Effectiveness and safety of polyacrylamide hydrogel injection for knee osteoarthritis: results from a 12-month follow up of an open-label study.

OBJECTIVE: There are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data. METHODS: This multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0-100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs). RESULTS: 49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (- 17.7 points (95% CI - 23.1; - 12.4); p < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI - 17.0; - 4.9), physical function (18.0 points; 95% CI - 19.1; - 10.6), and PGA (16.3 points; 95% CI - 23.1; - 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related. CONCLUSION: This open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection. TRIAL REGISTRATION: Clinicaltrials.gov NCT04179552.

Polyacrylamide gel versus hyaluronic acid for the treatment of knee osteoarthritis: a randomised controlled study.

OBJECTIVES: To assess non-inferiority of intra-articular injectable polyacrylamide hydrogel (iPAAG) to hyaluronic acid (HA) on symptomatic benefit in individuals with knee osteoarthritis (OA). METHODS: This randomised, controlled, multi-centre trial recruited adults with symptomatic and radiographic knee OA from 3 clinical rheumatology sites in Denmark; two private clinics and one public hospital department. Participants were randomised 1:1 to receive a single intra-articular 6 mL injection of either HA or iPAAG on an outpatient basis. Primary outcome was change from baseline in WOMAC pain subscale after 26 weeks. Secondary outcomes were changes from baseline in WOMAC stiffness and physical function subscales, patients' global assessment of disease impact, EuroQoL-5D-5L, and proportion of positive OMERACT-OARSI responders after 26 and 52 weeks. RESULTS: 239 adults were randomised: 120 to HA and 119 to iPAAG. For the primary outcome, the least squares mean changes in WOMAC pain were -14.8 (95% CI: -18.0 to -11.7) for HA and -18.5 (95% CI: -21.7 to -15.4) for iPAAG; group difference: 3.7 (95% CI: -0.7 to 8.1). The lower boundary of the 95% CI respected the pre-specified non-inferiority margin of 9 WOMAC pain points. No statistically significant differences were observed for the secondary outcomes. For HA, 9 participants (7.6%) reported 13 adverse device effects (ADEs). For iPAAG, 35 participants (28.9%) reported 41 ADEs. All ADEs were mild/moderate, with no serious ADEs reported. CONCLUSIONS: iPAAG was found to be as effective and safe as HA for treatment of knee OA symptoms for at least 1 year after a single injection.

Intra-articular 2.5% polyacrylamide hydrogel for the treatment of knee osteoarthritis: an observational proof-of-concept cohort study.

OBJECTIVES: There is a drought of effective treatments of knee osteoarthritis (OA) and new therapies are needed. The present study has been conducted to establish an initial estimate of effectiveness of intra-articular (IA) injection of a proprietary 2.5% cross-linked polyacrylamide hydrogel (PAAG) for the treatment of knee OA symptoms and signs. METHODS: Patients with knee OA were invited into a prospective open-label cohort study. The patients received up to two IA injections of 3 ml of PAAG 1 month apart. The WOMAC questionnaire was used to estimate effectiveness, and was collected at baseline and after 4, 7 and 13 months. Primary outcome was change from baseline for the WOMAC pain subscale after 4 months (Normalised to 0-100 points; 100 worst). Data was analysed using a mixed-effect model without imputation of missing data. RESULTS: 84 patients (48 females) received IA PAAG. Of these WOMAC data were available from 62 after 4 months, 59 after 7 months, and 56 after 13 months. There were statistically and clinically significant reductions in WOMAC pain after 4 months (mean change -14.6 points [95% CI: -18.9 to -10.2]; p<.0001). Similar results were found in WOMAC stiffness, physical function, and WOMAC total. The improvement was sustained throughout the observation period. CONCLUSIONS: These results suggest beneficial effects of IA injection of PAAG on knee OA symptoms, even in the long term (1 year). This initial estimation of effectiveness is promising but needs to be confirmed in a randomised study with adequate measures taken to reduce risk of bias.

Associations between abnormal ultrasound color Doppler measures and tendon pain symptoms in badminton players during a season: a prospective cohort study.

BACKGROUND: Color Doppler ultrasound is widely used to examine intratendinous flow in individuals with overuse tendon problems, but the association between color Doppler and pain is still unclear. HYPOTHESIS: Intratendinous flow is present and associated with pain in badminton players, and intratendinous flow and pain increase during a badminton season. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Ninety-five semiprofessional badminton players were included in the study at a tournament at the start of the badminton season. All players were interviewed regarding pain. The anterior knee tendons and Achilles tendons were studied. Each tendon was scored using a quantitative grading system (grades 0-5) and a qualitative scoring system (color fraction) using color Doppler ultrasound. Eight months later, 86 of the players (91%) were retested by the same investigators during an equivalent badminton tournament (including 1032 tendon regions; 86 players with 4 tendons each with 3 regions), thus forming the study group. RESULTS: At the start of the season, 24 players (28%) experienced pain in 37 tendons (11%), and at the end of the season, 31 players (36%) experienced pain in 51 tendons (15%), which was a statistically significant increase (P = .0002). Abnormal flow was found in 230 tendon regions in 71 players (83%) at the start of the season compared with 78 tendon regions in 41 players (48%) at the follow-up. The decrease in abnormal flow was statistically significant (P < .0001). Of the 37 painful tendons at the start of the season, 25 had abnormal flow (68%). In contrast, 131 tendons (85%) with abnormal flow at the start of the season were pain free. At the end of the season, 18 of the 51 painful tendons (35%) had abnormal flow. Ninety-six of the 131 pain-free tendons (73%) with abnormal flow at the start of the season were normalized (no pain and normal flow) at the end of the season. CONCLUSION: It was not possible to verify any association between intratendinous flow and pain at the start of the season or at the follow-up (end of the season). Intratendinous flow at the start of the season could not predict symptomatic outcome at the end of the season. The decrease in Doppler flow during the season might suggest that intratendinous flow could be part of a physiological adaptive response to loading and that intratendinous flow as previously believed is not always a sign of pathological changes.

Gene expression of myogenic factors and phenotype-specific markers in electrically stimulated muscle of paraplegics.

The transcription factors myogenin and MyoD have been suggested to be involved in maintaining slow and fast muscle-fiber phenotypes, respectively, in rodents. Whether this is also the case in human muscle is unknown. To test this, 4 wk of chronic, low-frequency electrical stimulation training of the tibialis anterior muscle of paraplegic subjects were used to evoke a fast-to-slow transformation in muscle phenotype. It was hypothesized that this would result from an upregulation of myogenin and a downregulation of MyoD. The training evoked the expected mRNA increase for slow fiber-specific markers myosin heavy chain I and 3-hydroxyacyl-CoA dehydrogenase A, whereas an mRNA decrease was seen for fast fiber-specific markers myosin heavy chain IIx and glycerol phosphate dehydrogenase. Although the slow fiber-specific markers citrate synthase and muscle fatty acid binding protein did not display a significant increase in mRNA, they did tend to increase. As hypothesized, myogenin mRNA was upregulated. However, contrary to the hypothesis, MyoD mRNA also increased, although later than myogenin. The mRNA levels of the other myogenic regulatory factor family members, myogenic factor 5 and myogenic regulatory factor 4, and the myocyte enhancer factor (MEF) family members, MEF-2A and MEF-2C, did not change. The results indicate that myogenin is indeed involved in the regulation of the slow oxidative phenotype in human skeletal muscle fibers, whereas MyoD appears to have a more complex regulatory function.

Effect of training on contractile and metabolic properties of wrist extensors in spinal cord-injured individuals.

Paretic human muscle rapidly loses strength and oxidative endurance, and electrical stimulation training may partly reverse this. We evaluated the effects of two training protocols on the contractile and metabolic properties of the wrist extensor in 12 C-5/6 tetraplegic individuals. The wrist extensor muscles were stimulated for 30 min/day, 5 days/week, for 12 weeks, using either a high-resistance (Hr) or a low-resistance (Lr) protocol. Total work output was similar in both protocols. The nontrained arm was used as a control. Maximum voluntary torque increased in the Hr (P < 0.05) but not the Lr group. Electrically stimulated peak tetanic torque at 15 HZ, 30 HZ, and 50 HZ were unchanged in the Lr group and tended to increase only at 15 HZ (P < 0.1) in the Hr group. Resistance to fatigue, however, increased (P < 0.05) in both Hr (42%) and Lr (41%) groups. Muscle metabolism was evaluated by (31)P nuclear magnetic resonance spectroscopy ((31)P-NMRS) during and following a continuous 40-s 10-HZ contraction. In the Hr group the cost of contraction decreased by 38% (P < 0.05) and the half-time of phosphocreatine (PCr) recovery was shortened by 52% (P < 0.05). Thus, long-term electrically induced stimulation of the wrist extensor muscles in spinal cord injury (SCI) increases fatigue resistance independent of training pattern. However, only the Hr protocol increased muscle strength and was shown to improve muscle aerobic metabolism after training. Muscle Nerve 27: 72-80, 2003

Training by low-frequency stimulation of tibialis anterior in spinal cord-injured men.

The tibialis anterior muscle of nine paraplegic men was chronically stimulated (2-6 h per day; at 10 Hz, 5 s on, 5 s off) under isometric loading conditions for 5 days per week for 4 weeks. After 4 weeks of training, muscle fatigue resistance in an electrically evoked test had increased by an average of 75% (P <.01, n = 9), but there were no changes in the relative composition of the three myosin heavy chain (MHC) isoforms. Five of the subjects continued training for an additional 5 weeks (2 h per day, 3 days per week). Although there was a tendency for twitch time to peak torque to increase after this additional period, no change occurred in relative MHC isoform content. However, in situ hybridization analysis revealed that even after 2 weeks of stimulation, there was evidence of upregulation of the mRNA for the MHC-I isoform and downregulation of the MHC-IIX isoform, a development that continued in weeks 4 and 9. This study provides evidence, at the level of gene transcription, that a fast-to-slow change in MHC isoform composition may be possible in human muscle when its usage is significantly increased.