Clinical Pharmacology, Merck Research Laboratories, Rahway, NJ,
1 Department of Medicine, Northwestern University Medical School, Chicago, IL,
2 Health Research of Hampton Roads, Newport News, VA,
3 Arthritis Northwest, Seattle, WA,
4 Hospital for Special Surgery, New York, NY,
5 Clinical Biostatistics, Merck Research Laboratories, Rahway, NJ and
6 Pulmonary-Immunology, Merck Research Laboratories, Rahway, NJ, USA
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Abstract |
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Methods. This two-part, randomized, double-blind, placebo- and active comparator-controlled trial was conducted in 617 adults with knee OA. In Part 1 (6 weeks), patients received placebo, etoricoxib 5, 10, 30, 60 or 90 mg q.d. In Part 2 (8 weeks), patients received etoricoxib 30, 60 or 90 mg q.d. or diclofenac 50 mg t.i.d., predetermined at Part 1 allocation. Efficacy and safety were evaluated. Primary efficacy end-points were the Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain subscale, Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status.
Results. At 6 weeks, etoricoxib 5, 10, 30, 60 and 90 mg each demonstrated clinical efficacy superior to placebo. Maximal efficacy was seen with 60 mg. In Part 2, etoricoxib 30, 60 and 90 mg were generally similar to diclofenac. Patients receiving etoricoxib 30, 60 or 90 mg in Parts I and II had sustained effects over 14 weeks. All treatments were well tolerated.
Conclusions. Etoricoxib 60 mg once daily showed maximal efficacy in treating OA in this study. Etoricoxib 590 mg once daily was generally well tolerated in OA patients for up to 14 weeks.
KEY WORDS: Etoricoxib, Osteoarthritis, Efficacy, Safety, Tolerability.
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Introduction |
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Methods |
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Study design
This was a two-part dose-finding study conducted over 14 weeks (Fig. 1). The study objectives were to demonstrate the clinical efficacy of etoricoxib in the treatment of OA of the knee, to define the clinically active dose range of etoricoxib in the treatment of OA in order to permit dose selection for further clinical trials, and to evaluate the overall safety and tolerability of etoricoxib with once-daily administration.
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Part 2 was an 8-week active comparator-controlled period. Treatments in Part 2 were etoricoxib 30, 60 and 90 mg once daily and diclofenac 50 mg three times daily, and were preassigned by the same allocation schedule as that used in Part 1. Patients receiving etoricoxib 5 or 10 mg or placebo in Part 1 received etoricoxib 30 mg or diclofenac in Part 2. Half of those patients receiving etoricoxib 30 or 60 mg in Part 1 received etoricoxib 60 or 90 mg respectively in Part 2, and the remaining patients received the same study medication during Part 1 and Part 2.
Study blinding was maintained by using a matching placebo for each study medication; all treatments were double-dummy. In Part 1, patients took two tablets each morning. In Part 2, patients took three tablets each morning (etoricoxib 30 mg or placebo, etoricoxib 60 mg or placebo, and diclofenac or placebo), one tablet (diclofenac or placebo) at midday and one (diclofenac or placebo) in the evening. After completing 2 weeks of treatment, patients were provided open-label acetaminophen, maximum daily dose of 2.6 g, that could be taken for osteoarthritic pain that was not adequately controlled by the study medication. Patients returned to the study centre following 1, 2, 4, 6, 8 and 14 weeks of therapy for efficacy and safety assessments. Patients who did not enter a voluntary extension at the end of Part 2 returned 710 days after their last dose of study medication for post-therapy safety assessments.
Entry criteria
Patients were a minimum of 40 yr old and had both clinical and radiographic evidence of OA. Patients with OA of the knee (tibiofemoral joint only) were eligible. Radiographic criteria were joint-space narrowing with the presence of osteophytes. The study joint had to be the primary source of pain or disability. Patients were in American Rheumatism Association (ARA) functional class I, II or III. All patients required NSAIDs for their OA pain for at least 25 of the 30 days prior to screening. Patients who satisfied entry criteria discontinued their prior NSAID therapy. Following a washout period of 315 days (depending on the dose and half-life of the prior therapy), these patients' Walking Pain (Question 1 of the WOMAC Pain Subscale) was assessed on a patient-reported 100 mm visual analogue scale (VAS) ranging from 0 (no pain) to 100 (severe pain). Patients were randomized into the study if they had moderate Walking Pain (at least 40 mm on VAS), a minimum increase (worsening) in Walking Pain (15 mm VAS) and an increase (worsening) in the Investigator's Assessment of Disease Status of 1 point [on a 5-point Likert scale ranging from 0 (very well) to 4 (very poor)], compared with values obtained at screening while patients were receiving their prior NSAID therapy.
Patients were excluded if they had significant renal impairment, clinically significant abnormalities on screening physical or laboratory examinations (calculated creatinine clearance 30 ml/min), Class III/IV angina or uncontrolled congestive heart failure, uncontrolled hypertension, stroke or a transient ischaemic attack within 2 yr, active hepatic disease, a history of recent neoplastic disease, acute meniscal injury to the study joint within 2 yr of study entry, arthroscopy in the study joint within 6 months of study entry, weight in excess of 280 pounds (127 kg) or allergy to acetaminophen or NSAIDs. Patients were excluded if they required corticosteroids, warfarin, low-dose aspirin or ticlopidine, or if they had required systemic corticosteroids or intra-articular steroids for joints other than the study joint within the month prior to study entry or to the study joint in the 2 months prior to study entry. Patients with a prior history of gastroduodenal ulcer or GI bleeding were allowed to participate. Patients were also excluded for any other condition which, in the opinion of the investigator, might confound study results, interfere with participation in the study or pose an undue risk to the patient.
Efficacy and safety assessments
Efficacy measurements were obtained at a screening visit, at randomization (after flare and prior to initiation of study therapy) and following 1, 2, 4, 6, 8 and 14 weeks of treatment. At each of these visits, the patients completed the WOMAC and patients and investigators completed global assessments of response to therapy and disease status.
There were three primary end-points for this study: the WOMAC Pain Subscale (100 mm VAS); Patient Assessment of Response to Therapy (5-point scale from 0=excellent to 4=none); and Investigator Assessment of Disease Status (5-point scale).
Other end-points included Patient Assessment of Disease Status (100 mm VAS ranging from 0=very well to 100=very poor), Investigator Assessment of Response to Therapy (5-point scale from 0=excellent to 4=none), WOMAC subscales of Stiffness and Physical Function (100 mm VAS ranging from 0=no stiffness/difficulty to 100=extreme stiffness/difficulty), Study Joint Tenderness (03 scale ranging from 0=no pain to 3=patient states there is pain, winces and withdraws), patient discontinuations due to lack of efficacy, the presence or absence of study joint swelling, and the amount (number of 325 mg tablets) of rescue acetaminophen consumed.
Spontaneously reported adverse experiences were recorded throughout the study. Vital signs were monitored and laboratory investigations, including haematology, chemistry and urinalysis, were performed at all visits. For each clinical adverse experience, the investigator recorded the intensity, relationship to test drug (related or not related), outcome and action taken. The investigator also assessed any laboratory adverse event as drug-related or not drug-related. All adverse experiences were identified and evaluated while the patient and investigator remained blinded to study treatment. Any experience meeting a regulatory definition of serious' was also identified by the investigator while still blinded to study treatment. All potential episodes of upper GI perforation, ulceration or bleeding or thrombotic cardiovascular events were submitted to blinded, external review committees for adjudication using prespecified case definitions [8].
Statistical analysis
The placebo-controlled period (Part 1) tested the hypothesis that etoricoxib 5, 10, 30, 60 and 90 mg once daily would have dose-related clinical efficacy compared with placebo. The primary efficacy evaluation for Part 1 of the study was based on the average treatment response over weeks 26 of the treatment period with a modified intention-to-treat approach. Patients with a baseline value and at least one value while on treatment were included in the analysis. In order to show efficacy, treatments had to show a significant difference from placebo for each of the primary end-points. Secondary and other end-points were used for confirmatory purposes only; thus, no adjustment for multiplicity was needed.
Changes from baseline in the primary and secondary end-points were analysed using an analysis of covariance (ANCOVA) model with treatment as the main factor and baseline as a covariate. Disease status at the flare/randomization visit was used as the baseline covariate for Global Assessment of Response to Therapy. Acetaminophen use for rescue purpose was analysed using an analysis of variance (ANOVA) model with treatment as the main factor.
For means and mean changes, comparisons of the MK-0663 doses with placebo were made using the TukeyCimineraHeyse trend test [12]. Between-dose comparisons were made using a pairwise t-test. Ninety-five per cent confidence intervals were calculated based on a pairwise t-test using the error variance from the ANCOVA or ANOVA model. The confidence limits were used to assess the clinical importance of the observed difference in treatment response [13].
To examine the treatment response over time, the least squares (LS) mean change from baseline at each study week was plotted against the standard error for each treatment group across the treatment period. The last-value-carried-forward method was used to impute missing values.
There was 96% power to detect treatment differences between the active dose (n=100) and placebo (n=50) groups for the three end-points simultaneously. In active-dose, pairwise comparisons, there was 86% power to detect a difference of 0.5 for Likert scales and 10 mm for VAS with a sample size of 100 patients in each dose group. For reference, clinical doses of rofecoxib resulted in a change of
15 mm on a VAS scale and 0.5 on a Likert scale [1416].
The efficacy evaluation in Part 2 focused on the dose escalation, the consistency of treatment effect over the 14 weeks and comparison of the treatment effect between diclofenac and etoricoxib. The effect of dose-escalation from Part 1 to Part 2 was assessed by analysing the difference in treatment response between weeks 6 and 8, based primarily on the graphical representation of the LS mean changes for the three primary end-points. Consistency of the treatment effect over 14 weeks was evaluated by examining plots of LS mean changes from baseline for those patients who maintained the same dose during Part 1 and Part 2 of the study. The comparative efficacies of diclofenac and etoricoxib were evaluated by comparing the LS mean changes from baseline among the Part 2 treatments (diclofenac 150 mg and MK-0663 30, 60 and 90 mg) at weeks 8 and 14. For all analyses in Part 2, the LS mean changes were estimated from an ANCOVA model with treatment as the main factor and baseline as the covariate.
For all adverse experiences reported during Part 1, the difference between the placebo group and the etoricoxib doses was evaluated using the CochranArmitage trend test (a step-down procedure starting with the comparison of the 90 mg dose with placebo) for the overall rate of adverse experiences considered by the investigator to be related to the study drug and for the rates of specific adverse experiences potentially associated with NSAID use or COX-2 inhibition (oedema, hypertension, congestive heart failure, pulmonary oedema, cardiac failure) and the rates of discontinuation due to hypertension and oedema. No inferential testing of safety data was performed in Part 2 due to the absence of a placebo group.
All statistical tests were two-tailed with =0.050. All P-values were rounded to three decimal places and a rounded P
0.050 was considered statistically significant.
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Results |
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There were no clinically important differences in the rate of discontinuation due to clinical adverse experience among treatment groups. Of the 550 patients who completed the 6-week placebo-controlled period and entered into Part 2 (198, 102, 148 and 102 in the 30, 60 and 90 mg etoricoxib and diclofenac groups respectively), 510 (91.1%) completed the eight-week active comparator-controlled period.
Three (1.5%), two (2.0%), six (4.1%) and five (4.9%) patients in the 30, 60 and 90 mg etoricoxib and diclofenac groups respectively discontinued due to an adverse experience. There were no significant differences in the rates of discontinuation due to lack of efficacy or adverse experiences between groups in Part 2.
Only six patients were discontinued due to a protocol deviation. Twenty-one patients (3.4%) were excluded from one or more efficacy analyses due to missing baseline data or absence of on-treatment data; absence of data was determined as prespecified in the protocol and prior to unblinding. All available data from each of these 27 patients were included in all safety analyses.
Efficacy
Placebo-controlled period (Part 1)
The response over time for the three primary end-points is presented in Fig. 2.
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These results were consistent with those for all secondary end-points (Table 2).
Active comparator-controlled period (Part 2)
In general, improvements seen at week 2 (Part 1) were sustained without significant changes across the 14-week treatment period for patients receiving etoricoxib 30, 60 or 90 mg during Parts 1 and 2 (Fig. 3).
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At the first measurement in Part 2, the efficacies of etoricoxib 30, 60 and 90 mg were generally similar for all end-points. Comparisons with diclofenac showed modest decreases in the diclofenac group (0.00.2 Likert units) vs individual etoricoxib groups on the Patient Global Assessment of Response to Therapy (Likert scale) and Investigator Global Assessment of Disease Status (Likert scale), but general similarity on the WOMAC Pain Subscale (VAS). At 14 weeks, all treatments appeared similar, as measured by the WOMAC Pain Subscale, Patient Global Assessment of Response to Therapy and Investigator Global Assessment of Disease Status (data not shown).
Safety
Most adverse experiences were transient and self-limited; few resulted in discontinuation of study therapy. No deaths occurred during Part 1 or Part 2 of the study.
Placebo-controlled period (Part 1)
The percentages of patients with adverse experiences considered drug-related by investigators were generally similar across all treatment groups; those occurring in more than 3% of patients are presented in Table 3.
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Individual NSAID-type GI adverse experiences of abdominal pain, acid reflux, dyspepsia, epigastric discomfort, nausea or vomiting considered to be related to the study drug occurred in 05 patients in each treatment group. Those reported in 3% or more of patients are included in Table 3. Of note, there was a small numerical increase in the percentage of patients experiencing diarrhoea in the etoricoxib 10, 30, 60 and 90 mg groups compared with etoricoxib 5 mg and placebo. No significant differences among groups were noted, nor were there significant dose-related trends in the incidence of these adverse experiences.
Renovascular adverse experiences were examined specifically. Drug-related hypertension and oedema occurred in fewer than 3% of patients in each group. Among those experiences considered to be related to study drug by investigators, hypertension was reported by one patient each in the placebo (1.7%) and 30 mg etoricoxib (1.0%) groups, and increased blood pressure in one patient each in the placebo (1.7%) and 10 mg etoricoxib groups (0.9%). Reports of drug-related oedema or lower extremity oedema occurred in one patient each in the placebo (1.7%) and 5 mg etoricoxib (0.9%) groups, two patients in the 10 mg group (1.8%), three (2.7%) patients in the 60 mg and three (2.7%) patients in the 90 mg group. No statistically significant or clinically relevant dose-related trends were noted for oedema or hypertension adverse experiences.
Ten patients had one or more serious adverse experiences; none were considered by investigators to be related to study drug. Four patients, in the 30, 60 or 90 mg etoricoxib groups, had serious cardiovascular adverse experiences (deep venous thrombosis, chest pain associated with angina pectoris and atrial fibrillation, atrial fibrillation and ventricular tachycardia); none were confirmed as cardiovascular thrombotic events by a blinded external review committee. The remaining serious adverse experiences were isolated events (dyspnoea, astrocytoma, renal colic, joint prosthesis complication) reported in one or two patients (basal cell carcinoma; 5 and 10 mg groups). No episodes of upper GI perforation, ulceration or bleeding were reported in Part 1, although one patient receiving 90 mg etoricoxib had a serious lower GI bleed. No episodes of congestive heart failure or acute renal failure were reported.
Eight patients (1.3%) had drug-related laboratory adverse experiences, including alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, increased serum creatinine, increased alkaline phosphatase, decreased haemoglobin, decreased leucocytes or hyperkalaemia. One (0.2%) patient receiving 10 mg etoricoxib discontinued due to a laboratory adverse experiences of increased ALT/AST. No dose-related trends or clinically important patterns were observed in specific laboratory adverse experiences.
Active comparator-controlled period (Part 2)
The overall percentage of patients with drug-related adverse experiences was generally similar across treatment groups for Parts 1 and 2 (Table 3). Only laboratory adverse experiences occurred at a rate of 3% or more in any individual treatment group during Part 2. No new dose-related trends or clinically important patterns were observed in specific clinical adverse experiences during Part 2.
In Part 2, 14 patients discontinued due to a clinical adverse experience. Of these, six were in the digestive system, two were episodes of dizziness (one associated with irregular heartbeat), two were skin adverse experiences and four were other adverse experiences (Menière's disease, taste loss, pneumonia and leg pain). All clinical adverse experiences resulting in discontinuation from the diclofenac group were GI-related; no other trends were seen in adverse experiences resulting in discontinuation.
Individual specific NSAID-type GI experiences (abdominal pain, dyspepsia, heartburn, nausea, diarrhoea or vomiting) considered to be related to the study drug were reported in fewer than 3% of patients in each treatment group. No one group had a specific increase compared with other groups and no new trends were noted for these events.
An examination of renovascular adverse experiences showed that 1% or fewer of patients in each group had an adverse experience of lower extremity oedema. One patient in each of the etoricoxib groups and three patients in the diclofenac group had an adverse experience of hypertension.
Serious adverse experiences were reported in three patients in each group except the 60 mg etoricoxib group; none were considered related to study drug. With the exception of malignancies (n=2; 30 mg) and cellulitis (n=2; 90 mg and diclofenac), all were isolated occurrences (arthralgia, abdominal hernia, cholecystitis, obstructive bronchitis). One patient in the diclofenac group had a serious lower GI bleed. No cardiovascular thrombotic event or episode of upper GI perforation, ulceration or bleeding was reported in Part 2.
Overall, nine patients (1.6%) had drug-related laboratory adverse experiences during Part 2: two patients on 90 mg etoricoxib and seven on diclofenac. The most common laboratory adverse experiences among the diclofenac-treated patients were increased ALT/AST (Table 4). Two (0.4%) patients receiving diclofenac discontinued due to laboratory adverse experiences, one for increased ALT/AST and one for increased serum creatinine and decreased haemoglobin.
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Discussion |
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Etoricoxib was generally well tolerated in this study. Most adverse experiences were transient and self-limited; few resulted in discontinuation of study therapy. No statistically significant, dose-related trends were identified in the rates of hypertension or oedema adverse experiences, and none of these experiences occurred at a rate of more than 3% in any treatment group. However, the sample size in this trial is too small to make definitive conclusions about the safety and tolerability profile of etoricoxib. This study was primarily designed as a dose-ranging study and therefore added study will be required to further define etoricoxib's safety profile. This holds true for generalizations to older patient populations with comorbid conditions, such as congestive heart failure and uncontrolled hypertension, who were excluded from this study.
Current American College of Rheumatology guidelines for the treatment of OA specifically mention the role of COX-2 inhibitors in combination with exercise, education and social support [17]. However, the variable response to NSAIDs in individual patients is well documented, and no specific factors have been shown to predict treatment failure with individual NSAIDs among patients with OA [18]. Physicians often manage treatment failure with NSAIDs by switching patients from one NSAID to another until they identify a compound which provides relief [19]. Currently, only two COX-2 selective NSAIDs are available, which limits choices for patients and physicians interested in using COX-2 inhibitors.
It should be noted that previous studies with NSAIDs have demonstrated a plateau of clinical analgesic efficacy, although additional anti-inflammatory effects might be seen with higher doses, which provides a rationale for the use of higher doses in chronic conditions with inflammatory components, such as rheumatoid arthritis [20]. This study defined a maximally effective clinical dose of etoricoxib in patients with OA, 60 mg. Identification of a clinically maximal dose is important information for clinicians, and may help prevent the use of higher doses than necessary to provide relief of painful symptoms without exposing patients to higher risks of adverse experiences.
In this study, etoricoxib doses of 5, 10, 30, 60 and 90 mg were generally well tolerated and the 30, 60 and 90 mg doses were generally effective in OA patients. All doses studied were generally safe and well tolerated for the 14 week treatment period. However, with regard to discontinuations due to clinical adverse experiences, there was a numerical increase in the 90 mg group compared with the other doses studied, in Parts 1 and 2. While no significant differences were noted between groups and the number of discontinuations on 90 mg etoricoxib and diclofenac was similar in Part 2, taking into account both safety and efficacy, the 60 mg dose provided the optimal benefit/risk relationship. With a greater degree of in vitro selectivity, a favourable pharmacokinetic profile and proven efficacy in the OA in this study, etoricoxib may prove to be an important addition to the therapeutic armamentarium. Further clinical studies with etoricoxib will explore more fully the therapeutic potential and tolerability of this selective COX-2 inhibitor in a broad spectrum of inflammatory conditions, cancer and neurological diseases.
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Acknowledgments |
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The Protocol 007 study group included the investigators who enrolled patients into the study: H. Collins, H. Baraf, R. Bettis, J. Block, B. Bockow, P. Bonafede, J. Box, R. Gillett, J. Conte, G. Dolan, G. Gladstein, G. Divittorio, M. Doyle, C. Fisher, M. Franklin, E. Gillie, M. Goldberg, R. Graham, W. Greth, W. Gruhn, D. Henry, C. Jackson, M. Colburn, S. Kafka, A. Kivitz, F. Larach, T. Lefton, R. Levin, T. Littlejohn, C. Ludivico, J. Markenson, L. McAdam, H. McIlwain, S. D. Miller, S. Miller, J. Newman, O. Oandasan, C. Oshrain, R. Zorba Paster, A. Patron, J. Poiley, M. Ryan, T. Schnitzer, E. Sheldon, P. Stein, W. Storms, R. Trapp, A. Weaver, C. Wise, S. Wolfe, M. Gutierrez, J. Zuzga, K. Bordenave, P. Mease, J. Hague and M. Peveler.
E. Ehrich contributed to study design, M. Huntington conducted additional study monitoring, J. Ng contributed to the data analysis plan for this study, L. Griffin and T. Garay provided data tables and A. Compton contributed to a preliminary in-house report of study data. A. Mehta provided additional document and data support.
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Notes |
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References |
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