A prospective, open-label, clinical investigation of a single intra-articular polyacrylamide hydrogel injection in participants with knee osteoarthritis: a 5-year extension study

Abstract

Background

Knee osteoarthritis is a highly prevalent and painful joint disorder with limited long-term treatment options. Intra-articular corticosteroids and hyaluronic acid offer only short-term relief and may have safety concerns. This study aimed to evaluate the long-term effectiveness and safety of a single intra-articular injection of 2.5% polyacrylamide hydrogel in individuals with moderate to severe knee osteoarthritis.

Methods

This prospective, multicentre, open-label, single-arm clinical study enrolled 49 participants who received a single 6 mL intra-articular injection of 2.5% polyacrylamide hydrogel. After 1 year, 35 participants entered an extension study with yearly assessments up to 5 years post treatment. The primary outcomes for the extension phase included changes from baseline in WOMAC subscales (pain, stiffness, physical function) and Patient Global Assessment (PGA). Safety was evaluated through the incidence of adverse events. Statistical analyses included a mixed model for repeated measures and sensitivity analyses using ANCOVA and baseline observation carried forward.

Results

Of the 49 participants, 27 completed the five-year follow-up. Statistically significant improvements from baseline were observed in WOMAC pain (−14.6; 95% CI: −21.4 to −7.7; p = 0.0002), stiffness (−19.6; 95% CI: −29.9 to −9.3; p = 0.0006), physical function (−12.5; 95% CI: −19.8 to −5.2; p = 0.0015), and PGA (−13.4; 95% CI: −23.3 to −3.5; p = 0.0100). These improvements were sustained throughout the five-year period. A total of 47 adverse events were reported in the extension study, with no serious events attributed to the investigational device. No new adverse device effects were reported in the extension study.

Conclusions

A single intra-articular injection of 2.5% polyacrylamide hydrogel demonstrated sustained improvements in WOMAC pain, stiffness, physical function, and PGA for up to five years, with a favourable safety profile. These findings support its potential as a long-term treatment option for knee osteoarthritis.

Trial registration

ClinicalTrials.gov Identifier: NCT04179552.

Background

Osteoarthritis (OA) represents the most common peripheral arthritis, currently affecting more than 595 million adults aged 30 and older across the globe, with forecasts indicating that this number could exceed 1.1 billion by 2050 [1], and with the knee being the most commonly affected joint [2, 3]. OA manifests with alterations in local joint tissues including cartilage degradation, bone remodelling, osteophyte formation, and joint inflammation that can lead to pain, disability, and loss of normal joint function [2, 3]. The global burden of knee OA is accelerated by demographic trends such as population aging, and increasing obesity prevalence [4]. The primary goals of treatment are to reduce pain and preserve function through a combination of non-pharmacologic and pharmacologic therapies, with knee OA management guidelines emphasizing a core set of non-pharmacologic interventions; analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), may help relieve pain when used alongside diet and exercise [2, 5–7]. Intra-articular (IA) glucocorticoid and hyaluronic acid injections are commonly used to manage pain in patients with moderate to severe OA symptoms [2]. However, the long-term use of glucocorticoids is limited due to potential negative effects on cartilage. Current level-I evidence suggests that IA hyaluronic acid injections may provide modest short-term pain relief, although improvements in function are inconsistent [8]. Accordingly, guidelines such as those from the National Institute for Health and Care Excellence (NICE) recommends that patients be informed that glucocorticoid injections are likely to offer only short-term relief, typically lasting between 2 and 10 weeks and further do not recommend IA hyaluronic acid to manage OA [9, 10]. Additionally, corticosteroid injections may increase the risk of periprosthetic joint infections if knee replacement surgery is performed within three months of injection [11].

Such limitations emphasize the necessity for therapeutic alternatives that demonstrate sustained efficacy alongside a well-established safety profile.

2.5% injectable polyacrylamide hydrogel (iPAAG; Contura International A/S, Søborg, Denmark) is a proprietary, cross-linked injectable polyacrylamide hydrogel composed of 2.5% polyacrylamide and 97.5% non-pyrogenic water. It is non-degradable, biocompatible synovial implant, and its molecular structure allows normal water exchange with surrounding tissues, providing structural stability and longevity. After IA injection, 2.5% iPAAG is integrated into the synovium and is permeable to salts and organic molecules. It has been used as a bulking agent for over 25 years in various applications, including soft tissue augmentation [12] and stress urinary incontinence [13].

Previous open labelled, clinical studies have demonstrated the safety and indicated effectiveness of 2.5% iPAAG in managing symptomatic knee OA for up to one year [14–16]. Additionally, a randomized controlled trial comparing a single 6 mL IA injection of 2.5% iPAAG to hyaluronic acid in 239 participants demonstrated non-inferiority of 2.5% iPAAG in reducing WOMAC pain at 26 weeks, with sustained benefits and comparable safety profiles at 52 weeks [17].

The current study is an extension of previous work [14, 15] and evaluated the long-term (5-year) effectiveness of a single 6 mL IA injection of 2.5% iPAAG in individuals with moderate to severe knee OA, focusing on participant-reported symptoms, functional ability during daily activities, and PGA of OA impact. Safety of IA 2.5% iPAAG was also assessed up to five years.

Methods

Study design

The study was a prospective, multicentre, open-label, single-arm clinical study, followed by an extension, enrolled 49 participants who each received a single IA injection of 6 mL 2.5% iPAAG (Arthrosamid®, Contura International A/S, Denmark). Data were collected from three study sites in Denmark starting on 21 August 2019, with the final participant visit for the 5-year extension study on 19 September 2024. After the first 12 months, the extension study continued at two clinical sites. The study protocol and subsequent amendments were approved by the local Health Research Ethics committee (reference number: H-19031685), the Danish Health Authorities, and registered at ClinicalTrials.gov (NCT04179552). The participants gave informed consent prior to participation and reconsent for participation in the extension. The study was conducted according to the principles of Good Clinical Practice.

The study was extended beyond 1 year to assess the long-term effectiveness and safety at years 2, 3, 4, and 5. At the end of year 1, participants were asked to sign a new consent form.

The main inclusion and exclusion criteria are presented in Table 1. The full inclusion and exclusion criteria have been reported previously [14, 15].

Table 1.

Main inclusion and exclusion criteria

Main inclusion criteria	Main exclusion criteria
Adults with a clinical diagnosis of knee OA according to the American College of Rheumatology criteria [18]	Any previous treatment with 2.5% iPAAG
Confirmed radiographic knee OA at mild to severe stages (Kellgren-Lawrence 2–4) [19]	Previous treatment with IA hyaluronic acid or its derivatives within 6 months, or any IA substance other than hyaluronic acid (e.g., corticosteroids) within 3 months in the target knee
Score of 2 or more (0–4 scale) on the WOMAC question A1 (pain while walking on flat surface) [20]	Skin diseases or infections in the area of the injection site
Body mass index < 35 kg/m2	Surgery in the target knee within 6 months
If relevant, a stable dose of analgesics for at least four weeks prior to entering the study	Significant valgus/varus deformity of the knee, ligamentous laxity or meniscal instability
–	Diseases in the target knee other than OA

IA, Intra-articular; iPAAG, injectable Polyacrylamide Hydrogel; OA, Osteoarthritis; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Outcomes

Primary objectives of the main study, 6-month and 1-year extension studies have been reported previously [14, 15]; only secondary objectives are reported here for the 5-year extension study.

The first secondary objective was to assess the extended effects of iPAAG on participant-reported WOMAC pain, stiffness and function and patient global assessment (PGA) by evaluating change from baseline to year 5. The second objective was to evaluate safety through Incidence of adverse events (AEs) and adverse device effects (ADEs).

Statistical methods

The study is a follow-up of an existing open label study.

Baseline data were defined as the most recent assessment with available data prior to the injection.

Changes from baseline to 5 years for effectiveness endpoints were analysed using a mixed model for repeated measurement (MMRM) with a restricted maximum likelihood (REML) based approach. The model included fixed categorical effects of week, baseline, and baseline by week interaction as covariates. Estimated changes based on the least square mean at year 5 are presented using 95% confidence intervals and corresponding p-values using the ITT analysis set.

Two additional sensitivity analyses were included to confirm the findings from the planned MMRM analyses. An ANCOVA model analysed the 5-year data of the entire population and missing values at year 5 were replaced by the participants’ baseline values (i.e., Baseline Observation Carried Forward, BOCF). The MMRM analysis was repeated using only the data from the 35 study participants entering the extension study.

Results

Disposition of participants

In summary, 50 individuals were screened, and 49 were enrolled. Of those, 46 completed the 52-week assessment, 35 entered the extension study, and 27 completed the extension study.

Demographic and baseline characteristics

The study population (N = 49) had a mean age of 70.0 years (range 44–86), with approximately two-thirds being female (63.3%). The mean BMI was 27.5 kg/m² (range 21.0–34.6), and the mean weight was 81.3 kg (range 55–125). All participants were White. A detailed overview of the demographic and baseline characteristics of the study participants included in the extension study, the group not included in the extension and the group of participants who completed the study are presented in Table 2.

Table 2.

Demographic and baseline characteristics

	Total N = 49	Not included in extension study n = 14	Included in extension study n = 35	Entered year 5 n = 27
Age (years)
Mean ± SD	70.0 (8.6)	71.4 (7.1)	69.4 (9.2)	70.1 (8.8)
Median	72.0	73.0	71.0	71.0
Range	44–86	56–83	44–86	50 – 86
Sex (n,%)
Female	31 (63.3)	9 (64.3)	22 (62.9)	18 (66.7)
Male	18 (36.7)	5 (35.7)	13 (37.1)	9 (33.3)
Race (n,%)
White	49 (100.0)	14 (100.0)	35 (100.0)	27 (100.0)
Height (cm)
Mean (SD)	171.6 (10.1)	170.3 (6.6)	172.2 (11.2)	170.9 (11.6)
Median	171.0	169.5	172.0	170.0
Range	150–191	159–180	150–191	150 – 191
Weight (kg)
Mean (SD)	81.3 (13.5)	78.5 (11.4)	82.4 (14.2)	81.0 (14.5)
Median	81.0	80.5	81.0	80.0
Range	55–125	61–99	55–125	55–125
BMI (kg/m2)
Mean (SD)	27.5 (3.3)	27.0 (2.9)	27.7 (3.4)	27.7 (3.6)
Median	27.2	26.6	27.4	27.2
Range	21.0–34.6	23.3–32.6	21.0–34.6	21.0 – 34.6
Baseline WOMAC pain
Mean (SD)	50.3 (11.8)	54.3 (9.6)	48.7 (12.3)	49.3 (13.2)
Median	50.0	57.5	50.0	50.0
Min—Max	20–75	40–65	20–75	20–75
Year 1 WOMAC pain
Mean (SD)	32.1 (20.0)	45.9 (23.2)	27.6 (16.8)	26.7 (15.9)
Median	30.0	55.0	25.0	22.5
Min—Max	0–70	0–70	0–60	0–55

BMI, Body Mass Index; N/n, Number of Participants; SD, Standard Deviation; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Effectiveness endpoints

Table 3 presents the results of the analysis of change from baseline to 5 years in WOMAC and PGA scores, while Fig. 1 shows the reductions from baseline in WOMAC pain (A), stiffness (B), physical function (C) and PGA (D) for the ITT analysis set (blue), extension participants (red), and BOCF data (green).

Table 3.

Analyses of change from baseline to 5 years in transformed WOMAC subscales (0–100) and Patient Global Assessment scores (0–100)

	Number of participants		LSMean (95% CI)	p-value
	At baseline	At 5 years
WOMAC pain subscale
Planned analysis	49	27	− 14.6 (− 21.4; − 7.7)	0.0002
Extension participants	35	27	− 15.6 (− 22.3; − 8.9)	< 0.0001
BOCF	49	49	− 9.1 (− 14.1; − 4.1)	0.0006
WOMAC stiffness subscale
Planned analysis	49	27	− 19.6 (− 29.9; − 9.3)	0.0006
Extension participants	35	27	− 21.6 (− 31.5; − 11.6)	0.0001
BOCF	49	49	− 12.2 (− 18.4; − 6.1)	0.0002
WOMAC phys. function subscale
Planned analysis	49	27	− 12.5 (− 19.8; − 5.2)	0.0015
Extension participants	35	27	− 12.2 (− 19.3; − 5.1)	0.0015
BOCF	49	49	− 7.5 (− 12.5; − 2.5)	0.0040
Patient Global Assessment
Planned analysis	49	27	− 13.4 (− 23.3; − 3.5)	0.0100
Extension participants	35	27	− 11.0 (− 20.5; − 1.6)	0.0244
BOCF	49	49	− 7.6 (− 14.0; − 1.1)	0.0232

BOCF, Baseline Observation Carried Forward; CI, Confidence Interval; LSMean, Least Squares Mean; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Fig. 1.

Mean plot of change from baseline in WOMAC subscales (0–100) and PGA (0–100) from baseline to year 5. Data are shown as mean + / − standard deviation. BOCF, Baseline Observation Carried Forward; CfB, Change from Baseline; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Safety endpoints

The safety results for Year 2 and Year 3 of the extension study have been previously reported [21, 22].

5 participants reported 5 AEs with onset between the year 3 and year 4 visits (arthralgia, bursitis, complicated appendicitis, synovial cyst, varicose vein operation), of which 1 was reported as serious (complicated appendicitis). Six participants reported 7 AEs with onset between the year 4 and year 5 visits (3 events of arthralgia, acute myocardial infarction, femoral neck fracture, foot fracture, musculoskeletal pain), of which 2 were reported as serious (femoral neck fracture, myocardial Infarction).

None of the adverse events reported between year 3 and 5 were assessed as related to the investigational device.

An overview of the safety results from the extension study between year 3 and 5 is presented in Table 4.

Table 4.

Overview of reported adverse events in year 4 and year 5 of the extension study

	Year 4* N (%) E	Year 5** N (%) E
Safety analysis set	35	35
Adverse events (AEs)	5 (14.3) 5	6 (17.1) 7
Serious AEs	1 (2.9) 1	2 (5.7) 2
Non-serious AEs	4 (11.4) 4	4 (11.4) 5
Treatment emergent AEs	5 (14.3) 5	6 (17.1) 7
Non-treatment emergent AEs	0	0
Adverse device effects (ADEs)	0	0
Serious ADEs	0	0
AEs leading to withdrawal from study	0	0
Fatal AEs	0	0

^*Reported post-year 3 visit or at the year 4 visit; ^**Reported post-year 4 visit or at the year 5 visit. AE, adverse event; ADE, adverse device effect; E, number of events; ITT, Intention-To-Treat; N, number of participants.

Discussion

Given the unmet need for sustained therapeutic benefits in the management of knee OA, with some injectables showing better outcomes in patients with early-stage OA [23], this study incorporated a long-term follow-up to evaluate the safety and effectiveness of 2.5% iPAAG in patients with moderate to severe OA over a five-year period. This report builds upon earlier reported data [14, 15] and represents the first to examine the five-year efficacy of a single, non-surgical 6-mL injection.

The treatment demonstrated sustained and significant effectiveness across all statistical analyses. Participants experienced significant reductions in WOMAC subscale scores for pain, stiffness, and physical function as well as increased quality of life. These improvements began as early as four weeks after treatment and were sustained through five years. At five years post-treatment, the observed improvements in WOMAC scores and PGA exceeded the established minimal clinically important improvement (MCII) thresholds for knee osteoarthritis: 9 points for pain, 6 points for function, and 7 points for stiffness on a 0–100 scale. [24] Given these results, 2.5% iPAAG may represent a useful treatment option for patients who are considered too young for, or who prefer to avoid, total knee replacement. By providing sustained symptom relief, 2.5% iPAAG could serve as a valuable non-surgical alternative or as a bridge therapy, helping to delay the need for joint replacement in appropriate patients.

Participants who did not participate in the extension study had higher baseline and year-one scores on the transformed WOMAC pain subscale. The study is limited by a high dropout rate due to various factors; however, the statistical analyses employed to assess treatment effectiveness were considered sufficiently robust to support the overall findings.

With respect to safety, a total of 47 AEs were reported in the extension study. The majority of these events (n = 39) were classified as mild or moderate in severity. Importantly, none of the reported AEs were assessed by investigators to be related to the study device, indicating a favourable long-term safety profile for IA 2.5% iPAAG.

While the precise mechanism of action is not fully understood, the therapeutic effects of 2.5% iPAAG are likely mediated through its interaction with the synovium. Following IA injection, iPAAG is integrated into the synovial tissue and forms a stable, long-lasting sub-synovial gel layer, which has been demonstrated in both healthy and osteoarthritic joints [25, 26], promoting angiogenesis and collagen production [26]. While speculative, it may be suggested that this biointegration enhances joint homeostasis by supporting synovial membrane regeneration, reducing inflammatory mediators, and improving the viscoelastic properties of the joint environment, thereby contributing to pain relief and improved mobility.

Limitations and strengths

The current study has some limitations. The possibility of bias is present due to the lack of a control group. The relatively small sample size, further diminished by participant attrition, constrains the generalizability of the findings. The study was also not originally designed with an extension in mind. Patients had to consent again to remain in the study, increasing the likelihood that those with a positive treatment response continued into the extension phase. This bias was addressed using a conservative baseline observation carried forward approach, which still showed statistically significant changes from baseline across all WOMAC subscales and the PGA at the year 5 visit.

Nonetheless, the study has several strengths. The study population represents the intended population to be treated with 2.5% iPAAG. Stringent exclusion criteria, such as the requirement for a stable dose of analgesics and exclusion of patients treated with corticosteroids or other IA therapies, strengthened the design by removing potential confounding effects that could introduce bias when interpreting results.

Conclusions

2.5% iPAAG remains safe and may be effective for its intended use five years after a single intra-articular injection. This study provides the first five-year data reporting both efficacy and safety outcomes following a single intra-articular injection, supporting the long-term therapeutic potential of 2.5% iPAAG in the management of knee osteoarthritis. Nevertheless, further research is needed to confirm these findings and to explore the role of long-term, non-surgical treatment options for patients with knee osteoarthritis.

Abbreviations

AE

Adverse event

ADE

Adverse device effect

ANCOVA

Analysis of covariance

BOCF

Baseline observation carried forward

BMI

Body mass index

CfB

Change from baseline

CI

Confidence interval

E

Number of events

IA

Intra-articular

iPAAG

Injectable polyacrylamide hydrogel

ITT

Intention-to-treat

LSMean

Least squares mean

MMRM

Mixed model for repeated measures

NICE

National institute for health and care excellence

NSAIDs

Non-steroidal anti-inflammatory drugs

OA

Osteoarthritis

PGA

Patient global assessment

REML

Restricted maximum likelihood

SAE

Serious adverse event

SD

Standard deviation

WOMAC

Western Ontario and McMaster Universities Osteoarthritis Index

Author’s contributions

**HB**: Conceptualization, methodology, investigation, writing—reviewing & editing. **AH**: investigation, writing—reviewing & editing. **JB**: investigation, writing—reviewing & editing **PGC**: Conceptualization, methodology, writing—reviewing & editing. **MH**: methodology, writing—reviewing & editing.

Funding

Open access funding provided by Copenhagen University. The study was sponsored by Contura International A/S. Contura International A/S was involved in the study design as well as analysis and interpretation of data. Contura International A/S was responsible for writing the clinical investigation report, has sponsored editorial and medical writing services for this manuscript and made the decision to submit it for publication. MH and HB are funded in part by the OAK Foundation that provides a core grant to The Parker Institute (OCAY-18–774-OFIL). PGC is funded in part through the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (NIHR203331). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethical approval and consent to participate

The study protocol and subsequent amendments were approved by the local Health Research Ethics committee (reference number: H-19031685), the Danish Health Authorities, and registered at ClinicalTrials.gov (NCT04179552). The participants gave informed consent prior to participation and reconsent for participation in the extension. The study was conducted according to the principles of Good Clinical Practice.

Consent for publication

Not applicable.

Competing interests

HB and MH have received travelling grants from Contura International A/S. HB has received consulting fees, honoraria, research or institutional support, educational grants, equipment, services or expenses from Abbott, Abbvie, Amgen, AstraZeneca, Aventis, Axellus, Bristol Myers Squibb, Cambridge Weight Plan, Contura, Dansk Droge, Eurovita, Ferrosan, GlaxoSmithKline, Hoechst, LEO, Eli Lilly, Lundbeck, MSD, Mundipharma, Norpharma, NOVO, NutriCare, Nycomed, Pfizer, Pharmacia, Pierre-Fabre, Proctor&Gamble, Rhone-Poulenc, Roche, Roussel, Schering-Plough, Searle, Serono, UCB, Wyeth. PGC has received consulting or speaker fees from AbbVie, Eli Lilly, Eupraxia, Formation Bio, Genascence, Grunenthal, Levicept, Medipost, Novartis, Pacira, Stryker and Takeda. MH has received consulting fees from the Thuasne Group and Leo Pharma and is associate editor of Osteoarthritis and Cartilage. JB and AH have reported no conflicts.