Efficacy of intra-articular 3% polyacrylamide hydrogel in the treatment of knee osteoarthritis: findings from the 24-month follow-up

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Abstract

Background. Osteoarthritis (OA) is among the most common chronic diseases and leading causes of disability globally. It places a significant burden on healthcare systems and adversely effects patients’ quality of life. The short-term efficacy of most therapies has driven the search for new treatment approaches in OA.

The aim of the study — to evaluate the duration of response to intra-articular injections of 3% polyacrylamide hydrogel in patients with knee osteoarthritis, factors influencing response duration, and the efficacy and safety of repeated treatment.

Methods. In a 6-month placebo-controlled randomized trial, patients with Kellgren-Lawrence (1957) grades II-III knee OA were randomly assigned to receive either intra-articular injections of 8.0 ml polyacrylamide hydrogel (PAAG) or placebo. Subjects from the PAAG group could roll over to the open-label extension (OLE) and if clinically indicated received the second course of PAAG. A survey of OLE participants was conducted at 24 months post-treatment. The efficacy of PAAG was assessed by the WOMAC index, a pain VAS, subjective evaluations of treatment outcomes by both the patient and the researcher, as well as by the daily requirement for paracetamol and nonsteroidal anti-inflammatory drugs. Safety was assessed by adverse events (AEs) monitoring.

Results. At month 6, PAAG was superior to placebo in reducing the WOMAC-T score (-604.44 versus -450.61, p = 0.011). Within 6-9 months of initial treatment, 26% of patients who had significantly higher baseline WOMAC scores and body weight required a repeat course of PAAG. In these patients, the mean reduction in WOMAC-T from baseline to month 12 was -361.33 and -795.64, respectively, compared to -688.53 with one course of PAAG (p = 0.107). At the end of the 24-month follow-up, the mean WOMAC-T reduction reached 714.13 versus -716.65 in the single-course group compared to two-course group. The majority of AEs were mild, and there were no serious AEs reported.

Conclusion. Polyacrylamide hydrogel has demonstrated a favorable safety profile and sustained symptomatic benefit over 2 years. In patients with risk factors for disease progression a repeated course is recommended.

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INTRODUCTION

Symptomatic knee osteoarthritis (OA) is a highly prevalent condition, particularly among older adults. By 2020, the global number of patients with OA reached 595 million, accounting for 7.6% of the world's population. Over the past thirty years, their number has increased by 132%, and is expected to exceed 1 billion in 2050 [1]. The individual burden of OA includes worsening knee pain and decline in lower limb function, which may eventually lead to physical disability. Osteoarthritis places a significant financial burden, representing a major challenge for health-care systems. The socioeconomic burden of the disease includes enormous diagnosis and treatment costs, along with research and develop-ment investments [2].

Symptomatic slow- and rapid-acting drugs are still the mainstay of treatment for OA [3, 4], but there is a growing trend towards the use of local therapies, particularly intra-articular (IA) glucocorticoids (GCs) or hyaluronic acid (HA) injections. Barriers to widespread use of IA GCs and HA in clinical practice include their controversial efficacy in placebo-controlled trials [5], short duration of effect [6, 7] and the risk of serious adverse events [8, 9]. One of the local therapies that has none of the above disadvantages, offers a long-term effect and a favorable safety profile is polyacrylamide hydrogel (PAAG), which has been used in clinical practice for over 20 years, particularly in patients with advanced OA not eligible for joint replacement.

The endoprosthesis of synovial fluid NOLTREX® (RC BIOFORM LLC, Russia) consisting of 3.0% cross-linked PAAG was approved in the Russian Federation and the EU in 2003 and 2007, respectively. In the USA and Canada, 4% PAAG (Noltrex®Vet) has been successfully used in the treatment of horses since 2014 [10].

Immediately after administration, PAAG acts as a classical viscosupplement (lubricant). The unique structure and high molecular weight (> 10 MDa) of PAAG [11] ensures a more lasting effect compared to other viscosupplements [12, 13]. While HA derivatives are broken down and actively removed from the joint cavity, non-biodegradable PAAG coats the internal structures of the joint, particularly the cartilage surface, with a thin layer reducing friction and protecting the cartilage from further destruction. Using an ex vivo cartilage explant model, K. Vishwanath et al. found that 4% PAAG is present and even concentrated in areas of cartilage damage, and observed a 30-40% reduction in friction after lubrication of articular cartilage with 4% PAAG [14]. The standalone clinical benefits of PAAG are most likely due to the combined effect resulting in improvement of the lubricating properties of synovial fluid and long-term protection of all IA structures. Due to its biological inertness, PAAG does not negatively affect surrounding tissues and cells [15, 16]. The most common adverse reactions associated with IA PAAG are temporary injection site pain and burning sensation in the joint during and after the procedure [17].

The aim of the study — to evaluate the duration of response to intra-articular injections of 3% polyacrylamide hydrogel in patients with knee osteoarthritis, factors influencing response du-ration, and the efficacy and safety of repeated treatment.

METHODS

Study design

A 6-month phase III double-blind, randomized, placebo-controlled trial (RCT — IA/PAAG-SI/OA/2019) to evaluate the efficacy and safety of IA PAAG in patients with knee OA followed by a 6-month open-label extension (OLE — IA/PAAG-SI/OA/2020) and a 12-month follow-up period (FU — IA/PAAG-SI/OA/2021) was conducted at four study sites in the Russian Federation (N.A. Semashko Clinical Hospital RZD-Medicine, Moscow; St. Petersburg Clinical Hospital RZD-Medicine; Clinical Hospital No 3, Yaroslavl; Clinical and Diagnostic Center Ultramed LLC, Omsk) from November 29, 2019 to September 28, 2022. The study outline is shown in Figure 1.

 

Figure 1. CONSORT 2010 flow diagram of the study design

 

Subject characteristics

Men and women aged over 50 years, meeting the ACR clinical criteria for knee OA [18], with Kellgren-Lawrence (1957) grade II or III, and radiographic joint space width ≥ 2.5 mm in the target knee joint (TKJ), were eligible to participate in the RCT. Anteroposterior X-rays of the knee were obtained in the standing fixed-flexion position using a SynaFlexer™ positioning frame (Synarc Inc., USA).

The main exclusion criteria were: secondary knee OA, history of TKJ injury/surgery, severe degeneration of the TKJ with clinically evident knee instability, acute TKJ inflammation, inflammatory or other rheumatic diseases; excessive varus or valgus knee deformity; PAAG injections into the TKJ within the prior 24 months, hyaluro-nic acid injections within the prior 12 months, glucocorticoid injections within the last month; oral use of nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks or paracetamol within 48 hours prior to enrollment.

Study intervention

Test medical device: 3% PAAG as a hydrous biopolymer with silver ions, Argiform (HBISA endoprosthesis of synovial fluid NOLTREX® according to Specification 9398-001-52820385-2015, manufactured by RC BIOFORM LLC, Russia), was supplied in 2.5 ml pre-filled syringes with 18G x 1½ (1.20 x 40 mm) injection needles.

Control: 0.9% sodium chloride (BUFUS 10.0 ml, manufactured by PFK Obnovlenie AO, Russia) was used as placebo.

Following local anesthesia with 2% lidocaine for injection (Lidocaine BUFUS 2.0 ml, manufac-tured by PFK Obnovlenie AO, Russia), patients received two weekly injections of 4.0 ml PAAG or placebo (total of 8.0 ml) into the TKJ. High-frequency ultrasound imaging (7.5-12 MHz) was used to visualize and target the knee joint space.

In OLE, patients who did not achieve a clinically significant reduction of at least 40% in their VAS pain scores [19] within 6 or 9 months received a repeat IA PAAG course, following the same procedure.

Subjects were allowed to take up to 4000 mg/day of paracetamol to control pain. If paracetamol proved insufficient for pain relief, the patients could switch to protocol-approved NSAIDs.

Randomization and blinding

Eligible patients were randomly assigned (1:1) to either the intervention (PAAG) or the control (placebo) group by block randomization with a block size of 4 using an interactive web response system (IWRS). Both investigators and participants were blinded to treatment allocation. To maintain blinding, IA injections of PAAG and placebo were performed by a non-blinded physician who was not involved in assessing patient outcomes. Statistical analyses were conducted by independent statisticians after the trial was completed and the database was locked.

Outcome measures

The primary endpoint was the change from baseline (RCT Visit 1, start of treatment) in the total WOMAC score (WOMAC-T) in the PAAG group at 6 (RCT Visit 5, compared with placebo), 9 (OLE Visit 3), 12 (OLE Visit 5) and 24 months (FU) post-treatment.

Secondary endpoints included the change from baseline (RCT Visit 1) to month 3 (RCT Visit 4), 6 (RCT Visit 5), 9 (OLE Visit 3), 12 (OLE Visit 5) and 24 (FU) post-treatment in:

  • WOMAC Pain / Stiffness / Physical Function;
  • pain VAS (except for month 3);
  • patient- and investigator-reported treat-ment outcomes.

Furthermore, the total number of paracetamol tablets taken in the prior period of the study was recorded at week 6 (month 1.5), month 3, 6 (RCT), 9 and 12 (OLE). Safety assessments included monitoring and analyzing adverse events (AEs) and withdrawals due to AEs throughout the study.

Pain intensity was assessed using a 100-mm Visual Analog Scale (VAS) [20]. The severity of OA was measured using the Russian version of the Western Ontario and McMaster Universities Osteoarthritis Index Version 3.1 Visual Analog Scale (WOMAC®VA3.1), based on a 100-mm VAS1 [21]. Patient- and investigator-reported outcomes were measured using a 6-point Likert scale (severe worsening, worsening, no change, slight improvement, improvement, significant improvement) [22].

Statistical analysis

The sample size was calculated using G*Power 3.1.9.2 software. Based on the anticipated 10% dropout rate, a total of 144 subjects randomized into 2 groups (1:1) would provide at least 80% power to detect a difference between PAAG and placebo (effect size of 0.25) at a significance level of 0.05. The effect size of 0.25 was determined based on findings from the study conducted by N.V. Zagorodny et al. [23].

All analyses were performed using the applied statistical software package R, version 3.5.1 (The R Foundation, Austria) with package version control adapted and validated by Microsoft (Microsoft, USA), in accordance with “A Guidance Document for the Use of R in Regulated Clinical Trial Environments”2.

The null hypothesis (Н0) of the RCT was no sig-nificant difference between the treatment groups in the mean change from baseline (BL) to month 6 in the total WOMAC score (the primary endpo-int). In contrast, the alternative hypothesis (HA) suggested that there was a significant difference.

Primary and quantitative secondary endpoints (based on WOMAC scores, VAS pain ratings, and the number of paracetamol tablets taken) were analyzed using an ANCOVA model adjusted for the baseline value, with treatment group and radiographic grade of OA as fixed factors. Quantitative variables were compared between the two groups (depending on the result of the Shapiro-Wilk normality test) using Student's t-test for independent samples (unpaired t-test) for normally distributed data or the Wilcoxon-Mann-Whitney test for non-normally distributed data in the RCT and one-way analysis of variance (ANOVA) or the Kruskal-Wallis test in the OLE and FU. If statistically significant differences were identified, the Tukey or Mann-Whitney post hoc tests were applied. Levene's test was used to assess the equality (homogeneity) of variances across three groups before conducting parametric tests. Intragroup comparisons (before vs after) were conducted using the Wilcoxon signed-rank test or the paired Student’s t-test.

Qualitative parameters (patient- and investigator-reported outcomes) were analyzed using the chi-squared (χ²) test (if the expected frequencies were > 5 and < 10) or Fisher’s exact test (if the expected frequencies were < 5).

Quantitative variables were presented as mean or mean difference ± standard deviation (M±SD) and 95% confidence intervals (95% CI), qualitative variables as absolute (relative) frequencies (n, %). P-values below 0.05 were considered statistically significant.

The efficacy analyses were conducted on the intent-to-treat (ITT) population, defined as all randomized subjects who received at least one dose of the study intervention. Missing data were handled using the last observation carried forward (LOCF) method. The additional analyses were performed in the per-protocol (PP) population consisting of subjects in the ITT population who completed the study without any major protocol deviations. The safety population included all patients who received any study intervention.

RESULTS

Randomized controlled trial

Of 151 patients screened, a total of 144 patients who met eligibility criteria were enrolled in the study and randomized (in a 1:1 ratio) to receive either PAAG (8.0 ml) (n = 72) or placebo (n = 72). The baseline demographic and clinical characteristics were well balanced between the groups, with no significant differences in mean age (63.40±7.26 vs. 62.15±7.54 years, p = 0.298), mean body mass index (BMI) (28.75±2.97 vs. 29.44±4.35, p = 0.627), sex (13 men (18.06%) and 59 women (81.94%) vs. 14 (19.44%) and 58 (80.56%), respectively), the number of patients with grade II and III knee OA (61 (84.72%) and 11 (15.28%) vs. 56 (77.78%) and 16 (22.22%) (p = 0.393), respectively). A total of 140 (97.22%) out of the 144 randomized patients completed the RCT.

Changes in the WOMAC scores over time are shown in Table 1 and Figure 2. In the PAAG group, statistically significant reductions in all WOMAC scores (p < 0.001) were observed as early as at 1.5 month (Visit 3) post-treatment. The difference between the treatments reached statistical significance by month 3 (Visit 4). All WOMAC scores continued decreasing until the end of the RCT (p-values for differences with the BL < 0.001 at all visits).

 

Table 1

Changes in WOMAC scores in the RCT, M±SD (95% CI)

Visit

Treatment group

WOMAC-T

WOMAC Pain

WOMAC Stiffness

WOMAC Physical function

Visit 1 (BL)

PAAG

(n = 72)

958.32±369.95

(871.38-1045.25)

186.82±81.05

(167.77-205.86)

86.90±41.80

(77.08-96.73)

684.60±282.53

(618.21-750.99)

Placebo

(n = 72)

1008.89±408.04

(913.00-1104.77)

204.12±87.61

(183.54-224.71)

83.50±43.12

(73.37-93.63)

721.26±305.38

(649.50-793.02)

P-value for the group comparison

0.437 (t)

0.221 (t)

0.631 (t)

0.456 (t)

Visit 3 (mo 1.5)

PAAG

(n = 71)

607.44±309.40

(534.20-680.67)

118.27±61.19

(103.78-132.75)

57.63±38.79

(48.45-66.81)

431.54±229.28

(377.27-485.80)

P-value (BL)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

Placebo

(n = 72)

711.46±397.51

(618.05-804.87)

141.71±85.29

(121.67-161.75)

55.90±40.33

(46.43-65.38)

513.85±290.62

(445.55-582.14)

P-value for the group comparison

0.131 (w)

0.141 (w)

0.604 (w)

0.091 (w)

Visit 4 (mo 3)

PAAG

(n = 71)

428.79±278.95

(362.76-494.81)

80.20±56.28

(66.88-93.52)

36.54±30.11

(29.41-43.66)

312.06±205.47

(263.42-360.69)

P-value (BL)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

Placebo

(n = 72)

598.79±395.62

(505.83-691.76)

114.03±79.24

(95.41-132.65)

49.79±40.19

(40.35-59.24)

434.97±291.38

(366.50-503.44)

P-value for the group comparison

0.013 (w)

0.019 (w)

0.049 (w)

0.011 (w)

Visit 5 (mo 6)

PAAG

(n = 70)

352.23±251.17

(292.34-412.12)

63.27±48.41

(51.73-74.81)

30.56±27.46

(24.01-37.10)

258.40±183.89

(214.55-302.25)

P-value (BL)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

< 0.001 (w)

Placebo

(n = 70)

556.17±395.96

(461.76-650.58)

102.57±80.00

(83.50-121.65)

44.99±34.89

(36.67-53.30)

408.61±295.61

(338.13-479.10)

P-value for the group comparison

0.002 (w)

0.006 (w)

0.004 (w)

0.002 (w)

Change from BL to Visit 5 (mo 6)*

PAAG

-604.44±348.52

(-686.34…-522.55)

-125.94 (±79.13)

(-144.81…-107.07)

-57.37 (±37.59)

(-66.33…-48.41)

-430.94 (±260.14)

(-492.97…-368.92)

Placebo

-450. 61±369.58

(537.46…-363.76)

-102.66±85.95

(-123.15…-82.16)

-37.66±39.69

(-47.12…-28.19)

-316.57±263.77

(-379.46…-253.68)

P-value for the group comparison

0.011 (t)

0.098 (t)

0.011 (w)

0.011 (t)

t — Student's t-test for independent samples; w — Wilcoxon-Mann-Whitney test; *— LOCF-imputed outcome data.

 

Figure 2. Changes in WOMAC scores within 6 months after the first course of PAAG (mm): a — WOMAC Pain; b — WOMAC Stiffness; c — WOMAC Physical Function; d — WOMAC-T

 

The trial met its primary endpoint. At month 6 (week 25) post-treatment, the WOMAC-T score had decreased from 958.32 to 352.23 (-604.44; 95% CI: -686.34...-522.55) and from 1008.89 to 556.17 (-450.61; 95% CI: -537.46...-363.76) in the PAAG and placebo groups, respectively. The inter-group difference was statistically sig-nificant (p = 0.011). Similar results were obtained for the WOMAC pain, stiffness and function subscales.

At month 6 (week 25), a total of 50 patients (71.43%) in the PAAG group rated their treatment outcomes as “significant improvement” or “impro-vement” compared with 29 patients (41.43%) in the placebo group (p = 0.002). “Improvement” or “significant improvement”, as assessed by the investigator, was achieved in 49 patients (70%) in the PAAG group versus 29 patients (41.43%) in the placebo group (p = 0.005).

The mean total number of paracetamol 500 mg tablets used at week 6, 13 (month 3) and 25 (month 6) decreased in the PAAG group (3.08±3.75; 1.75±1.39; 1.00±0.00, respectively) and increased in the placebo group (6.00±5.63; 8.47±6.67; 11.79±9.60, respectively). The inter-group difference reached statistical significance at week 13 (month 3) (p = 0.004).

Safety assessment

In the PAAG group, 5 AEs (constipation, abdomi-nal pain, asthenia, headache and dizziness) were reported in 2 patients (2.78%). Constipation and headache were considered possibly related to the study intervention. In the placebo group, 11 AEs (abdominal distension, constipation, abdominal pain, rhinitis, back pain, headache, oropharyn-geal pain) occurred in 2 patients (2.78%), with 8 AEs possibly related to placebo. All AEs were mild and transient. No patients discontinued the study due to AEs.

Open-label extension

Sixty-five patients from the PAAG group (n = 70) rolled over into the OLE. At month 6 and 9, 3 and 14 patients (n = 17; 26.00%) with an inadequate response to treatment (less than 40% reduction in the VAS pain score) received the second course of PAAG (8.0 ml) according to the study protocol.

Two and 29 patients (n = 31; 48.00%), who achieved the protocol-specified 40% reduction in the VAS pain score, chose to be retreated and received the second course of PAAG at month 6 and 9, respectively. Failure to comply with retreatment criteria was considered a protocol deviation, and a total of 31 patients were excluded from the PP population. Seventeen patients (26.00%) did not require retreatment (Table 2).

 

Table 2

Baseline characteristics of patients who lost or maintained response in the OLE, M±SD (95% CI)

Parameter

Loss of response

Maintenance of response, n = 17

(Group C)

P-value

At 6 mos, n = 3

(Group A)

At 9 mos, n = 14

(Group B)

Age, years

66.00±11.27

(38.01-93.99)

65.86±7.36

(61.61-70.11)

61.88±7.27

(58.14-65.62)

0.324 (aov)

BMI, kg/m2

32.43±1.25

(29.33-35.54)

27.88±2.82

(26.25-29.50)

27.18±1.82

(26.25-28.12)

0.003 (aov)

B – A: 0.010 C – A: 0.002 C – B: 0.674

Obesity, %

100.00 (n = 3)

21.43 (n = 3)

5.88 (n = 1)

0.010 (f)

WOMAC-T

528.33±408.54

(-486.55-1543.21)

1211.07±349.50

(1009.27-1412.87)

767.47±227.42

(650.54-884.40)

0.003 (kw)

B – A: 0.023 C – A: 0.410 C – B: 0.007

aov — one-way analysis of variance (ANOVA); f — Fischer's exact test; kw — Kruskal-Wallis test.

 

Tables 3, 4, and Figure 3 demonstrate the change in pain VAS and WOMAC scores over time in patients who lost response at 6 (n = 3) or 9 months (n = 14) post-treatment compared with patients maintaining their response (n = 17).

 

Table 3

100-mm VAS pain scores, M±SD (95% CI)

Visit

Loss of response at 6 mos (n = 3)

(Group A)

Loss of response at 9 mos (n = 14)

(Group B)

Maintenance of response (n = 17)

(Group C)

P-value

Visit 1 (BL, RCT)

50.67±22.37

(-4.90-106.23)

61.21±61.21

(56.20-66.23)

64.35±64.35

(58.77-69.94)

0.339 (kw)

1st course of PAAG 8.0 ml

Visit 5 (mo 6, RCT)

34.33±16.62

(-6.96-75.63)

reduction by 16.34 mm (32.25%)

2nd course of PAAG 8.0 ml is prescribed

27.43±8.47

(21.83-33.03)

reduction by 33.78 mm (55.19%)

9.47±5.51

(6.64-12.30)

reduction by 54.88 mm (85.28%)

< 0.001 (aov)

B – A: 0.422 C – A: 0.000 C – B: 0.000

Visit 3 (mo 9, OLE)

2nd course of PAAG 8.0 ml

44.14±81.05

(39.25-49.04)

16.71 mm (60.92%) raise

2nd course of PAAG 8.0 ml is prescribed

21.53±6.32

(18.28-24.78)

< 0.001 (aov)

B – A: 0.000 C – A: 0.074 C – B: 0.000

11.33±2.08

(6.16-16.50)

23.00 mm (67.00%) reduction from mo 6

Visit 5 (mo 12, OLE)

5.00±81.05 (-6.38-16.38)

29.33 mm (85.44%) reduction from mo 6

2nd course of PAAG 8.0 ml

4.88±81.05

(3.27-6.50)

< 0.001(aov)

B – A: 0.000 C – A: 1.000 C – B: 0.000

28.86±81.05

(22.46-35.25)

15.28 mm (34.62%) reduction

kw — Kruskal-Wallis test; aov — one-way analysis of variance (ANOVA).

 

Table 4

Changes in WOMAC scores, M±SD (95% CI)

Visit

Treatment group

WOMAC-T

P-value (compared to mo 6)

WOMAC Pain

WOMAC Stiffness

WOMAC Physical function

Visit 1 (BL, RCT)

Loss of response at 6 mos

(n = 3)

528.33±408.54

(-486.55-1543.21)

–

125.00±101.06

(-126.05-376.05)

71.67±90.47

(-153.07-296.40)

331.67±218.11

(-210.15-873.48)

Loss of response at 9 mos

(n = 14)

1211.07±349.50

(1009.27-1412.87)

227.79±77.55

(183.01-272.56)

93.79±36.82

(72.53-115.05)

889.50±278.97

(728.43-1050.57)

Maintenance of response (n = 17)

767.47±227.42

(650.54-884.40)

158.18±63.77)

(125.39-190.97)

69.94±26.93

(56.09-83.79)

539.35±170.29

(451.80-626.91)

P-value for the group comparison

0.003 (kw)

0.018 (aov)

0.226 (aov)

0.001 (kw)

Visit 5 (RCT) — Visit 0 (OLE) (mo 6)

Loss of response at 6 mos

(n = 3)

250.33±178.54 (-193.19-693.86)

−

55.67±43.98

(-53.59-164.92)

17.67±9.61

(-6.20-41.54)

177.00±127.58 (-139.92-493.92)

Loss of response at 9 mos

(n = 14)

575.64±246.22

(433.48-717.81)

103.14±57.40

(70.00-136.28)

38.79±33.40

(19.50-58.07)

433.71±169.82

(335.66-531.77)

Maintenance of response (n = 17)

260.29±150.02

(183.16-337.43)

44.24±28.77

(29.45-59.03)

26.29±18.11

(16.98-35.61)

189.76±109.22

(133.61-245.92)

P-value for the group comparison

0.001 (kw)

0.003 (aov)

0.270 (aov)

< 0.001(kw)

Visit 3 (mo 9, OLE)

Loss of response at 6 mos

(n = 3)

218.67±2.08 (213.50-223.84)

0.788 (t)

34.67±2.31 (28.93-40.40)

20.33±0.58 (18.90-21.77)

163.67±3.79 (154.26-173.07)

Loss of response

at 9 mos

(n = 14)

526.36±185.99

(418.97-633.74)

0.419 (t)

96.50±44.78

(70.65-122.35)

34.93±21.68

(22.41-47.44)

394.93±139.09

(314.62-475.24)

Maintenance of response (n = 17)

113.12±31.37

(96.99-129.25)

0.003 (w)

6.29±3.89

(4.30-8.29)

21.24±6.71

(17.78-24.69)

85.59±24.11

(73.19-97.99)

P-value for the group comparison

< 0.001 (aov)

 

< 0.001 (kw)

0.133 (kw)

< 0.001 (aov)

Visit 5 (mo 12, OLE)

Loss of response

at 6 mos

(n = 3)

167.00±60.80 (15.96-318.04)

0.416 (t)

19.67±12.70 (-11.89-51.22)

11.33±8.39 (-9.50-32.17)

136.00±42.72 (29.88-242.12)

Loss of response at 9 mos

(n = 14)

415.43±189.19

(306.19-524.66)

0.015 (t)

76.71±47.28

(49.41-104.02)

27.29±20.16

(15.64-38.93)

311.43±133.81

(234.17-388.69)

Maintenance of response (n = 17)

78.94±20.77

(68.26-89.62)

0.001 (w)

3.12±2.87

(1.64-4.59)

12.12±4.41

(9.85-14.39)

63.71±16.15

(55.40-72.01)

 

P-value for the group comparison

< 0.001 (aov)

 

< 0.001 (kw)

0.011 (aov)

< 0.001 (aov)

kw — Kruskal-Wallis test; aov — one-way analysis of variance (ANOVA); t — paired Student's t-test; w — Wilcoxon signed-rank test.

 

Figure 3. Changes in VAS pain scores

 

WOMAC scores, which had decreased more than two-fold 6 months after the 1st course of PAAG 8.0 ml, continued to decrease significantly by 9 and 12 months, indicating maintenance of response in 17 (26.00%) patients, and remained stable, but with a slight downward trend, in 17 (26.00%) patients with loss of response after the 2nd course of PAAG 8.0 ml (see Table 4).

At the same time, in patients with loss of res-ponse, the VAS pain score decreased by 55.19% from 61.21 at BL to 27.43 at month 6, increased to 44.14 (by 60.92%) at month 9, and returned to the 6-month level (28.86 at month 12) after a repeat course of PAAG (see Table 3). None of the 65 OLE participants took paracetamol or NSAIDs.

Safety assessment

In the group that received the 2nd PAAG course at month 6, one moderate AE (suspected coronavirus disease) was reported. It was considered not related to the study intervention.

Follow-up period

WOMAC scores were recorded in 47 patients, who had completed the OLE and agreed to participate in the survey. The “1 PAAG course” group consisted of patients (n = 17) who received one course of PAAG 8.0 ml at BL in the RCT, maintained their response and had not required retreatment in the OLE.

The “2 PAAG courses” group (n = 30) included patients who received the second course of PAAG 9 months after initial treatment either due to loss of response (n = 14) or by choice to sustain the improvement (n = 16).

Continued significant reductions in WOMAC scores from BL were seen in both groups throughout the 24-month follow-up period (Table 5, Figure 4). The VAS pain score in both groups at 24 months remained approximately at the same level as 6 months after the initial treatment course (Figure 5).

 

Table 5

Changes in WOMAC-T and WOMAC Pain scores over the 24-month follow-up period, M±SD (95% CI)

Group

Parameter

Visist 1

(BL, RCT)

1st course of PAAG 8.0 ml

Visist 0 (mo 6, OLE)

Visit 3

(mo 9, OLE)

Visit 5 OLE

(mo 12, OLE)

Mo 24, FU

1 PAAG course (n = 17)

WOMAC-T

767.47±227.42

(650.54-884.40)

260.29±150.02

(183.16-337.43)

113.12±31.37

(96.99-129.25)

78.94±20.77

(68.26-89.62)

50.82±31.78

(34.48-67.16)

WOMAC Pain

158.18±63.77

(125.39-190.97)

44.24±28.77

(29.45-59.030)

6.29±3.89

(4.30-8.29)

3.12±2.87

(1.64-4.59)

3.29±3.74

(1.37-5.22)

P-value (for the comparison with prior period)*

–

< 0.001 (w) / < 0.001 (t)

< 0.001 (t) / < 0.001 (t)

< 0.001 (t) / < 0.001 (w)

< 0.001 (w) / < 0.001 (w)

2 PAAG courses (n = 30)

WOMAC-T

1137.13±375.18

(997.04-1277.23)

445.33±252.01

(351.23-539.43)

405.77±221.26

(323.15-488.39)

2nd course of PAAG 8.0 ml

319.07±203.24

(243.18-394.96)

423.00±250.02

(329.64-516.36)

WOMAC Pain

233.20±77.68 (204.19-262.210)

80.93±50.74 (61.99-99.88)

75.03±45.94 (57.88-92.19)

59.70±43.68 (43.39-76.01)

80.27±51.92

(60.88-99.65)

P-value (for the comparison with prior period)*

–

< 0.001 (w) / < 0.001 (w)

< 0.001 (w) / < 0.001 (w)

< 0.001 (w) / < 0.001 (w)

< 0.001 (w) / < 0.001 (w)

*No correction for multiplicity was applied due to the descriptive nature of the presented P-values and considerable differences between visits; w — Wilcoxon signed-rank test; t — paired Student's t-test.

 

Figure 4. Changes in WOMAC-T scores over the 24-month follow-up period

 

Figure 5. Changes in VAS pain scores over the 24-month follow-up period

 

Safety assessment

Over this period of the study, AE data were not collected. Safety assessment involved recording and analyzing contraindications to repeat IA injections. In the study population, only one case of coronavirus disease (COVID-19) and one case of exacerbation of stage 2 hypertension were reported.

DISCUSSION

A single course of two weekly IA injections of PAAG (4+4 ml) led to significant improvements in pain, stiffness and physical function, as measured by WOMAC, within 4 weeks after treatment completion. A significant reduction in pain score on VAS was observed as early as 1 week after the first PAAG injection (4.0 ml). The difference in the WOMAC scores between the PAAG and placebo groups reached statistical significance at week 13 (month 3). In addition, the use of paracetamol was significantly lower in patients treated with PAAG compared to the placebo group. Significant and continued improvements were maintained over the 6-month period, until the end of the RCT.

In the next 12 months, inadequate response with less than a 40% reduction in the VAS pain score and worsening of pain from month 6 was observed in 26.00% of patients. A repeat course of PAAG continued to result in improvement of pain, which had reduced to the 6-month level, and stabilized the patient’s condition. It should be noted that this was the first study to evaluate the efficacy and safety of repeated courses of PAAG in patients with knee OA.

An additional analysis of the baseline cha-racteristics of patients who maintained and lost their response showed that the patients with loss of response were older, had more severe knee pain and higher BMI (a greater proportion of them were overweight or obese). These fac-tors are known to accelerate OA progression and worsen outcomes [24]. In particular, a large 2-year study involving 269 patients found that factors predicting the potential benefit of PAAG included older age, a lower knee OA grade, absence of diabetes mellitus, and bilateral rather than unilateral disease [25].

The modest improvement in OA symptoms in 31 patients who chose to be retreated suggested that preventive administration of PAAG in good responders is unreasonable.

In 17 patients, a single course of PAAG led to sustained symptom reduction through 2 years (FU). A repeat course of PAAG helped maintain improvements achieved in the RCT over the next 15 months (from month 9 to the end of follow-up).

No serious AEs were reported in the PAAG groups. All AEs were classified as mild and considered either unrelated or unlikely to be related to the study intervention. Repeated injections were not associated with any adverse reaction, indicating an excellent safety profile of PAAG comparable to that of placebo. The absence of the most common adverse reaction “injection site pain” could be attributed to the administration of a local anesthetic.

Currently, only one short-term study has not found a significant reduction in the WOMAC pain score (11±4) compared to baseline (12±3.5) and a methylprednisolone acetate 1 ml/40 mg group (9±3.4) at 3 months after a single IA injection of 2.5 ml of 3% PAAG [26]. It should be noted that the study used a very low dose of PAAG.

In a study by V.V. Zar et al., evaluating the efficacy of a single IA injection of 5 ml of 3% PAAG that included 236 patients with grades II and IV knee OA, improvements in pain and functional mobility became more pronounced by 6 months post-treatment [27]. Five weekly IA injections of 2.5 ml of 3% PAAG (total dose 12.5 ml) controlled the pain and other symp-toms of grade III knee OA in 30 patients over a 9-month follow-up period [23].

The evident dose-dependent effect of PAAG provided the rationale for selecting a relatively high dose of 8.0 ml and evaluating the efficacy and safety of a repeated treatment course in the reported study.

Study findings that have been published in recent years showed the continued long-term efficacy of PAAG over at least two years. In particular, in a prospective, open-label clinical study evaluating the long-term effectiveness of a single 6 ml IA injection of 2.5% PAAG (Arthrosamid®, Contura International A/S, Den-mark) statistically significant improvements were sustained throughout the five-year follow-up period in 27 patients with knee OA [13].

No significant differences in WOMAC score reduction were observed within one year after a single IA injection of 6 ml of 2.5% PAAG (n = 119) vs. 2 ml (60 mg) of cross-linked HA (Synvisc One®, Sanofi, France) (n = 120) in a comparative study [28]. At 12 months after a single injection of 2.5% PAAG (6 ml), HA (0.6-1.2 MDa, 60 mg/2 ml), or GCs (40 mg) (n = 50 in each treatment group), the VAS pain score returned to baseline with HA and GCs, and remained slightly improved with PAAG (p = 0.219) [29].

This study differs from the earlier PAAG effi-cacy studies [12, 23] in methodological approa-ches. First, it was the first randomized trial with a control group that received a placebo (normal saline). Second, the study, for the first time, explored factors affecting the duration of response to PAAG, as well as the need for retreatment, the efficacy and safety of a repeat course of PAAG, and demonstrated a consistent safety profile of the device after two treatment courses. Third, the number of injections was reduced to two to lower the risk of infection. Nevertheless, the RCT, OLE and FU generally support the main findings from previous studies. There is strong evidence that PAAG provides sustained symptomatic relief for up to 24 months in patients with non-end-stage knee OA [12, 13, 25].

Limitations of the study

This study has several potential limitations. High concomitant use of paracetamol could improve efficacy outcomes in the placebo group in the RCT; otherwise, the between-group differences might have been more pronounced. In the OLE, only 17/65 patients (26.00%) met the retreatment criteria. Additionally, 31 (48.00%) of 65 patients received a second course to prolong the clinical effect of PAAG. This interfered with the assessment of the duration of response. Further studies with a follow-up period of more than 2 years are needed to determine the optimal timing for repeat courses of PAAG and indica-tions for retreatment.

CONCLUSION

Intra-articular polyacrylamide hydrogel demon-strates an excellent safety profile and long-term efficacy in reducing pain and stiffness and improving physical function, which persisted throughout the 24-month follow-up period in patients with Kellgren-Lawrence grades II-III knee osteoarthritis. A personalized approach to polyacrylamide hydrogel dose selection and repeat courses in patients with risk factors for disease progression may improve treatment outcomes.

DISCLAIMERS

Author contribution

Noskov S.M. — study concept and design, editing the manuscript, data acquisition, analysis and interpretation.

Popov V.V. — study concept and design, data acquisition, analysis and interpretation.

Shunkov V.B. — data acquisition, analysis and interpretation.

Gorokhova V.A. — literature search, data acquisition, analysis and interpretation.

Leper E.I. — drafting and editing the manuscript, literature search.

All authors have read and approved the final version of the manuscript of the article. All authors agree to bear responsibility for all aspects of the study to ensure proper consideration and resolution of all possible issues related to the correctness and reliability of any part of the work.

Acknowledgements. We appreciate the support from the Department of Biomedical Statistics at Statandocs LLC (headed by K.A. Voronov), which performed statistical analyses.

Funding source. The study was sponsored by Research Center BIOFORM LLC but the company was not involved neither in analysis of the study results nor in manuscript preparation.

Disclosure competing interests. S.M. Noskov, V.V. Popov, and V.B. Shunkov received research support from RC BIOFORM LLC for consulting and conducting this clinical study. V.A. Gorokhova declares no conflict of interest. E.I. Leper is an RC BIOFORM LLC representative.

Ethics approval. The study was approved by the local ethics committees of 4 research centers: Clinical Hospital No 3 (protocol No 97, 22.08.2019), N.A. Semashko Clinical Hospital RZD-Medicine (protocol No 9.1, 05.09.2019), Clinical and Diagnostic Center Ultramed LLC (protocol No 28, 14.11.2019), St. Petersburg Clinical Hospital RZD-Medicine (protocol No 08/2019-19, 07.08.2019).

Consent for publication. Written consent was obtained from the patients for publication of relevant medical information and all of accompanying images within the manuscript.

Use of artificial intelligence. No generative artificial intelligence technologies were used in the preparation of this manuscript.

Data availability. The description and results of this study are available on ClinicalTrials.gov (NCT03897686, NCT06429319, NCT06523491).

 

1 The WOMAC scale is a proprietary tool protected by copyright. The Sponsor (RC BIOFORM LLC) purchased the rights to use the adapted Russian language version of WOMAC in the study from the right holder Nicholas Bellamy, MD, MSc, DSc, MBA, FRACP (license agreement dated July 27, 2019).

2 The R Foundation for Statistical Computing. R: Regulatory Compliance and Validation Issues: A Guidance Document for the Use of R in Regulated Clinical Trial Environments. 2021. URL: https://www.r-project.org/doc/R-FDA.pdf.

×

About the authors

Sergey M. Noskov

Yaroslavl State Medical University; Clinical Hospital No 3, Yaroslavl

Author for correspondence.
Email: noskov03@gmail.com
ORCID iD: 0000-0003-3456-9409
SPIN-code: 4528-7378

Dr. Sci. (Med.), Professor

Russian Federation, Yaroslavl; Yaroslavl

Vladimir V. Popov

N.A. Semashko Clinical Hospital RZD-Medicine; Russian Biotechnological University

Email: clinpharmcb6@mail.ru
ORCID iD: 0000-0002-1570-2748
SPIN-code: 8287-8266

Dr. Sci. (Med.), Professor

Russian Federation, Moscow; Moscow

Victor B. Shunkov

St. Petersburg Clinical Hospital RZD-Medicine

Email: shunkov.victor@mail.ru
ORCID iD: 0000-0001-9703-0537

Cand. Sci. (Med.)

Russian Federation, St. Petersburg

Victoria A. Gorokhova

Clinical Hospital No 3, Yaroslavl

Email: vagorokhova@yandex.ru
ORCID iD: 0000-0003-3253-4085
SPIN-code: 3765-2925
Russian Federation, Yaroslavl

Ekaterina I. Leper

Research Center Bioform LLC

Email: eleper@yandex.ru
ORCID iD: 0009-0002-7547-5644
Russian Federation, Moscow

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Supplementary files

Supplementary Files
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2. Figure 1. CONSORT 2010 flow diagram of the study design

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3. Figure 2. Changes in WOMAC scores within 6 months after the first course of PAAG (mm): a — WOMAC Pain; b — WOMAC Stiffness; c — WOMAC Physical Function; d — WOMAC-T

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4. Figure 3. Changes in VAS pain scores

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5. Figure 4. Changes in WOMAC-T scores over the 24-month follow-up period

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6. Figure 5. Changes in VAS pain scores over the 24-month follow-up period

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