Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren–Lawrence grade 1–4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was − 54.0 ± 38.1% in the IA PN group and − 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.
Intra-articular (IA) injection therapy has an important role in the treatment of osteoarthritis, especially in patients with insufficient response to medication or comorbidities that restrict medical treatment[
Intra-articular polynucleotide (IA PN) has been proposed as an alternative of IA HA for viscosupplementation over the past decade[
Several studies have compared the efficacy and safety of IA PN and HA, and IA PN has shown comparable or superior clinical outcomes than those of IA HA. Vanelli et al[
However, previous comparative studies have mainly used only low or medium MW HAs, and studies that have used IA HMWHA or cross-linked HA as a control for IA PN are very limited. Considering that many studies have reported the superior efficacy of IA HMWHA compared to low-or medium MWHA[
Therefore, the present randomized controlled study aimed to investigate the efficacy and safety of IA PN compared with IA HMWHA in the treatment of knee OA. We hypothesized that IA PN could be a useful alternative of HMWHA in the treatment of knee OA.
The PN used in this clinical study was Conjuran® (PharmaResearch, Gangneung-si Kangwon-do, Republic of Korea). A prefilled syringe containing 2 ml of viscoelastic PN solution 20 mg/ml that was extracted from salmon. It was approved as a medical device in Korea for physical viscosupplementation in patients with knee OA. The HA used in this study was Hyruan Plus
The present randomized, double-blind, multicenter (two investigational sites) study was conducted from January 2020 to March 2021. After patient screening and a wash-out period of two weeks, 60 patients with symptomatic knee OA were randomly allocated to each group (PN or HMWHA) using the block randomization method (Microsoft Excel
Sixty patients with symptomatic knee OA diagnosed based on the American College of Rheumatology Classification[
All patients received three IA PN (20 mg/ml) injections or three IA HMWHAs (20 mg/2 ml) injections at intervals of 1 week. In each institute, the injection was aseptically administered by an independent, skillful orthopedic surgeon. The first injection was administered at the beginning of the treatment (baseline), and the second and third injections were administered at 1 week and 2 weeks from the baseline, respectively. After three IA injections, patients were followed up at 8 weeks and 16 weeks for clinical evaluation. During the study period, use of Acetaminophen (≤ 4 g/day) were allowed for the pain rescue drug (Fig. 1).
Graph: Figure 1Study flow diagram.
The primary endpoint of this study was the VAS (100-mm) change rate for WBP at 16 weeks compared with baseline. The secondary endpoints were as follows: (
The sample size was calculated using an a priori power analysis. Based on previous literature that reported mean VAS difference of 1.7 mm with a standard deviation of 1.8 mm at 16 weeks after IA PN injection (α = 0.05, β = 0.8), it was expected that at least 19 cases were required for each group. Anticipating possible loss, 30 patients were enrolled in each group. Statistical analysis was conducted using SPSS version 25.0 (IBM, Armonk, NY, USA), and p < 0.05 was considered statistically significant. Depending on the data normality, Student's t-test or Wilcoxon signed-rank and rank sum tests were used to evaluate intergroup differences in continuous variables. Categorical variables were analyzed using Pearson's chi-squared or Fisher's exact tests.
After screening 67 patients, 60 patients were randomly allocated into the study groups, and 47 patients completed the study (IA PN = 21, IA HMWHA = 26) (Fig. 2). Six patients were excluded due to lack of primary outcome assessment, five patients were excluded due to the use of contraindicated drugs, and two patients were excluded due to follow-up loss. Demographic variables including age, sex, smoking, drinking, K–L grade, and combined medical comorbidities showed no significant difference between the two groups (Table 1).
Graph: Figure 2Flow chart of patient enrollment.
Table 1 Demographic and baseline characteristics.
IA PN (n = 30) IA HMWHA (n = 30) Age 63.6 ± 6.7 65.4 ± 8.2 0.364 (t) Sex 0.136 (c) Male 5 (16.7) 10 (33.3) Female 25 (83.3) 45 (75.0) Kellgren–Lawrence grae, n (%) 0.614 (f) Grade I 0 (0.0) 1 (3.3) Grade II 12 (40.0) 8 (26.7) Grade III 16 (53.3) 18 (60.0) Grade IV 2 (6.7) 3 (10.0) K-WOMAC (baseline) 38.5 ± 19.5 39.3 ± 16.3 0.889 (t) EQ-5D 11.4 ± 3.2 10.7 ± 2.6 0.404 (t) Smoker 1 (3.3) 1 (3.3) 1.000 (f) Drinking 6 (20.0) 2 (6.7) 0.254
IA PN Intraarticular polynucleotide, IA HMWHA Intraarticular high molecular weight hyaluronic acid, SD standard deviation. Testing for coutinuous variables between-treatment groups (two sample t-test). Testing for categorical variables between-treatment groups (Pearson's chi-square test (c) or Fisher's exact test (f)).
The VAS (100-mm) change rate for WBP from baseline to 16 weeks was − 54.0 ± 38.1% in the IA PN group, and − 42.8 ± 35.8% in the IA HMWHA group, and the IA PN group showed a higher VAS change rate than the IA HMWHA group. However, there was no statistically significant difference in the VAS change rate at 16 weeks between the two groups (p = 0.296) (Fig. 3). Both groups showed improvement in WBP at 16 weeks compared to baseline.
Graph: Figure 3Comparison of change rate of weight-bearing VAS between IA PN and IA HMWHA at week 16. Significant reduction of weight-bearing VAS was observed from the baseline in both groups. However, there were no significant difference in change rate of weight-bearing VAS between two groups (IA PN = − 54.0 ± 38.1%, IA HMWHA = − 42.8 ± 35.8%, p = 0.296) IA Intraarticular, PN Polynucleotide, HMWHA High molecular-weight hyaluronic acid, VAS Visual analogue scale.
All secondary endpoints related to pain VAS (100 mm) change and change rate for WBP, pain at rest, and walking pain at 8 and 16 weeks significantly improved from baseline, and VAS change gradually increased up to 16 weeks in both groups. However, there was no significant difference in any of the secondary endpoints related to pain VAS change between the IA PN and IA HMWHA groups (Table 2). The K-WOMAC change rate and EQ-5D, CGI, and PGI scores at 8 and 16 weeks also improved from baseline scores in both groups. However, there was no significant difference in any of the clinical scores between the IA PN and IA HMWHA groups (Table 3). Pain reduction and functional improvement were rapidly observed at two weeks from baseline, and clinical effects were sufficiently maintained until 16 weeks from baseline in both the IA PN and HMWHA groups (Fig. 4). The consumption of pain rescue drug (acetaminophen) at every visit was also similar between the two groups (Fig. 5).
Table 2 Comparison of Outcomes associated with pain VAS between IA PN and IA HMWHA groups.
IA PN (n = 22) IA HMWHA (n = 27) Weight bearing VAS change rate Week 8—baseline (%) − 33.9 ± 35.8 − 36.0 ± 40.2 0.847 Week 16—baseline (%) − 54.0 ± 38.1 − 42.8 ± 35.8 0.296 At rest VAS change rate Week 8—baseline (%) − 38.4 ± 73.7 − 26.6 ± 67.9 0.610 Week 16—baseline (%) − 63.6 ± 76.3 − 60.5 ± 55.8 0.890 Walking VAS change rate Week 8—baseline (%) − 28.6 ± 60.9 − 20.7 ± 55.0 0.639 Week 16—baseline (%) − 41.2 ± 45.3 − 28.3 ± 51.2 0.374 Weight bearing VAS change (100 mm) Week 8—baseline (mm) − 16.5 ± 16.5 − 19.3 ± 22.5 0.624 0.000* 0.000* Week 16—baseline (mm) − 27.4 ± 17.5 − 22.8 ± 19.8 0.000* 0.000* At rest VAS change rate (100 mm) Week 8—baseline (mm) − 11.1 ± 22.1 − 8.7 ± 22.8 0.713 0.028* 0.057 Week 16—baseline (mm) − 16.7 ± 21.1 − 14.2 ± 23.0 0.709 0.002* 0.004* Walking VAS change rate (100 mm) Week 8—baseline (mm) − 16.3 ± 17.6 − 14.1 ± 25.1 0.729 0.000* 0.007* Week 16—baseline (mm) − 21.4 ± 17.7 − 17.5 ± 24.2 0.538 0.000* 0.001*
IA PN Intraarticular polynucleotide, IA HMWHA Intraarticular high molecular weight hyaluronic acid. p-value (within) : paired t-test, p-value : two sample t-test, *statistical significance (+).
Table 3 Comparison of clinical outcomes between IA PN and IA HMWHA groups.
IA PN (n = 22) IA HMWHA (n = 27) K-WOMAC change Week 8—Baseline (score) − 12.8 ± 13.4 − 10.6 ± 16.5 0.618 0.000* 0.003* Week 16—Baseline (score) − 16.5 ± 15.2 − 13.6 ± 18.0 0.566 0.000* 0.001* EQ-5D change Week 8—Baseline (score) − 1.9 ± 2.7 − 1.3 ± 2.9 0.454 0.004* 0.032* Week 16—Baseline (score) − 2.4 ± 2.7 − 1.2 ± 3.1 0.148 0.001* 0.070 CGI Score Week 8 Very much improved 1 (4.5) 2 (7.4) 0.811 Much mproved 10 (45.5) 9 (33.3) Minimally improved 8 (36.4) 10 (37.0) No change 3 (13.6) 4 (14.8) Minimally worse 0 (0.0) 1 (3.7) Much worse 0 (0.0) 1 (3.7) Very much worse 0 (0.0) 0 (0.0) Week 16 Very much improved 2 (9.5) 1 (3.8) 0.334 Much mproved 10 (47.6) 8 (30.8) Minimally improved 8 (38.1) 14 (53.8) No change 0 (0.0) 2 (7.7) Minimally worse 1 (4.8) 0 (0.0) Much worse 0 (0.0) 1 (3.8) Very much worse 0 (0.0) 0 (0.0) PGI Score Week 8 Very much improved 1 (4.5) 0 (0.0) 0.433 Much mproved 6 (27.3) 10 (37.0) Minimally improved 12 (54.5) 10 (37.0) No change 3 (13.6) 4 (14.8) Minimally worse 0 (0.0) 2 (7.4) Much worse 0 (0.0) 1 (3.7) Very much worse 0 (0.0) 0 (0.0) Week 16 Very much improved 2 (9.5) 1 (3.8) 0.434 Much mproved 10 (47.6) 8 (30.8) Minimally improved 6 (28.6) 13 (50.0) No change 2 (9.5) 3 (11.5) Minimally worse 1 (4.8) 0 (0.0) Much worse 0 (0.0) 1 (3.8) Very much worse 0 (0.0) 0 (0.0)
IA PN Intraarticular polynucleotide, IA HMWHA Intraarticular high molecular weight hyaluronic acid, K-WOMAC Korean Western Ontario and McMaster Universities Osteoarthritis, EQ-5D Evaluation of quality of life, CGI Clinical Global Impression, PGI Patients global impression. *Statistical significance (+).
Graph: Figure 4Comparative analysis of serial change of pain VAS, K-WOMAC, EQ-5D between IA PN and IA HMWHA during study period. Change of weight-bearing, at rest, and walking VAS, K-WOMAC, and EQ-5D scores were significantly increased from the baseline, and gradually increased until 16 weeks in both IA PN and HMWHA groups. However, there were no significant difference between two groups at all timepoints.
Graph: Figure 5Consumption of pain rescue drug. Consumption of pain rescue drug in IA PN group decreased gradually until 16 weeks. There was no significant difference in consumption of pain rescue drug at every visits between IA PN and HMWHA groups.
In local AEs, three patients showed knee pain in the IA PN group, and one patient showed knee swelling in the IA HMWHA group, and there was no significant difference between the two groups (p = 1.000) (Table 4). All four local AEs relieved without any treatment within a few days. Regarding systemic AEs, the IA PN group reported two serious AEs (one of diarrhea and one of hematochezia), and the IA HMWHA group reported one AE (hyperthyroidism). However, two serious AEs in the IA PN group had no causal relationship with the IA PN injection. None of the patients discontinued the study because of local or systemic AEs.
Table 4 Comparison of adverse events (AEs) between IA PN and IA HMWHA groups.
IA PN (n = 30) IA HMWHA (n = 30) Local AEs Pain of knee 3 0 Swelling 0 1 Total 3 1 1.000 (f) Systemic AEs Diarrhea serious AE(+) Relationship (none) 1 0 Hematochezia serious AE (+) Relationship (none) 1 0 Hyperthyroidism 0 1 Total 2 1 1.000 (f)
IA PN Intraarticular polynucleotide, IA HMWHA Intraarticular high molecular weight hyaluronic acid. Testing for categorical variables between-treatment groups (Fisher's exact test (f)).
The principal finding of this study was that IA PN showed efficacy and safety comparable to IA HMWHA for the treatment of knee OA. Although statistical difference was not significant, the value of VAS (100-mm) change rate for WBP from baseline to 16 weeks was higher in IA PN group (− 54.0 ± 38.1%) than in IA HMWHA group (− 42.8 ± 35.8%). Clinical outcomes of the IA PN groups assessed by using K-WOMAC and EQ-5D were also comparable to that of the IA HMWHA group. All parameters associated with pain VAS and clinical outcomes significantly improved from baseline in both the IA PN and IA HMWHA groups.
Previous clinical trials that compared the analgesic efficacy between IA PN and IA HA have shown similar results. Vanelli et al[
Table 5 Clinical trials comparing clinical efficacy and safety between IA PN and HA in knee osteoarthritis.
Publication Study Design Treat Control Patients Number (Treat/Control) Injection times Results Clinical efficacy Safety Current Study (Korea) RCT PN (Conjuran®) HA (Hyruan Plus®) High MW (3000 kDa) 60 (30/30) 3 Reduced pain VAS/NSAID use, and improved K-WOMAC / EQ-5D in both group from the baseline No significant difference in all pain VAS, clinical scores, and rescue drug use between IA PN and IA HMWHA groups PN: knee pain (n = 3) HA: knee swelling (n = 1) → natual relief Significant difference (−) No severe AEs 2014 (Italy) RCT PN (Condrotide®) HA (Hyalubrix®) Medium MW (1500–2000 kDa) 72 (36/36) 3 Reduced pain / NSAID consumption, and KOOS improvement in both group Significant KOOS "symptom" improve ment(PN : week 2 versus HA : week 18) No significant AEs 2013 (Romania) RCT PN (Condrotide®) HA (Synocrom®) Medium MW (1600 kDa) 30 (15/15) 3 Reduced pain, and improved KOOS and KKS in both group from the baseline Significantly superior KKS improvement in PN group compare to HA group Mild knee pain (PN: n = 2, HA : n = 1) → alleviated in a few hours No significant AEs 2013 (Italy) Retrospective PN HA Low MW 60 (30/30) 4 2010 (Italy) RCT PN (Condrotide®) HA (Sinovial®) Low MW (800–1200 kDa) 60 (30/30) 5 Reduced pain VAS/NSAID use, and improved KOOS from the baseline in both group Similar trends in pain score between PN and HA groups PN : mild knee pain (n = 1) → subsided within one hour
In the present study, IA HMWHA, with a mean MW of 3000 kDa, was used as a control for IA PN, and the results of this study support the use of IA PN as an alternative of IA HMWHA. Despite the well-established clinical efficacy of IA HA, recent OA treatment guidelines report a lack of generalized effects as a limitation of IA HA use[
Another interesting finding of this study was that IA PN showed a fast onset of clinical efficacy and a sufficient duration of clinical effect. In this study, pain VAS during weight-bearing, at rest, and walking rapidly reduced within 2 weeks from the baseline and showed a similar pattern in the IA PN and IA HA groups. In Giarrantana et al. study[
Regarding AEs related to treatment, minimal local AEs were reported (IA PN: three knee pain, IA HMWHA: one knee swelling) in this study, and local AEs spontaneously relieved without any treatment within a few days. Two systemic and serious AEs in IA PN were found to have no causal relationship with IA injections. The results of this study correspond well with those of previous studies that reported minimal AEs associated with IA PN administration, except for mild joint pain that resolved spontaneously within a few hours (Table 4).
Our study had several limitations. First, the number of enrolled centers, patients, and total sample size was relatively small, and therefore, a sufficient number of OA patients with diverse KL grades were not included, and the influence of OA K-L grade on the outcome of intra-articular injection was not evaluated. However, the number of patients in this study was calculated based on statistical power analysis, and there was no significant difference in KL grades between the two groups. Second, in this study, objective imaging assessment was not performed. However, numerous studies on clinical efficacy of intraarticular viscosupplementation such as hyaluronic acid, and polynucleotide mainly investigate pain, and clinical outcomes. It maybe because primary expectation for the use of IA viscosupplementation is pain relief and functional improvement rather structural improvement that can be evaluated with cartilage thickness on MRI or joint space narrowing on plain radiograph. Almost clinical decision to use or stop IAHA or IA PN in outpatient department also performed based on patient's pain or functional improvement. Therefore, we believe that the results of this study can provide meaningful clinical information related with IA PN use. Third, the maximum follow-up period was 16 weeks from baseline, which was not sufficient for the evaluation of the long-term effects of each treatment. However, both IA PN and HMWHA groups showed a gradual increase in clinical effect until 16 weeks and these two IA viscosupplementations can compensate for the short-acting IA corticosteroids.
IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be an useful alternative to IA HMWHA for the treatment of knee OA.
C.B.C., and S.-B.K. designed the study, and organized the collected data. C.Y.S., and T.W.K. analyzed the data, and wrote the manuscript. M.J.C. analyzed the data, and performed statistical analysis.
This study was funded s by Pharma Research, Ltd. The funding sources had no involvement in the study design, collection, analysis, or submission to journal.
Data described in this study will be made available upon request pending application and approval from the corresponding author.
The authors declare no competing interests.
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By Tae Woo Kim; Moon Jong Chang; Chung Yeop Shin; Chong Bum Chang and Seung-Baik Kang
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