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Efficacy and safety of single-dose onabotulinumtoxinA in the treatment of symptoms of osteoarthritis of the knee: results of a placebo-controlled, double-blind study
Address correspondence and reprint requests to: T.J. Schnitzer, Northwestern University Feinberg School of Medicine, 710 N. Lake Shore Dr, Room 1020, Chicago, IL 60611, USA. Tel: 312-503-2315; Fax: 312-503-1505.
To evaluate intraarticular onabotulinumtoxinA 400 U and 200 U in reducing symptoms of knee osteoarthritis (OA) in patients with nociceptive pain.
Design
A multicenter, double-blind, randomized, placebo-controlled study was conducted in adults with knee OA and a painDETECT questionnaire score of ≤12 (indicating nociceptive pain). Patients were randomized to receive intraarticular onabotulinumtoxinA 400 U or 200 U or placebo (saline) in the study knee on a 1:1:2 ratio and were followed-up for 24 weeks posttreatment. The primary efficacy measure was the daily average numeric rating scale pain score for the study knee over 7 days at week 8. Secondary efficacy measures included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function scores, the patient global impression of change score and the 7-day average worst pain score.
Results
Of the 176 enrolled patients, 158 completed the study. The daily average pain score was reduced by approximately two points for all treatments (week 8); the reduction was sustained throughout follow-up, with no significant between-group difference between onabotulinumtoxinA and placebo (both doses: 0.22 [95% confidence interval (CI): −0.33, 0.76]; 400 U: 0.42 [95% CI: −0.26, 1.10]; 200 U: −0.03 [95% CI: −0.70, 0.64]). Similar results were found for all secondary efficacy measures. Treatment-related adverse events occurred in 3.4% of the pooled onabotulinumtoxinA group and placebo group; none were serious.
Conclusions
There were no significant differences between onabotulinumtoxinA and placebo in reducing average pain score at week 8 compared with baseline in patients with knee OA. No safety concerns were identified.
. Pain and disability associated with OA are prominent, with OA ranked in the top 10 noncommunicable diseases globally and OA of the knee representing 83% of the total OA burden
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
. Several structures of the joint may be involved, including the articular cartilage, subchondral bone, ligaments, periarticular muscles and the synovial membrane
. In addition to local mechanisms, there is evidence to suggest central sensitization plays a role in pain. Patients with OA have been found to have lower pressure pain thresholds at affected and unaffected sites. Sensitization may be key to the chronicity of pain and could play an important role in response to treatment
In a systematic review of available guidelines, nonpharmacologic approaches, including exercise and weight loss, were recommended as first-line treatment
A systematic review of recommendations and guidelines for the management of osteoarthritis: the Chronic Osteoarthritis Management Initiative of the U.S. Bone and Joint Initiative.
OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
A systematic review of recommendations and guidelines for the management of osteoarthritis: the Chronic Osteoarthritis Management Initiative of the U.S. Bone and Joint Initiative.
Coxib and traditional NSAID Trialists' (CNT) Collaboration Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
that can limit their suitability for long-term administration, particularly in certain patient groups. Thus, there remains a need for effective and well-tolerated treatment options for the long-term management of pain in patients with knee OA, particularly in those patients not suited for surgical management or unable to tolerate typically recommended therapies
Recent evidence suggests that onabotulinumtoxinA may have a role in nociceptive pain. OnabotulinumtoxinA inhibits fusion of intracellular vesicles with the nerve membrane and consequently impairs neuropeptide and neurotransmitter release, mitigating the development of peripheral and central sensitization
. Most recently, a placebo-controlled phase 1b study in 121 patients with knee OA (Kellgren–Lawrence grade I‒III) who received IA onabotulinumtoxinA 200 U was conducted. Although pain scores for the overall active treatment cohort were similar to placebo, a post-hoc analysis of the subgroup of patients with nociceptive pain showed reduced pain scores on the Western Ontario McMaster Universities Arthritis Index (WOMAC) and improved the pressure pain thresholds
in patients treated with onabotulinumtoxinA compared with placebo-treated patients. Given the need for novel treatment approaches for OA, and the post-hoc analysis finding that onabotulinumtoxinA improves knee OA pain in those with nociceptive pain, this study was undertaken to test the hypothesis that onabotulinumtoxinA effectively reduces symptoms of knee OA in patients with predominantly nociceptive pain.
Method
Study design and treatments
A phase 2, multicenter, double-blind, randomized, placebo-controlled (IA saline), parallel-group study was conducted between October 2014 and March 2016 at sites in the United States and Europe to assess the effectiveness of a single IA dose of onabotulinumtoxinA in the management of pain in patients with knee OA. The study was undertaken over 28 weeks, including a 2-week screening and wash-out period (to avoid confounding effects of concomitant medications, acute and chronic pain medications were prohibited other than acetaminophen 3 g/24 h), a 2-week baseline period, and a 24-week posttreatment follow-up period, and included a total of 10 visits (Fig. 1).
Patients were randomly allocated on a 1:1:2 ratio to either onabotulinumtoxinA 400 or 200 U or placebo, stratified into two groups by the average of the daily pain score (average daily pain score = 4.0–6.0 or 6.1–9.0; rated on an 11-point scale of 0 [no pain] to 10 [worst pain possible]) over the first 7 days of the baseline period and balanced within each investigator center. Randomization was assigned via an interactive voice-response or web-response system (IVRS/IWRS) based on a randomization scheme prepared by the sponsor. Synovial fluid effusion, if any, was aspirated from the knee, and then onabotulinumtoxinA 400 or 200 U or placebo (0.9% saline) in a total volume of 2 mL was injected into the study knee by IA injection using ultrasound guidance, a method reported to reduce procedural pain and improve patient outcomes
. All study treatments were reconstituted by an independent individual to maintain blinding by study investigators and patients. Posttreatment observations at weeks 1 and 4 and every 4 weeks thereafter to week 24 were undertaken. Synovial fluid samples, if any, were aspirated at week 12 from those patients who had synovial fluid aspirated at baseline.
The study was conducted in compliance with the Good Clinical Practice regulations and guidelines, and the investigators gained approval from the Independent Ethics Committee or Institutional Review Board at each site before initiation of the study. All patients provided written informed consent. The trial was registered with ClinicalTrials.gov; Clinical Trial identifier NCT02230956.
Concomitant treatments
Oral acetaminophen, up to 3 g per 24-h period, was the only medication permitted for knee OA pain control during the course of the study. Assistive devices, such as knee braces or supports or shoe lifts, were also allowed but assistive walking devices were not. Concomitant physiotherapy or occupational therapy could continue unchanged; however, concomitant transcutaneous electrical nerve stimulation or acupuncture to the lower extremities was not permitted.
Patients
Adults aged 40–75 years meeting the following criteria were eligible for study inclusion: stable painful primary idiopathic OA of the knee of ≥52 weeks' duration, diagnosed based on the American College of Rheumatology modified clinical classification criteria
Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
. Patients with bilateral knee OA were included if pain was dominant in one knee, which was designated the study knee. Patients were required to discontinue anti-inflammatory medicines and analgesics at least 2 days before the baseline visit. To be eligible to continue in the study, patients had to have an average daily pain score of 4.0–9.0 in the first 7 days of the baseline period (based on at least 5 days of patient-recorded diary data), and the patient had to assess their OA knee as fair, poor, or very poor at the baseline visit. Patients were required to be ambulatory without assistive walking devices and maintain their usual level of activity throughout the duration of the study.
Exclusion criteria
To ensure that the study focused on patients with nociceptive pain, patients scoring ≥13 on the painDETECT questionnaire (PD-Q), a questionnaire designed to detect neuropathic pain in patients with back pain
, at the baseline visit were excluded from the study. Patients with PD-Q scores of ≤12, indicating pain that is predominantly nociceptive, remained in the study
Patients with unstable medical conditions or concurrent chronic pain conditions were excluded from the study, as were those with evidence of rheumatoid arthritis or the presence of any condition indicative of a secondary cause for the OA of the knee. Patients with moderately severe or severe depression and those with severe anxiety were also excluded from the study.
Prior IA treatment with corticosteroid (12 weeks) or hyaluronic acid (24 weeks) before study enrollment was prohibited, as was any prior treatment with any botulinum toxin. Other standard exclusion criteria included pregnancy, known sensitivity or allergy to the study medication, and the presence of any condition that may interfere with the ability of the patient to participate in the study.
Outcomes
All pain assessments were based on the pain felt by the patient in the designated study knee and were based on an 11-point, 0–10 numeric rating scale unless otherwise noted. The daily pain score was recorded by the patients in their electronic diary, preferably each evening.
The primary efficacy measure was the daily average pain score for the study knee for the 7 days ending at the week 8 visit. The average daily pain score was compared to the average at baseline. The average daily pain scores for each 7-day period throughout the study were also assessed.
Secondary efficacy measures included the WOMAC pain score, the WOMAC physical function (difficulty performing daily activities) score, the patient global impression of change (PGIC; −3 to +3 from baseline) and the daily worst pain score at each follow-up visit compared with baseline. The WOMAC pain score measures pain across five components, with each item assessed on an 11-point scale (0 [no pain] to 10 [extreme pain]), and averaged to provide a WOMAC pain score between 0 and 10. Similarly, the WOMAC physical function score measures physical function across 17 components, assessed from 0 (no difficulty) to 10 (extreme difficulty). Exploratory measures were also collected, including biomarker concentrations in the synovial fluid effusion of the knee.
Data on the safety and tolerability of onabotulinumtoxinA were also collected. Adverse events reported by patients were recorded at each visit, and physical and clinical laboratory examinations were undertaken at screening and the final follow-up visit. The study knee, including the skin at the injection site, was inspected at baseline, after the IA injection, and at each follow-up visit to identify any adverse event. The muscle strength of knees and ankles on the treated and contralateral side was tested at baseline and every follow-up visit.
Statistical analysis
For analysis purposes two populations were defined; the safety population, which included all patients who received the study treatment (analyzed according to the treatment received), and the intention-to-treat (ITT) population, which included all randomized patients (also analyzed according to the treatment assigned). Regardless, all randomized subjects were treated with their assigned treatment, so the two populations and treatment groupings were identical.
Missing data for 7-day diary scores (the cumulative scores for daily pain, daily worst pain, the counts of rescue medications used and the number of rescue medication days) were imputed using modified last observation carried forward (mLOCF) if a patient reported data for <5 days during the 7-day diary window. For the missing data, mLOCF adjusted the most recent observation by the change rate of non-missing data to the time point of interest, i.e., LOCF multiplied by the change factor. Missing days among daily diary records were accounted for by prorating the available data if there were at least 5 days of data in the 7-day period. Missing data were not imputed for WOMAC scores or for PGIC.
Statistical comparison was done by analysis of covariance (week 8 adjusted for baseline pain score as a covariate; fixed effects included treatment, investigator center, and dose-by-center interaction); the difference between the least squares (LS) mean of the pooled onabotulinumtoxinA and placebo outcomes was the primary comparison of interest and was assessed using a 2-sided test, with P value ≤ 0.05 considered statistically significant. The LS means between-group difference of ≥1 point was chosen as the minimal clinically meaningful difference for the purpose of this analysis. A sample size of 160 was estimated to provide 96% power for pooled doses and 84% power for each dose group to detect a between-group difference of 1.14 in pain scores (an effect size of 0.6 on the 0–10 scale) and 88% power for pooled doses and 71% power for each dose group to detect a between-group difference of 0.95 in pain scores (an effect size of 0.5).
Results
Patient disposition and demographics
A total of 538 patients were screened for eligibility, and 176 patients met the enrollment criteria and were randomized to receive treatment in 18 study centers (US, 11 study centers; Europe, seven study centers). Of the 176 patients enrolled, 158 patients completed the study (89.8%), with 18 patients (10.2%) discontinuing because of the following reasons: lost to follow-up (n = 4), personal reasons (n = 4), lack of efficacy (n = 3), other reasons (n = 3), adverse events (n = 2), and protocol violations (n = 2; Fig. 2).
Fig. 2CONSORT diagram: patient disposition at key points in the study. *Of the 362 patients who failed screening, 77 had a PD-Q ≥ 13.
The majority of patients were women (60.8%) and white (80.1%), with a mean [standard deviation (SD)] age of 60.8 (8.0) years and a mean (SD) body mass index (BMI) of 31.1 (6.2) kg/m2. The mean (SD) age of onset of knee OA was 52.7 (10.2) years; bilateral knee OA (66.5%) was the most common presentation, and the right knee was more frequently involved (58.0%). Baseline demographics and clinical characteristics, including daily average pain scores and WOMAC pain scores were generally similar across all treatment groups (Table I). The WOMAC physical function score was slightly lower at baseline in the placebo group (5.0) compared with the onabotulinumtoxinA groups (onabotulinumtoxinA 400 U, 5.6; onabotulinumtoxinA 200 U, 5.4), and more patients in the placebo group had received IA hyaluronic acid previously (n = 13, 14.6%; onabotulinumtoxinA 400 U, n = 1, 2.3%; onabotulinumtoxinA 200 U, n = 4, 9.3%; Table I). There was no baseline imbalance among the treatment groups (P ≥ 0.073, Table I).
Table IPatient demographics and clinical characteristics at baseline
Across the study population, daily diary compliance rates were >90% for each 7-day reporting period, and compliance rates were similar across treatment groups.
Both onabotulinumtoxinA and placebo groups demonstrated improvements from baseline in LS mean daily average pain score at week 8, with onabotulinumtoxinA 400 U reducing the daily average pain score by 1.6 points, onabotulinumtoxinA 200 U reducing the average daily pain score by 2.1 points, and placebo reducing the daily average pain score by 2.1 points. The reduction in daily pain scores were maximal for onabotulinumtoxinA and placebo at approximately week 6 and were sustained throughout the 24-week follow-up period (Fig. 3). There was no significant difference between the reduction in daily average pain score observed between groups receiving onabotulinumtoxinA 400 U and placebo at week 8 compared with baseline (between-group difference: 0.42 [95% CI: −0.26, 1.10]; P = 0.228). Similarly, there was no difference between groups receiving onabotulinumtoxinA 200 U and placebo (−0.03 [95% CI: −0.70, 0.64]; P = 0.929) or between the pooled onabotulinumtoxinA groups and the placebo group (0.22 [95% CI: −0.33, 0.76]; P = 0.437).
Fig. 3Mean change from baseline in daily average pain scores* for IA onabotulinumtoxinA and placebo (0.9% saline). mLOCF = modified last observation carried forward. *Daily average pain scores assessed on an 11-point scale (0 indicating no pain to 10 indicating worst pain possible) over a 7-day period and compared to the average pain scores in the first 7 days of the baseline period, adjusted for baseline daily average pain as a covariate (fixed effects include treatment, investigator center, and dose-by-center interaction); missing scores were imputed using mLOCF. SEMs are within treatment, unadjusted for baseline treatment differences. There were no significant differences between mean daily average pain score at baseline (pairwise P-values >0.527; Table I).
Similarly, for all secondary efficacy outcomes, both onabotulinumtoxinA and placebo demonstrated a benefit that was sustained throughout the study period, and no statistically significant differences were observed in any secondary efficacy outcome between either onabotulinumtoxinA dose group and placebo or the pooled onabotulinumtoxinA groups and placebo at any time point. Compared with baseline scores, onabotulinumtoxinA and placebo reduced WOMAC pain scores [1.5–2.0 across all time points; Fig. 4(A)] and physical function scores [1.1–1.7 across all time points; Fig. 4(B)], indicating less pain and less physical difficulty, respectively. However, there was no significant difference in WOMAC pain scores between groups receiving onabotulinumtoxinA and placebo at any time point (e.g., at week 8: onabotulinumtoxinA 400 U vs placebo, −0.3 [95% CI: −0.99, 0.48], P = 0.494; onabotulinumtoxinA 200 U vs placebo, 0.2 [95% CI: −0.50, 0.99], P = 0.513; both onabotulinumtoxinA doses vs placebo; 0.0 [–0.61, 0.59], P = 0.979).
Fig. 4Mean change from baseline in (A) WOMAC pain scores,* (B) WOMAC physical function scores,† (C) PGIC scores,‡ and (D) 7-day average worst pain scores§ for IA onabotulinumtoxinA and placebo (0.9% saline). PGIC = patient global impression of change; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index. *WOMAC pain scores were assessed on an 11-point scale across five components (0 indicating no pain to 10 indicating extreme pain) and averaged and compared to the WOMAC pain score at baseline. †WOMAC physical function scores were assessed on an 11-point scale across 17 different functional components (0 indicating no difficulty to 10 indicating extreme difficulty) and averaged and compared to the WOMAC physical function score at baseline. ‡PGIC was assessed on a 7-point scale (−3 indicating very much worse and +3 indicating very much improved) compared with baseline. §7-Day average worst pain score is the average worst pain score assessed on an 11-point scale (0 = no pain to 10 = worst pain possible) over a 7-day period and compared to the average worst pain score in the first 7 days of the baseline period, adjusted for baseline daily worst pain as a covariate (fixed effects include treatment, investigator center, and dose-by-center interaction); missing scores were imputed using mLOCF. SEMs are within treatment, unadjusted for baseline treatment differences. There were no significant differences between mean daily worst pain score at baseline (pairwise P-values >0.261; Table I).
The PGIC score improved for all treatment groups from the first assessment at week 1, and improvements were sustained throughout the study [Fig. 4(C)]. At each assessment point >55% of patients in each treatment group reported that their condition was minimally, much, or very much improved compared with baseline; 31.0–42.3% of the pooled onabotulinumtoxinA groups and 33.8–40.2% of the placebo group reported being much or very much improved across all assessment weeks. However, there was no significant difference between the PGIC scores for groups receiving onabotulinumtoxinA and placebo at any time point (e.g., at week 8: onabotulinumtoxinA 400U vs placebo, 0.1 [95% CI: −0.35, 0.50], P = 0.719; onabotulinumtoxinA 200 U vs placebo, −0.2 [95% CI: −0.58, 0.28], P = 0.489; both onabotulinumtoxinA doses vs placebo, 0.0 [95% CI: −0.38, 0.31], P = 0.842).
The daily worst pain scores over each 7-day period were reduced from baseline in all treatment groups, and reductions reached maximal levels at approximately week 4–5 (reductions of 1.7–2.1 points) and then were generally sustained at that level throughout the study period [Fig. 4(D)]. There was no significant difference between the reduction in daily worst pain scores observed between groups receiving onabotulinumtoxinA 400 U and placebo at week 8 compared with baseline (difference: 0.39 [95% CI, −0.35, 1.12], P = 0.299). Similarly, there was no difference between groups receiving onabotulinumtoxinA 200 U and placebo (0.14 [95% CI, −0.58, 0.86], P = 0.704) or between the pooled onabotulinumtoxinA groups and placebo (0.28 [95% CI, −0.30, 0.86], P = 0.337).
Synovial fluid was withdrawn from 48 patients at baseline (onabotulinumtoxinA 400 U: n = 11; onabotulinumtoxinA 200 U, n = 14; placebo, n = 23), and 18 of these patients had synovial fluid removed at week 12 (onabotulinumtoxinA 400 U: n = 5; onabotulinumtoxinA 200 U, n = 4; placebo, n = 9). OnabotulinumtoxinA 200 U but not 400 U was associated with a significant reduction in glutamine levels compared with placebo (P = 0.028; Table II).
Table IIPercentage change in biomarker concentration at week 12 after IA onabotulinumtoxinA or placebo
Biomarkers were not isolated from the synovial fluid of all patients; number of patients with biomarker present at both baseline and week 12 indicated by [n = X].
Biomarkers were not isolated from the synovial fluid of all patients; number of patients with biomarker present at both baseline and week 12 indicated by [n = X].
Biomarkers were not isolated from the synovial fluid of all patients; number of patients with biomarker present at both baseline and week 12 indicated by [n = X].
∗ Data presented as mean (SD), if available; percentage change in biomarker concentration at week 12 compared with baseline.
† Biomarkers were not isolated from the synovial fluid of all patients; number of patients with biomarker present at both baseline and week 12 indicated by [n = X].
‡ Significant difference compared with placebo, P < 0.05.
Treatment-emergent adverse events (TEAEs), although relatively common across all groups, did not appear to be dose-related, with TEAEs occurring more frequently in patients receiving onabotulinumtoxinA 200 U (69.8%) than those receiving 400 U (54.5%; Table III). Commonly reported TEAEs were new-onset or worsening arthralgia (pooled onabotulinumtoxinA group, n = 13, 14.9% vs placebo, n = 9, 10.1%), OA, (typically worsening of the OA in the knees: onabotulinumtoxinA, n = 3, 3.4% vs placebo, n = 7, 7.9%), and nasopharyngitis (onabotulinumtoxinA, n = 3, 3.4% vs placebo, n = 7, 7.9%). There were no statistically significant between-group differences in muscle strength after treatment in either the leg muscles of the designated knee or of the contralateral side. Two patients discontinued onabotulinumtoxinA treatment because of adverse events (OA in the contralateral knee and stroke as a consequence of infarction of the basal ganglia); in neither case did the study investigators consider these adverse events to be treatment related.
Table IIISummary of AEs occurring in each treatment group and the pooled onabotulinumtoxinA treatment groups
Treatment-related adverse events (TRAEs) occurred at a similar frequency regardless of the treatment received, with TRAEs in three patients (3.4%) in the pooled onabotulinumtoxinA groups and three patients (3.4%) receiving placebo. None of the TRAEs were serious, and there were no deaths in the study. No safety concerns were identified during the course of the study.
Discussion
Administration of IA onabotulinumtoxinA 400 U or 200 U and IA placebo were all associated with improvements in daily average pain scores within 4 weeks, reaching a peak at approximately 6 weeks and remaining for 24 weeks after treatment. The reduction in average daily pain scores observed for all treatments (onabotulinumtoxinA 400 U, 1.6 points; onabotulinumtoxinA 200 U, 2.1 points; placebo, 2.1 points) was consistent with a clinically meaningful response of much or very much improved
However, despite reduction in knee pain in patients receiving onabotulinumtoxinA in this study, a similar reduction in knee pain was seen in patients receiving placebo (IA saline). Thus, there is no evidence that onabotulinumtoxinA contributed significantly to the pain reduction observed. This is similar to the results of an earlier pilot phase 1b study, where there was no difference in efficacy outcomes between IA onabotulinumtoxinA 200 U and placebo in the overall patient group, including patients with nociceptive pain and those without evidence of nociceptive pain. However, unlike the results seen in this study, post hoc analysis of the subgroup of patients with nociceptive pain in the earlier study demonstrated a more favorable outcome with onabotulinumtoxinA
In the current study, the placebo group was consistently associated with a positive effect across the range of primary and secondary efficacy measures. Most remarkably, the placebo effect was clinically meaningful (typically an improvement of two points on the 11-point pain scales) and sustained throughout the 24-week follow-up. Altman et al. have recently undertaken a systematic review of the clinical benefit of IA saline in knee OA
Clinical benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: a systematic review and meta-analysis of randomized trials.
. In both short-term (≤3 months) and long-term (6–12 months) trials, IA saline provided significant improvement in knee pain, leading the authors to suggest that IA saline may provide a physiologic effect per se and is not a true placebo. Further, it is suggested that IA saline, possibly through arthrocentesis into the knee joint, influences the nociceptive response
. If the benefit of IA saline and arthrocentesis is most pronounced in patients with nociceptive pain, particularly when synovial fluid has been aspirated from the knee joint, this may help to explain the relatively large placebo response in our study, which was undertaken in patients identified as having nociceptive pain using the PD-Q tool validated in patients with back pain
. However, the presence of a physiologic effect associated with a placebo comparator does little to explain the difference in outcomes between the results of this study and the results of a post hoc analysis in the earlier phase 1b study, which also used IA normal saline 2 mL as the placebo control and aspirated any synovial fluid present
. In comparison to the earlier phase 1b single-center study, our study was multicentered and powered to detect between-group differences in pain scores, suggesting that the results from the earlier post-hoc analysis of a subpopulation in the phase 1b study may have been spurious. The presence of a physiologic effect with placebo also does little to explain the lack of a dose response for onabotulinumtoxinA or the lack of difference of clinical effect between onabotulinumtoxinA and placebo in this study.
It was found that a single IA injection of onabotulinumtoxinA 400 U and 200 U into the knee was well tolerated compared with placebo and had no detrimental effect on muscular strength. This replicates the findings of other studies using lower IA doses of onabotulinumtoxinA (20–200 U)
Results from a single center, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy and safety of intra-articular onabotulinumtoxinA for osteoarthritis knee pain (Poster 330).
in: Presented at: World Congress on Osteoarthritis. Osteoarthritis Research Society International [OARSI],
Paris, FranceApril 24–27, 2014
This study is not without its limitations. The relatively small sample size may limit the generalizability of the results. While the sample size was powered to detect a clinically meaningful difference in response between onabotulinumtoxinA and placebo, the large placebo effect was not expected. The evaluation of efficacy after single dose administration of onabotulinumtoxinA may also limit the applicability of results in a population with chronic pain. In other chronic pain populations, such as those with chronic migraine, repeated administration of onabotulinumtoxinA provides additional benefit
Another limitation could have been using solely patient-related subjective measures to assess efficacy. In a meta-analysis of randomized controlled trials, Zhang et al. reported that although including a placebo typically was effective in reducing patient-related subjective outcomes such as pain, it was less effective in improving more objective performance-based measures such as timed walking distances
OARSI Clinical Trials Recommendations: key analytic considerations in design, analysis, and reporting of randomized controlled trials in osteoarthritis.
, in this study the addition of a performance-based measure may have been useful to fully determine the effect of placebo.
An additional limitation to the current study is the use of the PD-Q screening questionnaire as a screening tool to identify nociceptive pain in patients with knee OA. At the time of the pilot study, the PD-Q was the best available tool to identify patients with nociceptive pain; it had been validated in patients with low back pain of varying origins
modified the PD-Q (mPD-Q) and reported the mPD-Q was valid to detect central sensitization in patients with knee OA. However, they did not recommend using a cut-off point of 12 and recommended further validation of the mPD-Q, a sentiment echoed by others
Pain phenotype in patients with knee osteoarthritis: classification and measurement properties of painDETECT and self-report Leeds assessment of neuropathic symptoms and signs scale in a cross-sectional study.
. In our patient group, a total of 24 of 176 patients (13.6%; 13 in the pooled onabotulinumtoxinA group and 11 in the placebo group) were classified as having nociceptive pain (PD-Q≤12) at the baseline visit but not at the screening visit. Subgroup analysis of the patients classified as nociceptive at the screening visit and at baseline did not demonstrate any significant difference between onabotulinumtoxinA and placebo (data not shown). Additionally, biomarkers could only be assessed in patients who had sufficient fluid to aspirate and therefore, due to the small numbers of patients with sufficient fluid aspirated, the interpretation of the observed lack of difference in biomarkers is inconclusive. For some biomarkers (substance P, collagen C-telopeptide−2 [CTX-2], aggrecan, matrix metalloprotease-3 [MMP-3], and hyaluronic acid) there appeared to be a dose-related reduction in synovial fluid concentration; however, such an observation must be interpreted carefully.
Conclusions
In this multicenter, double-blind, randomized, placebo-controlled study, both IA onabotulinumtoxinA and placebo (IA saline injection) resulted in similar reductions from baseline in the daily average pain score at week 8 and in the WOMAC pain score, WOMAC physical function score, and daily worst pain scores at all posttreatment time points, indicating patients had less pain or dysfunction after treatment, which was sustained through the 24-week study period. However, no statistically significant differences between onabotulinumtoxinA and placebo were observed, despite an earlier post hoc analysis in a phase 1b study suggesting that IA onabotulinumtoxinA effectively reduces nociceptive pain associated with OA of the knee. Further investigation may be considered to evaluate the role for onabotulinumtoxinA, if any, in the management of pain from knee OA. OnabotulinumtoxinA was well tolerated and no new safety concerns were identified during the study.
Author contributions
All authors have made substantial contributions to (1) the conception and design of the study, acquisition of data and analysis/interpretation of data, (2) revising the manuscript critically for intellectual content, and (3) final approval of the version to be submitted. Specifically, TEM, US, DB, SA, TG, RED, KK, and TJS participated in the analysis and interpretation of the data; TEM, US, DB, SA, TG, RED, KK, and TJS critically revised the manuscript for important intellectual content; TEM, US, DB, SA, TG, RED, KK, and TJS approved the final submitted version of the paper; TEM, US, and TS provided patients for the study; and RED and KK provided statistical expertise. All authors had access to the data from the study and take responsibility for the integrity of the work as a whole, from inception to finished article (Timothy McAlindon: [email protected]; Ulla Schmidt: [email protected]; Denise Bugarin: [email protected]; Till Geib: [email protected]; Ronald DeGryse: [email protected]; Kimmie Kim: [email protected]; Steve Abrams: [email protected]; Thomas J Schnitzer: [email protected]).
Competing interest statement
Timothy E. McAlindon has received consultancy fees (<$5000/y) from Allergan, Pfizer, Sanofi, Novartis and Flexion. Ulla Schmidt has no financial disclosures to declare. Denise Bugarin, Steve Abrams, Till Geib, Ron DeGryse, and Kimmie Kim are employees of Allergan plc and may own stock in the company. Thomas J. Schnitzer discloses research support to his institution from AbbVie, Pfizer, Regeneron, Grunenthal, Axsome, and Amgen.
Role of the funding source
This study was sponsored by Allergan plc (Dublin, Ireland). Allergan funded the editorial and writing support, and provided support for the study design, and the collection, analysis and interpretation of the data. Allergan did not have a role in the final decision of which data to include in the manuscript and on the decision to submit the manuscript for publication.
Acknowledgments
Writing and editorial assistance was provided to the authors by Lee Hohaia, PharmD, and Dana Franznick, PharmD, of Complete Healthcare Communications, LLC (Chadds Ford, PA, USA), a CHC Group company, and funded by Allergan plc (Dublin, Ireland). All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship.
The following principal investigators participated in this study: USA: Timothy McAlindon (Boston, MA), Dinh Dinh (Artesia, CA), Rakesh Patel (Salisbury, NC), Paul Lunseth (Tampa, FL), John Ledbetter (Monroe, LA), Vishala Chindalore (Anniston, AL), Alan Matsumoto (Wheaton, MD), Marvin Tark (Marietta, GA), Atul T. Patel (Overland Park, KS), Thomas Schnitzer (Chicago, IL), Angela Rowe (Altoona, PA), O. Taunton (Bedford, TX); Czech Republic: Tomas Hala (Pardubice), Nadezda Fiserova (Brno), Jan Rosa (Prague), Petr Vitek (Zlin); Denmark: Martin Jensen (Aalborg), Peter Alexandersen (Vejle), and Ulla Schmidt (Ballerup).
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