101 (marketed under the brand name of SUVENYL®) is a high-molecular-weight (HMW) HA product (average 1500–3900 kDa) produced by a biological fermentation process. NRD101 was confirmed by randomized controlled trial (RCT) to have greater effectiveness in the treatment of knee osteoarthritis in Japanese patients compared with an avian-derived low-molecular-weight (LMW) HA product (averaging 500–1200 kDa) (10). Although there are conflicting reports as to whether differences in HA products have any clinically significant difference in efficacy and safety (11), several RCTs have shown that LMW HA products of 800–1500 kDa are superior to other HA products of lower molecular weight (500–730 kDa) in efficacy with a similar safety profile (12) and that biological fermentation–derived HMW HA (2400–3600 kDa) has a better safety profile than that of avian-derived crosslinked HMW HA (6000 kDa) with comparable efficacy (13).

In light of the above, we conducted a multicenter, prospective, randomized, double-blind, positive-drug, parallel, active control, non-inferiority study to compare the efficacy and safety of IA injection of biological fermentation–derived HMW HA (NRD101) with that of avian-derived LMW HA (Artz) in Chinese patients with knee osteoarthritis.

Methods

Results

Patient disposition and demographics

A total of 351 patients were screened from 14 sites. Of these, 84 failed screening, and finally 267 patients were randomized, including 133 in the NRD101 group (test group) and 134 in the Artz group (control group). Among all randomized patients, 259 patients (97%) completed the study and 8 patients (3%) discontinued the study (Fig. 1). The reasons for early discontinuation were as follows: five patients withdrew consent, including two from the NRD101 group and three from the Artz group; two patients discontinued due to the occurrence of an AE, all in the Artz group; one patient in the NRD101 group was withdrawn due to being mistakenly injected with Artz (this discontinuation was at the suggestion of the site’s ethics committee). In whole, the persistence rate of subjects in this study remained high, and there was no clear difference in early discontinuation between the two groups.

For analysis set classification, 264 subjects were included in the safety analysis set, including 131 in the NRD101 group and 133 in the Artz group; 250 subjects were included in the full analysis set, including 127 in the NRD101 group and 123 in the Artz group; 230 subjects were included in the per protocol set, including 118 in the NRD101 group and 112 in the Artz group. Three subjects were excluded from the safety analysis set due to a violation of the informed consent process (an unblinded investigator signed the informed consent form as an impartial witness of these illiterate subjects).

Of the 250 patients in the full analysis set, 82.0% were female, the mean age was 60.9 ± 8.19 years old, and the mean body mass index was 25.3 ± 3.39 kg/m². The mean baseline of WOMAC NRS pain was 6.60 ± 1.135, and the median duration of chronic pain of study knee was 1.88 years. For K-L grade, 48.8% of subjects were judged as Grade 2. There was no difference in baseline characteristics between the two groups (Table 1).

Efficacy outcomes

In the full analysis set, the change in WOMAC NRS pain from baseline on a Last Observation Carried Forward basis at Week 5 was −2.98 ± 0.193 points in the NRD101 group and −2.66 ± 0.194 points in the Artz group; the difference between the two groups was 0.33 ± 0.258 points with a 95% CI of −0.18 to 0.83 points. The lower limit of 95% CI was −0.18 points, which was not below the non-inferiority margin of −0.925 points. Therefore, it is considered that the NRD101 group was not inferior to the Artz group, and the trial attained the primary efficacy end point. The improvement in WOMAC pain in the NRD101 group tended to be greater than in the Artz group from Week 3 to the end of the study (Fig. 2). The change in WOMAC NRS stiffness from baseline at Week 5 was −2.63 ± 2.393 points in the NRD101 group and −2.21 ± 2.422 points in the Artz group, and the change in WOMAC NRS physical function was −2.48 ± 2.155 in the NRD101 group and −2.31 ± 1.986 in the Artz group. For most items of the WOMAC, the NRD101 group consistently tended to show greater improvement from baseline at Week 5 than did the Artz group (Table 2). On the other hand, rates of improvement of local pain were similar between the NRD101 and Artz groups (Table 3). The range of motion in the joint was significantly improved compared with baseline in both treatment groups although no difference between the groups was observed. The mean change in maximum extension angle (degree) from baseline at Week 5 was −1.13 (95% CI −1.70, −0.55) in the NRD101 group and −1.22 (95% CI −1.76, −0.68) in the Artz group; the mean change in maximum flexion angle (degree) from baseline at Week 5 was 7.48 (95% CI 5.66, 9.30) in the NRD101 group and 5.93 (95% CI 4.13, 7.72) in the Artz group. The number of patients showing an overall improvement ([number showing ≤2-point change from baseline]/[total number of patients]) at Week 5 was higher in the NRD101 group (60.0%) than in the Artz group (53.4%), but no statistically significant difference was observed between the two groups (odds ratio: 1.31, [95% CI 0.79, 2.18]).

The results of the pre-specified subgroup analyses of primary outcome (WOMAC NRS pain change at Week 5) were essentially consistent with the results in the overall population, with NRD101 tending to be more effective than Artz in most subgroups (Table 4). Among them, NRD101 showed the tendency of greater pain reduction than Artz in the subgroup of patients whose duration of chronic pain was >1 year and ≤5 years (difference: −1.01 [95% CI −1.83, −0.19]) and patients whose body weight was >50 kg and ≤60 kg (difference: −1.22 [95% CI −2.23, −0.21]).

Overall, there was no difference in the use of acetaminophen as a rescue therapy between the two groups.

Safety

Among all subjects in the safety analysis set, the percentage of subjects with AEs was 32.2% (85/264): 26.0% (34/131) in the NRD101 group and 38.3% (51/133) in the Artz group (Table 5). The most common AEs were viral upper respiratory tract infection 5.3% (14/264), upper respiratory tract infection 3.8% (10/264), and arthralgia 3.0% (8/264). There was no difference between the two groups in the incidence of arthralgia (3.1% [4/131] for NRD101 and 3.0% [4/133] for Artz). As for injection site–related events, there was only one subject with injection site erythema and one subject with injection site pain in the NRD101 group, and one subject with injection site rash in the Artz group. The proportion of subjects who experienced severe AEs was 0.8% in the NRD101 group and 2.3% in the Artz group. Two out of 264 subjects (0.8%) developed serious AEs: sleep apnea syndrome (one event in one subject in the NRD101 group) and hypertension worsened (one event in one subject in the Artz group). Neither serious AE was related to the study drug, and the dose of study drug remained unchanged. Among all subjects in the safety analysis set, 14 (5.3%) experienced 20 adverse reactions: 4.6% (6/131) in the NRD101 group and 6.0% (8/133) in the Artz group. AEs leading to discontinuation occurred only in the Artz group (one subject due to arthralgia and plica syndrome, one subject due to rash). No subject died during the study. Thus, no new safety concerns were identified throughout the study.

Discussion

In this study, we evaluated the efficacy and safety of five consecutive intra-articular injections of HMW HA derived from a biological fermentation process (NRD101) into patients with osteoarthritis of the knee, and we succeeded in verifying its non-inferiority to avian-derived LMW HA (Artz) in the symptomatic improvement of pain. In addition, for many efficacy endpoints (e.g., treatment effect in each domain of WOMAC, overall improvement, etc.), NRD101 tended to be consistently more effective than Artz. Furthermore, statistically significant differences were observed in some subgroup analyses of WOMAC pain reduction, while the opposite result (the effect of Artz being significantly greater than NRD101) was not observed in any of the pre-defined subgroup analyses, suggesting that HMW HA may be more powerful than LMW HA in terms of control of clinical symptoms. These findings are essentially consistent with the results of previous RCTs in which NRD101 or intermediate-molecular-weight HA (GO-ON; Rottapharm Madaus, Monza, Italy) were found to have better efficacy than LMW HA (10, 12). A head-to-head RCT designed to confirm superiority is considered necessary to conclude whether the differences in efficacy observed here are truly clinically meaningful or not.

In terms of safety, there were trends toward fewer AEs in the NRD101 group than in the Artz group , and the numbers of severe AEs, adverse reactions to the HA preparation, and AEs leading to trial discontinuation also tended to be less in the NRD101 group than in the Artz group. These two formulations have different manufacturing processes: NRD101 is a HA derived from a biological fermentation process, and Artz is avian-derived HA. These differences might influence safety outcomes. A systematic review that aimed to determine product differences in HAs for osteoarthritis of the knee showed that biological fermentation–derived HAs caused a significantly smaller incidence of effusion compared with avian-derived HAs, and also the former demonstrated fewer acute flare-ups at the injection site than did the latter (15). Nevertheless, in the current study, the incidence rates of AEs of interest, such as injection site–related events and arthralgia were not different between the two groups; therefore, it is impossible to rule out the possibility that the differences in incidence rates of AEs observed in this study were a chance result. In addition, in recent years, potential safety concerns have arisen about whether crosslinked HMW HA may pose a higher risk of injection site–related events such as painful acute local reactions (16). Thus, further investigations including real-world data are required in order to clarify the differences in safety profiles among different HA formulations.

NRD101 has the intrinsic properties of endogenous HA, especially in terms of molecular weight and production process. The molecular weight of NRD101 is comparatively high but is regarded as close to that of endogenous HA in healthy knee joints (17). In addition, NRD101 is produced by a biological fermentation process (and is not animal-derived), without artificial cross-linking. The results of this study and accumulated evidence suggest that NRD101 may provide a better effect with respect to symptomatic pain and function with fewer AEs compared with animal-derived LMW HAs, and may also have a better safety profile than that of artificially crosslinked HMW HA products.

However, this study has a number of several limitations. First, this study was not a placebo-controlled study. In trials of knee osteoarthritis, intra-articular saline injections are usually employed as the “placebo” control (IA-placebo). In some previous trials examining the treatment effect of IA-HA compared with IA-placebo, results obtained were not consistent, probably due to the lack of unity of the trial designs (18, 19), and there is still uncertainty with regard to the therapeutic effects of different types of HA products on knee osteoarthritis (16). Therefore, in this study, we carefully considered which comparator drug to use and we selected Artz, which has robust evidence showing efficacy and safety superior to that of IA-placebo. For instance, its superiority over IA-placebo has been strongly confirmed by an individual-patient-data-driven meta-analysis selecting only clinical trials that used Artz (20). Although our study results combined with the evidence of Artz suggest that NRD101 would be superior to IA-placebo in symptomatic endpoints, there is no doubt that direct comparison with IA-placebo would provide more robust evidence. Second, the planned observations were of relatively short-term clinical symptoms and functional improvement. In other words, the study period was just 8 weeks including 4 weeks after the end of the last dose, and it was not designed to observe long-term effects. Although the carryover effect of repeated IA-HA has been reported for other HA products (21), it is not realistic to extrapolate that data to NRD101 directly. Third, the effect on cartilage preservation was not assessed in this study. Recent clinical evidence in patients with knee osteoarthritis has shown that IA-HA extends the period before total knee replacement surgery is required (22) and preserves knee-joint cartilage (23). NRD101 showed a preventive effect on cartilage destruction in a rabbit model of knee osteoarthritis induced by partial meniscectomy (24), but its actual effect on humans is still unclear. Altman et al. (17) suggested on the basis of basic research that a higher molecular weight HA product might provide better chondroprotective effects. Disease modification properties including preservation of cartilage are clinically important and need to be investigated through RCTs with different HA products.

Conclusions

In conclusion, NRD101 as a biological fermentation–derived HMW HA product improved knee pain in patients with osteoarthritis after five consecutive weekly injections, and was non-inferior to Artz. In addition, NRD101 tended to be consistently more effective than Artz in most items of WOMAC, and several subgroup analyses showed significant differences between the two groups, favoring NRD101. No new safety concerns were identified. On the other hand, it is not possible to conclude whether the differences seen here between the two HA products truly contribute to improved clinical benefit, necessitating a superiority trial on a larger scale and with a longer follow-up period.

Abbreviations

ACR: American College of Rheumatology; AE: Adverse event; CI: Confidence interval; HA: Hyaluronic acid; HMW: High-molecular-weight; IA-HA: Intra-articular HA injections; K-L: Kellgren–Lawrence; LMW: Low-molecular-weight; NRS: Numeric rating scale; OARSI: Osteoarthritis Research Society International; RCT: Randomized controlled trial; VAS: Visual Analogue Scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index

Declarations

Funding

This study was funded by Chugai Pharmaceutical Co., Ltd. The sponsor planned this study and implemented data collection, analysis, and interpretation in conjunction with the lead principal investigator and scientific advisor. The sponsor also provided editorial and writing support for this manuscript.

Ethics approval and consent to participate

This study was conducted in accordance with the principles laid down by the Declaration of Helsinki (Edinburgh, 2008), and was also conducted in compliance with Good Clinical Practice (GCP) and the national laws and regulations of China. The study conduct was approved by the China Food and Drug Administration (Approval No. 2016L08917). The protocol was approved by the ethics committee at each center, and informed consent was obtained from each patient.

Consent for publication

Not applicable

Acknowledgements

The following investigators participated in this trial: Qingyun Xue, Beijing Hospital; Qing He, Navy General Hospital PLA China; Jingmin Huang, Tianjin Hospital; Biao Cheng, Shanghai Tenth People’s Hospital; Liaobin Chen, Zhongnan Hospital of Wuhan University; Zhanjun Shi, Nanfang Hospital, Southern Medical University; Lijun Liu, Shenzhen Second People’s Hospital; Yaping Li, General Hospital of Ningxia Medical University; Shijun Gao, The Third Hospital of Hebei Medical University. R&G PharmaStudies Co., Ltd. (Beijing, China) also supported this study as a contract research organization.

Authors’ contributions

Haoyang Wang and Wei Wang participated in interpretation of the study data and drafted this article. Zongke Zhou and Xisheng Weng contributed to study planning and design, and critically revised the manuscript for important intellectual content. Ryota Kobayashi supported the implementation of this study and provided administrative, technical, and logistic support. Yuya Matsuda provided statistical expertise and led data analysis and interpretation. Yongsheng Xu, Jianan Li, and Kang Liu contributed to patient enrolment for the study. All authors have made substantial contributions to the review and final approval of this manuscript.

Competing interests

HW, WW, YX, JL, KL, ZZ and XWeng declare that they have no conflict of interest. RK and YM are employees of Chugai Pharmaceutical Co., Ltd.

Availability of data and materials

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). For further details on Chugai’s Data Sharing Policy and how to request access to related clinical study documents, see www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html.

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Tables

Table 1. Baseline demographics (full analysis set)

SD = standard deviation; BMI = body mass index; NRS = numeric rating scale; KL = Kellgren–Lawrence

Table 2.  Forest plot of changes from baseline for each item of WOMAC at Week 5 (full analysis set)

Categories of WOMAC (24 items):

Pain (5 items): walking on flat surface (A01), going up or down stairs (A02), at night while in bed (A03), sitting or lying (A04), and standing upright (A05)

Stiffness (2 items): after first awakening in the morning (B06) and after periods of inactivity later in the day (B07)

Physical function (17 items): descending stairs (C08), ascending stairs (C09), getting out of a chair (C10), remaining in a standing position (C11), bending to pick something up off the floor (C12), walking on a flat surface (C13), getting in and out of a car (C14), going shopping (C15), putting on socks or stockings (C16), getting out of bed (C17), taking off socks or stockings (C18), lying in bed (C19), getting in and out of the bathtub/shower (C20), remaining in a sitting position (C21), getting on or off the toilet (C22), performing heavy domestic duties (C23), and performing light domestic duties (C24)

Table 3.  Improvement rate for local pain* (full analysis set)

*As assessed by an investigator.

Table 4.  Pre-defined subgroup analysis of primary outcome (change in WOMAC NRS pain at Week 5) (full analysis set)

Table 5.  Complications (safety analysis set)

AE = adverse event