Comparison of Oral Robenacoxib and Carprofen for the Treatment of Osteoarthritis in Dogs: A Randomized Clinical Trial

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Elanco

Data de Publicação

01/11/2018

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Kazuya EDAMURA, Jonathan N. KING, Wolfgang SEEWALD, Nobuhiro SAKAKIBARA and Masahiro OKUMURA

ABSTRACT. The efficacy and tolerability of robenacoxib for the treatment of osteoarthritis in dogs were evaluated in a prospective, multicenter, randomized, noninferiority design clinical trial. A total of 32 dogs presenting with osteoarthritis were allocated randomly to receive, orally once daily for 28 days, either 1–2 mg/kg robenacoxib (n=21) or 3.5–5 mg/kg carprofen (n=11). Dogs were assessed by clinicians and owners using numerical rating scale scores at baseline and days 14 and 28. The primary efficacy endpoint was the global functional disability score, which was the sum of clinician scores for standing posture, lameness at walk, lameness at trot, willingness to raise the contralateral limb and pain at palpation. There was a good to excellent level of efficacy in both treatment groups. Differences between days 14 and 28 compared to day 0 were significant for all 11 clinician and owner scores for robenacoxib, and for 6 of 11 scores for carprofen. The efficacy of robenacoxib was numerically superior to carprofen for all 13 endpoints, but differences were not statistically significant. For the global functional disability score, the estimated efficacy of robenacoxib was 1.244 (95% confidence interval 0.555–2.493) relative to carprofen. The tolerability of both treatments was good as assessed from adverse events, clinical signs, and hematology and serum biochemistry variables. In conclusion, once daily administration of robenacoxib tablets had noninferior efficacy and tolerability compared to carprofen for the treatment of the clinical signs of osteoarthritis in dogs.

Canine osteoarthritis is a common disorder affecting dogs of all ages, with an incidence as high as 73% in some breeds. It is characterized by articular cartilage lesions, underlying bone remodeling with osteophytes, inflammation and pain. The most frequently involved joints are the stifle, elbow and hip.

At present, there are no drugs proven capable of reversing the pathological changes of osteoarthritis, and therefore the main aim of therapy remains the reduction of pain and inflammation with nonsteroidal anti-inflammatory drugs (NSAID). NSAIDs maintain mobility and quality of life.

In Japan, several NSAIDs are registered for use in canine osteoarthritis (carprofen, firocoxib, ketoprofen, meloxicam and tepoxalin), but older NSAIDs are associated with gastrointestinal side-effects. Recently, experimental investigations in healthy Beagle and mixed breed dogs have confirmed the propensity of carprofen, etodolac, flunixin, ketoprofen and meloxicam to cause lesions of the upper gastrointestinal tract, when administered at recommended dosages.

Robenacoxib is a new coxib NSAID, developed solely for companion animal use. It is highly selective for the cyclo-oxygenase (COX)-2 enzyme in dogs. In whole blood assays, robenacoxib was 129 fold more potent for COX-2 relative to COX-1 in vitro, and ex vivo a dosage of 1–2 mg/ kg administered orally significantly inhibited COX-2 but had no effect on COX-1. Moreover, robenacoxib was well tolerated and had a high safety index in healthy dogs.

In a European clinical trial, robenacoxib had noninferior efficacy compared to carprofen in dogs with osteoarthritis when administered once daily for 12 weeks. In the present study, robenacoxib was administered once daily for 28 days, and was compared to carprofen as a positive control in a noninferiority clinical trial in Japan.

The objective of this study was to evaluate the efficacy and tolerability of a tablet formulation of robenacoxib for the treatment of the clinical signs of osteoarthritis in dogs in Japan. Since breed distribution and management of dogs in Japan may differ from Europe, the Japanese regulatory authorities require that new medicines are evaluated in local field studies. Repetition of field studies in different geographical locations also provides more confidence in the results.

Materials and Methods

Animals and study design: The study was a prospective, randomized, parallel-group design noninferiority clinical trial with 2 treatment groups, robenacoxib and carprofen.

It was multi-centered, involving 17 veterinary practices from several geographic locations in Japan, and was conducted in compliance with Good Clinical Practice for Veterinary Pharmaceutical Products (Ordinance No. 75, Ministry of Agriculture, Forestry and Fisheries, Japan, 1997).

The study protocol was approved by the Japanese regulatory authorities and internal Novartis reviews taking into account scientific, ethical, and animal welfare guidelines. All dog owners provided written consent for their animal to participate in this study. The schedule is provided in Table 1.

Inclusion and exclusion criteria: A detailed investigation of each dog was performed at baseline on day 0 by the clinician investigator. Inclusion criteria were dogs: ≥6 weeks of age, body weight 2.5 to 80 kg, of both sexes and any breed, presenting with both clinical signs and radiographic evidence (e.g. articular surface erosion, presence of osteophytes) of osteoarthritis; lameness and/or pain in affected joints present on palpation.

If several joints were affected by osteoarthritis, the most severely affected joint was selected for efficacy assessment. The diagnosis was based on history, general physical examination, orthopaedic examination, clinical signs and, if required, by additional analyses, including radiographs.

Exclusion criteria were a primary neurological disorder; lameness associated with neoplasia or known immunological disorder; surgery conducted on any joint during the previous 60 days; gross instability of the stifle joint; pregnant or lactating female dogs or dogs intended for breeding; dogs with severe concomitant disorders (heart, kidney or liver insufficiency, gastrointestinal disorder) that might have affected assessment of response to treatment; dogs which had received prior to inclusion local or systemic NSAIDs within 14 days, corticosteroids within 30 days (systemically) or 90 days (intra-articularly); and dogs known not to be available for the full duration of the study.

Randomization and blinding procedures: After selection for the trial, dogs were allocated randomly to one of the treatment groups in a 2:1 (robenacoxib:carprofen) ratio using randomization lists prepared using a computer randomnumber generator for each trial site.

Because robenacoxib and carprofen tablets have a different appearance, masking of clinician assessments was achieved by the “blinding by function” method, using 2 investigators. One (the clinician) was responsible for clinical assessments, and the 2nd (the dispenser) was responsible for dosing on first administration, dispensing tablets to the owners and control of treatment compliance. Owners were not formally blinded.

Drugs and dosing procedures: Dogs received orally once daily either robenacoxib or carprofen. The dosage of robenacoxib was the registered dosage of 1–2 mg/kg. The dosing scheme was one tablet containing 5, 10, 20 and 40 mg robenacoxib (Onsior tablets, Novartis Animal Health K.K., Tokyo, Japan), respectively for dogs weighing 2.5–5.0, 5.0– 10.0, 10.0–20.0 and 20.0–40.0 kg, and two 40 mg tablets for dogs weighing 40.0–80.0 kg.

For carprofen, the registered mean dosage of 4.4 mg/kg (range 3.5–5 mg/kg) once daily was administered, using Rimadyl Chewable Tablets 25, 75 and 100 mg tablets (Pfizer Japan, Inc., Tokyo, Japan). Carprofen was chosen as the positive control for this study, as it is the most widely used NSAID licensed for the relief of osteoarthritis pain in Japan.

Assessment of efficacy: The clinician investigators, who were masked to the treatment groups, assessed the dog using numerical rating scales (NRSs) for 5 indices: standing posture, lameness at walk, lameness at trot, willingness to raise the contralateral limb and pain on palpation/mobilization (Table 2).

These scores were recorded on days 0, 14 (range 12–16) and 28 (range 24–32) (Table 1). The primary endpoint was the global functional disability score, which was the sum of the individual 5 NRS values. Animal owners, who were not blinded to the treatment group, also assessed the activity, stiffness, lameness, and overall quality of life of their dog on each dosing day using NRSs (Table 3).

Both clinicians and owners also assessed the overall response to treatment on days 14 and 28 (Tables 2 and 3). All individual clinician assessments and all owner assessments except for primary endpoint were secondary endpoints.

Concomitant treatments: Disallowed concomitant treatments were all classes of analgesics including opioids and other NSAIDs, corticosteroids, sodium pentosan polysulphate, glucosamine, chondroitin sulphate and highly protein bound drugs. Other concomitant treatments were allowed, as long as they did not interfere with the objectives of this study. When concomitant treatments were used, details of treated conditions and dosing schedules were recorded.

Tolerability: The clinician investigator examined each dog, recording appetite, vigor and fecal consistency on days 0, 14 (range 12–16) and 28 (range 24–32). The clinician investigator also collected and recorded data on adverse events by interviewing the owner on days 14 and 28.

Clinical chemistry and hematology: Blood samples for clinical chemistry and hematology were collected before treatment on day 0 and then on days 14 (range 12–16) and 28 (range 24–32). Serum clinical chemistry variables comprised activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyl transferase, and concentrations of creatinine, total protein and urea. Hematology variables comprised hematocrit, hemoglobin concentration, red blood cell count, platelet count, and total and differential white blood cell counts.

Statistical analyses: The software SAS, Version 9.1.3. (SAS®, Cary, NC, U.S.A.) was used for all calculations. Data are presented as mean ± standard deviation (S.D.). To determine statistical significance, tests were 2-sided on a 5% level (α=0.05). The primary analysis of both efficacy and tolerability variables was performed on the per-protocol (PPR) data set. A secondary analysis was conducted using the all-randomized animal (ARA) data set. There were no relevant differences in conclusions from the analyses of the PPR and ARA data sets, therefore only results from the PPR analysis are reported.

Demographic and baseline data were compared between groups using the Mann-Whitney test for ordinal (e.g. body weight) or binary data (e.g. sex), the Kruskal-Wallis test for non-binary nominal data (e.g. combination of sex and neutered status), and Fisher’s Exact test for frequency data.

For efficacy scores, clinical chemistry and hematology data, analysis of variance (ANOVA) models was fitted. Covariance models (ANCOVA) were used, if there was at least one covariate (e.g. baseline pain). Repeated measures models (RMANOVA or RMANCOVA) were used, if there were repeated measurements after baseline, as for most efficacy scores. Responses were in some cases log- or power-transformed to produce the best approximation of a normal distribution.

For summary statistics and non-parametric analyses, but not (RM)AN(C)OVA analyses, missing values were imputed using the last observation carried forward method. For efficacy assessments, the initial RMANCOVA models contained the following variables: baseline value, subject (as a random effect), treatment group, time, treatment group x time interaction. Covariables (except for treatment group) which gave P>0.10 were deleted from successive iterations of the model.

Noninferiority comparisons of the efficacy of robenacoxib compared to carprofen were performed by calculating estimates and 95% confidence intervals [CI] for the ratio of the reciprocal of efficacy scores (mean of values at V2 and VFinal, Table 1) in the robenacoxib group/carprofen group from the RMANOVA models. Reciprocals of clinical scores were used so that estimates >1 indicate superior efficacy of robenacoxib. A delta (δ) value of 0.25 was selected, as was used in a recent NSAID clinical trial in children, so that noninferiority was concluded if the lower boundary of the 95% CI for the ratio was greater than 0.75 (1-δ).

Differences between groups at each time point were also compared with the Mann-Whitney test. Change from baseline in efficacy scores was analyzed using the pairedsamples Wilcoxon test.

Results

Baseline and demographic data: A total of 40 dogs (ARA population) were enrolled in this study. A total of 8 dogs violated pre-admission exclusion criteria (1 case received NSAIDs within 14 days prior to inclusion, and 7 cases did not have any data post-treatment) and were removed from the PPR data set.

Therefore, a total of 32 dogs were included in the primary PPR population analysis (21 received robenacoxib, 11 received carprofen). There were no significant differences between groups in demographic and baseline data except for duration of clinical signs which was significantly longer (P=0.049) in the dogs that subsequently received carprofen (Table 4).

This was judged not to be relevant since the intensity of clinical signs was not significantly different between groups at baseline, and scores at baseline were higher in the robenacoxib group for the primary endpoint, the global functional disability score (Table 5). The joints affected included the elbow, hip, metacarpal/tarsal,stifle,spine, and other not defined. A total of 16 breeds were represented with no significant difference between groups (P=0.18).

The commonest breeds were cross-bred (5), Labrador Retriever (4), Golden Retriever (3) and Minature Dachshund (3). All other breeds were represented by 1 or 2 dogs only. The mean ± S.D. dosage of the test articles administered was 1.55 ± 0.34 mg/kg robenacoxib and 4.29 ± 0.53 mg/kg carprofen.

Clinician investigator efficacy assessment: The clinician investigator’s efficacy assessments on days 0 (before treatment), 14 and 28 are summarized in Table 5. Values for all assessed variables were similar at all three time points and there were no significant differences between the groups for any endpoint at any of the time points. At the time of the final assessment (on day 28), the percentage ± S.D. decrease in mean values compared to baseline for the global functional disability score was 70.1 ± 29.9 for robenacoxib and 51.2 ± 52.9 for carprofen.

There was a good to excellent level of efficacy of similar magnitude in both treatment groups. Differences between days 14 and 28 compared to day 0 were highly significant (P<0.001, paired-samples Wilcoxon test) for all 6 clinician global and NRS scores for robenacoxib (Table 5).

For carprofen, differences at days 14 and 28 compared to baseline were significant (P<0.05) for only 3 of 6 scores (global functional disability score, standing posture and lameness at walk). RMANCOVA analysis on the PPR data set indicated no significant (P>0.1) effects of treatment group or treatment group x time interaction. There was a significant time effect (P<0.05), with a decrease in scores with time for all clinician endpoints.

Noninferiority of robenacoxib compared to carprofen was demonstrated for only one clinician endpoint, pain at palpation (lower limit of CI>75%, Table 6). For the primary endpoint (global functional disability score), the estimated efficacy of robenacoxib was 1.244 (95% CI 0.555 − 2.493) relative to that of carprofen.

Owner efficacy assessment: For all 5 owner assessed global and NRS scores, robenacoxib demonstrated clear improvement at both the 14 and 28 day assessments and differences from baseline were highly significant (P<0.0005, Table 7). For carprofen, changes from baseline on both days 14 and 28 were significant for 3 of the 5 scores (P<0.05). At day 28, mean ± S.D. percentage decreases from baseline of the global owner score were 60.8 ± 30.8 for robenacoxib and 49.8 ± 44.8 for carprofen.

Differences between group means were not statistically significant. Using RMANCOVA, noninferior efficacy of robenacoxib compared to carprofen was demonstrated for the global owner score and the owner’s assessment of stiffness (Table 8).

Tolerability: There were no reported adverse events in the carprofen group and 3 benign adverse events in the robenacoxib group, comprising single instances of diarrhoea (2 dogs) and vomiting (one dog). Differences were not significant (P=0.54).

Clinical chemistry and hematology: Summary data of clinical chemistry and hematology variables with nonparametric statistical analyses are shown in Tables 9 and 10. There were no significant changesfrom baseline for any variable using either ANCOVA or the Wilcoxon test. There were no significant differences between groups for any variable using RMANOVA except for alkaline phosphatase during treatment which showed a significantly (P=0.016, data not shown) higher increase from baseline with carprofen compared to robenacoxib.

There were no significant differences between groups at days 14 and 28 using the Mann-Whitney test (Tables 9 and 10). Serum creatinine concentrations were higher (P=0.013) at baseline in the dogs randomized to the robenacoxib group, but there were no significant differences between groups at days 14 or 28 (Table 9).

Concomitant treatments: There were no significant differences between groups for numbers or drug classes of concomitant treatments. No adverse interactions between concomitant treatments and the test articles were observed.

Discussion

The principal findings of this study are that the new NSAID robenacoxib had noninferior efficacy and tolerability compared to carprofen for the treatment of the clinical signs of osteoarthritis in dogs.

The relative efficacy of robenacoxib was better than for carprofen for the primary efficacy endpoint and all 12 secondary endpoints, although differences were not statistically significant. Statistical noninferior efficacy of robenacoxib was shown for only 3 secondary endpoints and not for the primary endpoint, due to wide confidence intervals explainable by a combination of relatively high variability in scores and low sample sizes.

For the primary endpoint, the global functional disability score, the relative efficacy of robenacoxib versus carprofen was 1.244 (95% confidence interval 0.555–2.493). Therefore, we conclude that the efficacy of robenacoxib was at least as good as for carprofen. Noninferior efficacy of robenacoxib compared to caprofen was demonstrated also in a previous field study conducted in the EU.

The major differences between the 2 studies are that the EU study involved treatment for 3 months, and included more dogs (188), and these had a higher mean body weight (32.1 kg) compared to the mean body weight of 17.9 kg in our 40 dogs. The commonest breeds in the EU study [19] were Labrador Retriever (21%), crossbred (16%) and German Shepherd (12%), compared to crossbred (16%), Labrador Retriever (13%), Golden Retriever (9%) and Minature Dachshund (9%) in the present study.

The finding of similar conclusions in the 2 independent studies provides higher confidence in the results. In contrast to humans, animals cannot articulate their experience of pain, so that evaluating animal pain presents significant challenges. Holton et al. concluded that the assessment of pain in dogs is best achieved by observing and recording changes in behavior, locomotion and demeanor.

For these and other observations, NRSs were used in the present study. They were preferred to simple descriptive scales which lack of sensitivity and visual analogue scales for which high inter-observer variability is common. Therefore, although the estimation of pain was subjective, the assessments used in the present study are considered to have provided good indications of efficacy, especially as several endpoints were used.

Carprofen was selected as the positive control drug for this study for several reasons. First, carprofen is the most widely used NSAID in Japan for treating osteoarthritis in the dog. Second, published data on carprofen are extensive; its efficacy has been well established in previous clinical trials in comparison with other NSAIDs, placebo or no alternative treatment.

Superior efficacy of carprofen compared to a placebo has been demonstrated in dogs with the urate synovitis model of arthritis[1] and in dogs with spontaneous osteoarthritis. Thirdly, carprofen had the best gastrointestinal tolerability of 5 NSAIDs (carprofen, etodolac, flunixin, ketoprofen and meloxicam) in a comparative study when administered daily for 6 week. Previously, Forsyth et al. concluded that carprofen produced less gastroduodenal lesions than ketoprofen or meloxicam.

In light of these published findings, carprofen may be regarded as the preferred NSAID against which to assess a new agent such as robenacoxib for canine osteoarthritis therapy from both efficacy and safety perspectives.

Carprofen is preferentially selective for COX-2 in dogs (COX2/COX1 potency ratio of S+ enantiomer is 18), while robenacoxib is highly selective (COX2/COX1 potency ratio is 129). Of clinical relevance is the fact that COX-1 sparing properties have been confirmed in dogs with chronic osteoarthritis with carprofen and in healthy Beagle dogs with robenacoxib.

The tolerability of both treatments was good as assessed from adverse events, clinical signs, serum chemistry and hematology variables. The rationale behind the development of the coxib NSAIDs is that they should cause less damage to the gastrointestinal tract and less inhibition of blood clotting compared to non-selective NSAIDs.

Lumiracoxib, an analogue of robenacoxib, was proven to produce less frequent serious gastrointestinal tract adverse events (bleeding, perforation or obstruction) compared to the non-selective NSAIDs ibuprofen and naproxen in humans. The clinical trial in dogs described in this study was not powered to test for superior tolerability or safety; notably the number of dogs was too small, the treatment time was short (1 month) and the safety variables measured were not sensitive.

A dedicated study with larger numbers of dogs and/or specific assessments of the gastrointestinal tract are needed to test for potential superior safety. Robenacoxib has a good safety index in healthy dogs, producing no biologically relevant toxicity at dosages as high as 40 mg/kg daily for 1 month and up to 10 mg/kg daily for 1 month.

Strengths of the present study include the fact that it followed the gold-standard design of being multi-centered, prospective and randomized. The principal limitations of the study are related to non-blinding of owner assessments, the relatively small group sizes and inherent weaknesses of the non-inferiority design.

Clinician investigator assessments were masked via the use of the “blinding by function” technique. Inclusion of an additional placebo group, to provided internal validity, was judged unnecessary, since the efficacy of carprofen, the positive control, has been proven to be superior to placebo both in the challenging urate crystal synovitis model and in clinical dogs with osteoarthritis.

Furthermore, both Holtsinger et al. and Vasseur et al. established the efficacy of carprofen compared to placebo using NRSs similar to those used in the present study. In optimally designed noninferiority studies, the methods and outcome measures should be similar to those used in the original studies of the active control.

Furthermore, inclusion of a placebo group would have caused ethical concerns, since several NSAIDs are registered and widely used to treat canine osteoarthritis in Japan. In conclusion, once daily administration of robenacoxib tablets had noninferior efficacy and tolerability compared to carprofen for the treatment of the clinical signs of osteoarthritis in dogs.

Acknowledgments

We thank Drs Shinji Abe, Jun Ando, Masaya Hikosaka, Koji Hosomizo, Tatsuo Kaneshige, Masako Kawamata, Hirokazu Kimura, Toru Kurita, Yasushi Matsumura, Noriyuki Minegishi, Masaaki Mochizuki, Toshiaki Mogi, Hideyuki Nagae, Shigeru Nakamura, Shinichi Namba, Yuzuru Sakai and Masahiro Takahashi for seeing clinical cases and Professor Peter Lees for assistance with the manuscript.

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