Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.955169

Vol. 30, No. 12, 2014, 2399–2408

Article FT-0304.R1/955169 All rights reserved: reproduction in whole or part not permitted

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Original article Etoricoxib in the treatment of Korean patients with osteoarthritis in a double-blind, randomized controlled trial Abstract Myung Chul Yoo Kyung Hee University Hospital, Seoul, Republic of Korea

Objective: We evaluated the COX-2 inhibitors, etoricoxib and celecoxib, in Korean patients with osteoarthritis (OA).

Wan Hee Yoo Chonbuk National University Hospital, Jeollabuk-do, Republic of Korea

Seung Baek Kang Seoul Metropolitan Boramae Medical Center, Seoul, Republic of Korea

Yong-Wook Park Chonnam National Univ. Medical School and Hospital, Gwangju, Republic of Korea

Sung Soo Kim University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Republic of Korea

Kyoung Ho Moon Inha University Hospital, Incheon, Republic of Korea

Yeong Wook Song Seoul National University Hospital, Seoul, Republic of Korea

Byung Woo Min Kyemyung University Dongsan Medical Center, Daegu, Republic of Korea

Yoon Je Cho Kyung Hee University Hospital, Seoul, Republic of Korea

Seong-Hwan Moon

Methods: This study included patients (40 years of age) with a clinical and radiographic diagnosis of knee OA. Patients were randomized to etoricoxib 30 mg (qd) or celecoxib 200 mg (qd) in a 12 week randomized, controlled, double-blind study. Prior NSAID users were to demonstrate a worsening of symptoms upon withdrawal of medication. Efficacy endpoints included the time-weighted average change from baseline in the WOMAC VA 3.0 Pain Subscale (100 mm Visual Analog Scale [VAS]; primary endpoint), the WOMAC VA 3.0 Physical Function Subscale (100 mm VAS), and Patient Global Assessment of Disease Status (PGAD) (100 mm VAS). The primary hypothesis was that etoricoxib 30 mg is non-inferior to celecoxib 200 mg as assessed by the primary endpoint (the non-inferiority margin was set at 10 mm VAS). Adverse events (AEs), laboratory parameters, and vital signs were monitored. Results: There were 239 patients (89.5% female; mean age: 63.3 years) randomized to etoricoxib 30 mg (n ¼ 120) and celecoxib 200 mg (n ¼ 119). The differences (etoricoxib vs celecoxib) in least square (LS) mean change (95% CI) for WOMAC Pain, WOMAC Physical Function, and PGAD were 1.63 mm (5.37, 2.10), 1.32 mm (4.88, 2.23), and 1.09 mm (5.48, 3.30), respectively. Drug-related clinical AEs occurred in 6.7% (etoricoxib) and 2.5% (celecoxib) of patients. This study was limited because it was not designed or powered to adequately capture and evaluate rare AEs associated with NSAID treatment. Conclusions: Etoricoxib 30 mg administered once daily in Korean patients with knee OA demonstrated non-inferior clinical efficacy to celecoxib 200 mg over 12 weeks of treatment as assessed by all primary and secondary outcomes. Etoricoxib 30 mg qd and celecoxib 200 mg qd were generally safe and well tolerated.

Severance Hospital, Seoul, Republic of Korea

Seong-Il Bin Asan Medical Center, Seoul, Republic of Korea

Clinical trial registration: NCT01554163.

Han-Joo Baek Gachon University Gil Hospital, Incheon, Republic of Korea

Seung Cheol Shim Chungnam National University Hospital, Daejeon, Republic of Korea

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Sung Won Lee Dong-A University Medical Center, Busan, Republic of Korea

Dae Hyun Yoo Hanyang University Medical Center, Seoul, Republic of Korea

Anish Mehta Aleksandar Skuban Diane M. Cukrow Kristel Vandormael Li Yan Curr Med Res Opin Downloaded from informahealthcare.com by Selcuk Universitesi on 01/17/15 For personal use only.

Merck & Co. Inc., Whitehouse Station, NJ, USA Address for correspondence: Dr. Li Yan MD PhD, 2033 Saint Andrews Dr., Berwyn, PA 19312, USA. Tel.: +1 732-594-0950; [email protected] Keywords: Celecoxib – COX-2 inhibitor – Etoricoxib – Korean patients – NSAIDs – Osteoarthritis Accepted: 12 August 2014; published online: 3 September 2014 Citation: Curr Med Res Opin 2014; 30:2399–408

December 2014

Introduction Osteoarthritis (OA) is a degenerative condition characterized by damage to articular cartilage, subchondral bone alterations, and synovitis. These physical changes lead to chronic pain, stiffness, and disability, all of which have a significant detrimental impact on quality of life for patients who are afflicted with this condition1,2. OA is among the leading causes of disability worldwide and its prevalence in Asia is increasing along with the aging of populations and increase in obesity3. In Korea, symptomatic knee OA is estimated to affect 24.2% of older individuals4. First-line therapy for OA includes non-pharmacologic modalities, such as diet and exercise, which can help reduce bodyweight and improve joint biomechanics, and mild analgesics such as acetaminophen/paracetamol. In patients who require greater analgesia, the most common pharmacologic treatments are non-steroidal anti-inflammatory drugs5,6 (NSAIDs). The analgesic effect of NSAIDs is due to their inhibition of cyclooxygenase (COX), primarily the COX-2 isoenzyme, which leads to inhibition of prostaglandin synthesis. There are currently a number of NSAIDs available including both traditional (COX-1 and COX-2 inhibitors) and COX-2 selective varieties; however, inter-individual variability with regard to treatment efficacy and safety of these analgesics has been observed7–12. Additionally, there is variability with regard to tolerability issues making it important to have enough choices to help clinicians and patients meet individual needs for analgesia and tolerability. Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in a variety of painful conditions including osteoarthritis in Western populations13–16. The present 12 week, randomized controlled trial was conducted in order to assess the efficacy and safety of etoricoxib in a population of Korean patients with osteoarthritis of the knee compared with celecoxib, another COX-2 selective NSAID. The primary hypothesis of this trial was that etoricoxib 30 mg would be non-inferior to celecoxib 200 mg.

Patients and methods This study (Protocol # 112; Clinical Trials Registry # NCT01554163) was approved by an institutional review board at each study center and was conducted from 12 April 2012 to 4 March 2013. All patients provided written informed consent prior to their participation in the study. This study was conducted in compliance with principles of Good Clinical Practice.

Study design This was a Phase III, 12 week, randomized, active-comparator-controlled, parallel-group, double-blind study to evaluate the safety and efficacy of etoricoxib 30 mg once daily for the treatment of OA of the knee. Patients who met entry criteria were randomized to either etoricoxib 30 mg once daily, or celecoxib 200 mg once daily. Patients were evaluated for safety and efficacy at 2, 6, and 12 weeks of therapy. The diagnosis of OA at the knee joint was confirmed by clinical and radiographic entry criteria. Two types of patients with OA were enrolled: prior non-steroidal anti-inflammatory drug (NSAID) users and prior acetaminophen/paracetamol users. Patients were stratified based on the VAS score of Pain Walking on a Flat Surface (WOMAC Section A, Question 1) at Visit 2. Approximately 50% of patients were enrolled into each stratum as follows: Stratum 1: patients scoring 70 mm and Stratum 2: patients scoring 470 mm. 2400

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Patients were allocated to one of two treatment sequences using a computer-generated randomized allocation schedule. Each patient was assigned a unique allocation number that was used to identify the patient for data collection. Prior to administration of study medications, patients had to discontinue previous analgesic medications and exhibit a symptom flare (i.e., a worsening of pain from OA). The NSAID washout period was 3–14 days for most NSAIDs taken prior to administration of study medication. Exceptions include washout periods for celecoxib and naproxen (both were 4–14 days) and meloxicam (5– 14 days). Patients were given either etoricoxib 30 mg (once daily) or celecoxib 200 mg (once daily). The daily dose contained one tablet of etoricoxib 30 mg or matching placebo and one capsule of celecoxib 200 mg or matching placebo. The study was conducted under double-blinding conditions with in-house blinding procedures (the investigator/study staff, patients, and the sponsor were all blinded). A patient’s treatment could not be unblinded without prior approval from the sponsor except in the case of an emergency (e.g., for a serious adverse event [SAE]).

Patients Patients who were included in this trial were male or female, 40 years of age or over, and with a clinical diagnosis of OA of the knee (tibiofemoral joint) for greater than 6 months. Eligible patients must have been of American Rheumatism Association Functional Class I, II, or III, and, with the exception of OA, judged to be in good general health based on medical history, physical examination, and routine laboratory tests. Patients who were prior NSAID users also had to have a history of positive therapeutic benefit with NSAIDs and had taken NSAIDs on a regular basis and at a therapeutic dose level prior to study enrollment (assessment of ‘Pain Walking on a Flat Surface’ at Visit 1 was less than 80 mm [100 mm VAS]). Following discontinuation of NSAIDs during the washout period, these patients were to satisfy the following three flare criteria at Visit 2: minimum of 40 mm on patient reported ‘Pain Walking on a Flat Surface’; increase of 15 mm on patient reported ‘Pain Walking on a Flat Surface’ compared to pre-study baseline recorded at Visit 1; and a worsening in Investigator Assessment of Disease (IGAD) of at least one category on a five-category scale compared to the Visit 1 recording. Patients who were prior acetaminophen/paracetamol users had to have taken acetaminophen/paracetamol (1.2 to 4.0 g) on a regular basis prior to study enrollment and did not use NSAIDs for the treatment of OA of the knee. At both Visits 1 and 2, these patients had to satisfy the following three criteria: a minimum of 40 mm on patient-reported ‘Pain Walking on a Flat Surface’; an IGAD category of fair, poor, or very poor; ! 2014 Informa UK Ltd www.cmrojournal.com

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and a minimum of 40 mm on Patient Global Assessment of Disease Status (PGAD; 100 mm VAS). Patients were excluded from the trial if they had a concurrent medical/arthritic disease that could confound or interfere with evaluation of efficacy or had a history of acute ligamentous or meniscal injury of the study joint within the previous 2 years or arthroscopy of the affected knee within 6 months prior to Visit 1; patients could not have had a history of gastric or biliary surgery (including gastric bypass surgery), or small intestine surgery that caused clinical malabsorption. The following conditions also led to trial exclusion: allergy or hypersensitivity to study medication or aspirin and NSAIDs; mild to severe congestive heart failure or kidney dysfunction; established ischemic heart disease, cerebrovascular disease, or peripheral vascular disease; uncontrolled hypertension (systolic 4140 mmHg or diastolic 490 mmHg); moderate or severe hepatic insufficiency defined as Child Pugh score46; history of certain neoplastic diseases; morbidly obesity (body mass index [BMI] 35 kg/m2); an active peptic ulcer or a history of inflammatory bowel disease; personal or family history of an inherited or acquired bleeding disorder; clinically significant abnormalities in laboratory safety tests; use of recreational or illicit drugs or a recent history (within the last 5 years) of drug or alcohol abuse or dependence; or the patient was pregnant or breast-feeding during the treatment period. In addition, use of the following medications also led to exclusion from the trial: oral contraceptives; intra-articular steroids or hyaluronic acid injections to the study knee or other immunosuppressant medication within three months of Visit 1; intravenous, intramuscular, or oral corticosteroids, intra-articular steroids or hyaluronic acid injections to any joint other than the study joint within one month of Visit 1; non-study NSAID during the study treatment period, with the exception of low-dose aspirin (325 mg/day); ongoing treatment with warfarin; Chinese traditional arthritis treatment within one week of Visit 1; or low-dose aspirin concomitantly with ticlopidine or clopidogrel.

Efficacy measurements The primary efficacy endpoint was the time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Pain Subscale (100 mm VAS). The key secondary efficacy endpoints were the time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Physical Function Subscale (100 mm VAS) and the time-weighted average change from baseline over 12 weeks in PGAD (100 mm VAS). Other secondary endpoints included time-weighted average response over 12 weeks in Patient Global Assessment of Response to Therapy (PGART) (0–4 point Likert); time-weighted Etoricoxib 30 mg in Korean osteoarthritis patients Yoo et al.

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average change from baseline over 12 weeks in IGAD (0–4 point Likert); time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Stiffness Subscale (100 mm VAS); and time-weighted average response over 12 weeks in Investigator Global Assessment of Response to Therapy IGART (0–4 point Likert). Responder rates were also evaluated based on the timeweighted average percentage change from baseline over the 12 weeks and percentage change from baseline at Week 12 in WOMAC VA 3.0 Pain Subscale (100 mm VAS), WOMAC VA 3.0 Physical Function Subscale (VAS), and PGAD (VAS).

Safety assessments A complete physical examination was performed at Visit 1 (screening) and Visit 5 (or discontinuation) including measurement of vital signs and weight (also done at Visit 2). Blood pressure was monitored at each patient visit. Laboratory measurements were also performed. Serum chemistry was collected at Visit 1 while hematocrit/hemoglobin was collected at Visits 1, 2, 4, and 5 (or discontinuation). Urinalysis was done at Visits 2, 4, and 5 (or discontinuation). Serum b-hCG, serum FSH, serum digoxin, and prothrombin time were collected at Visit 1 only. Urine b-hCG was performed at Visits 2, 4, or 5 (or discontinuation). Change from baseline in laboratory parameters was recorded at each time point. Adverse events were monitored throughout the study. Change from baseline in vital signs (systolic blood pressure, diastolic blood pressure, heart rate, and weight) was recorded at each time point and the percentage of patients with adverse experiences (AEs) were noted. Thrombotic cardiovascular AEs and upper gastrointestinal AEs were pre-specified for adjudication by an expert committee external to the study sponsor.

Statistical analysis This study was planned to randomize approximately 110 patients into the etoricoxib group and 110 patients in the celecoxib group. One hundred and five evaluable patients per treatment group would achieve approximately 90% power to demonstrate that etoricoxib is non-inferior to celecoxib with respect to the primary endpoint, the time-weighted average change from baseline over 12 weeks in WOMAC Pain Subscale (VAS), at a onesided, 2.5% alpha level. The modified intention-to-treat (mITT) population was used for the primary efficacy analysis and the per protocol population was used as a supportive analysis for the primary and secondary endpoints. The primary hypothesis was evaluated based on the primary efficacy endpoint, the time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Pain 2402

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Subscale (VAS) using an analysis of covariance model with factors for treatment group, stratum (WOMAC VA Walking Pain: 70 mm,470 mm VAS at randomization), and baseline value as a covariate. Etoricoxib 30 mg was considered non-inferior to celecoxib 200 mg if the upper bound of the two-sided 95% confidence interval (CI) of the between-treatment difference (etoricoxib minus celecoxib) in least-squares (LS) mean change from baseline for this endpoint was no greater than 10 mm VAS (noninferiority margin). The study was considered positive if etoricoxib 30 mg was shown to be non-inferior to celecoxib 200 mg with respect to the primary endpoint. If the upper limit of the 95% CI for the difference in LS mean change from baseline in WOMAC VA 3.0 Pain Subscale (VAS) between the two treatment groups was 10 mm, then a subsequent test was to be performed to determine whether or not etoricoxib was superior to celecoxib (i.e., p-value for treatment difference 0.050). The two key secondary hypotheses were evaluated in a similar manner with respect to the time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Physical Function Subscale (VAS) and PGAD (VAS) each with a non-inferiority margin of 10 mm VAS. With regard to the multiplicity approach, if the noninferiority of etoricoxib 30 mg to celecoxib 200 mg with respect to the primary endpoint was demonstrated, the key secondary endpoints were evaluated. Statistical testing for the two key secondary endpoints was done in the following order: WOMAC Physical Function Subscale (VAS), then PGAD (VAS). The superiority of etoricoxib with respect to WOMAC Pain Subscale (VAS) was only explored if the non-inferiority of etoricoxib to celecoxib was established for this endpoint. This comparison was not considered in the multiplicity strategy. No multiple testing adjustments were made for the other efficacy endpoints, as these endpoints were considered supportive to the primary analyses. The all patients as treated population was employed for safety analyses. The analysis of safety followed a tiered approach. The percentage of patients with hypertensionrelated AEs, edema-related AEs, AEs of congestive heart failure, pulmonary edema, or cardiac failure, discontinuation due to hypertension-related AEs, discontinuation due to edema-related AEs and discontinuation due to digestive body system or abdominal pain AEs were prespecified as events of interest, and were considered Tier 1 events. For the Tier 1 events, p-values and 95% CIs using the Miettinen and Nurminen method were provided for the comparison between etoricoxib and celecoxib. Specific AEs, system organ classes, and predefined limits of change that were not part of Tier 1 AEs, plus certain broad AE categories (i.e., any AEs, drug-related AEs, serious AEs [SAEs], drug-related SAEs, AEs leading to discontinuation, drug-related AEs leading to discontinuation, SAEs leading to discontinuation, drugrelated SAEs leading to discontinuation, and deaths) www.cmrojournal.com ! 2014 Informa UK Ltd

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were considered Tier 2 events when there were 4 patients in any treatment group with the event. No multiple testing adjustments were made for the evaluation of the safety parameters.

(etoricoxib vs celecoxib) was 1.63 mm (95% CI: 5.37, 2.10). Etoricoxib 30 mg was shown to be non-inferior to celecoxib 200 mg as the upper bound of the 95% CI was no greater than the non-inferiority margin (10 mm VAS) (Table 2; Figure 2). The largest observed improvement was achieved by Week 12 for both the etoricoxib 30 mg treatment group and the celecoxib 200 mg treatment group. The results of the secondary endpoints confirmed those of the primary endpoint and showed that the upper limit of the 95% CI for the LS mean difference did not exceed the non-inferiority margin of 10 mm VAS. The LS mean difference between groups (etoricoxib vs celecoxib) was 1.32 mm (95% CI: 4.88, 2.23) for WOMAC Physical Function Subscale (VAS) and 1.09 mm (95% CI: 5.48, 3.30) for PGAD (VAS) (Table 2). Results for other secondary endpoints are shown in Table 2.

Results Patients

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There were 239 patients who were randomized to treatment (120 for etoricoxib and 119 for celecoxib; 119 in each group received treatment). Of these patients, 221 completed (112 in the etoricoxib group and 109 in the celecoxib group) (Figure 1). The etoricoxib and celecoxib treatment groups in the randomized population were similar in the patient demographics presented. Most patients (214 of 239, 89.5%) were female and all patients were Korean. The mean (SD) age of 63.3 (8.38) years was typical for a population with OA and the mean (SD) BMI was 25.2 (2.85) kg/m2. A similar distribution of BMI values was presented between the normal and overweight population for both treatment groups, with only 5.4% of patients in this study being obese (Table 1).

Responder rates An analysis of responder rates (i.e., rate of patients with at least 50% improvement) showed that 32.8% of patients in the etoricoxib 30 mg treatment group and 24.4% of patients in the celecoxib 200 mg treatment group achieved at least 50% improvement from baseline in WOMAC Pain Subscale (treatment difference in responder rates was 8.40% (95% CI: 3.07, 19.79). The rate of response for the secondary endpoint of improvement from baseline in WOMAC Physical Function Subscale was 25.2% of patients in the etoricoxib 30 mg treatment group and 23.5% of patients in the celecoxib 200 mg treatment group; the difference in responder rates was 1.68%

Efficacy The primary hypothesis for the study was addressed by the time-weighted average change from baseline over 12 weeks in WOMAC VA 3.0 Pain Subscale (VAS). The between-treatment difference in the LS means

Screened N=257

Excluded Due To Screening Failure

Randomized

N=18

N=239 Etoricoxib 30 mg

Celecoxib 200 mg

N=120

N=119

Treated (APaT Population)

Treated (APaT Population)

N=119 (99.2)

N=119 (100.0)

N (%) Completed Study 112 (93.3) Treated and Discontinued From Study 7 (5.8) AE 3 (2.5) Lack of Efficacy 1 (0.8) Withdrawal by Patient 1 (0.8) Other* 2 (1.7)

N (%) Completed Study 109 (91.6) Treated and Discontinued From Study 10 (8.4) AE 0 (0.0) Lack of Efficacy 0 (0.0) Withdrawal by Patient 5 (4.2) Other** 5 (4.2)

Not Treated N=1

Figure 1. Patient disposition throughout study. *Includes non-compliance with study drug and lost to follow up. **Includes non-compliance with study drug, lost to follow up, and protocol violation. APaT ¼ All Patients Treated; AE ¼ Adverse Event.

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Table 1. Baseline patient characteristics. Etoricoxib 30 mg N ¼ 120 n (%)

Celecoxib 200 mg N ¼ 119 n (%)

Total N ¼ 239 n (%)

110 (91.7)

104 (87.4)

214 (89.5)

64.0 (8.13) 46.0–81.0

62.7 (8.61) 44.0–87.0

63.0 44.0–87.0

120 (100.0)

119 (100.0)

239 (100.0)

25.4 (2.90) 7 (5.8) 56 (46.7) 57 (47.5) 0 (0.0)

24.9 (2.79) 6 (5.0) 47 (39.5) 65 (54.6) 1 (0.8)

25.2 (2.85) 13 (5.4) 103 (43.1) 122 (51.0) 1 (0.4)

111 (92.5) 9 (7.5)

109 (91.6) 10 (8.4)

220 (92.1) 19 (7.9)

8 (6.7) 78 (65.0) 34 (28.3)

15 (12.6) 74 (62.2) 30 (25.2)

23 (9.6) 152 (63.6) 64 (26.8)

2.5 (3.69) 0.0–20.1

2.1 (2.91) 0.0–14.6

2.3 (3.32) 0.0–20.1

Gender (female) Age Mean (SD) Range Race Asian BMI (kg/m2) Mean (SD) n (%) obese n (%) overweight n (%) normal n (%) underweight Prior use of medication NSAIDs [n (%)] Acetaminophen/paracetamol ARA function class Class I [n (%)] Class II [n (%)] Class III [n (%)] Duration of OA (years) Mean (SD) Range

BMI ¼ Body Mass Index; NSAIDs ¼ Non-Steroidal Anti-Inflammatory Drugs; ARA ¼ American Rheumatism Association; OA ¼ Osteoarthritis.

Table 2. Summary of efficacy endpoints.

LS Mean Time-weighted Average Change from Baseline over 12 Weeks in WOMAC VA 3.0 Pain Subscale (VAS; mm) Time-weighted Average Change from Baseline over 12 Weeks in WOMAC VA 3.0 Physical Function Subscale (VAS; mm) Time-weighted Average Change from Baseline over 12 Weeks in Patient Global Assessment of Disease Status (VAS; mm) Time-weighted Average Response over 12 Weeks in Patient Global Assessment of Response to Therapy (Likert) Time-weighted Average Change from Baseline over 12 Weeks in Investigator Global Assessment of Disease Status (Likert) Time-weighted Average Change from Baseline over 12 Weeks in WOMAC VA 3.0 Stiffness Subscale (VAS; mm) Time-weighted Average Response over 12 Weeks in Investigator Global Assessment of Response to Therapy (Likert) Responder Rates (% of patients with 50% improvement) Based on the Time-weighted Average Change in WOMAC VA 3.0 Pain Subscale (VAS; mm) Responder Rates (% of patients with 50% improvement) Based on the Time-weighted Average Change in WOMAC VA 3.0 Physical Function Subscale (VAS; mm) Responder Rates Based on the Time Weighted Average Percent Change from Baseline over 12 Weeks in Patient Global Assessment of Disease Status (VAS; mm)

Etoricoxib 30 mg Mean (95% CI)

Celecoxib 200 mg Mean (95% CI)

Difference in LS Mean Change (95% CI)

21.40 (24.06, 18.74)

19.76 (22.41, 17.12)

1.63 (5.37, 2.10)

17.78 (20.31, 15.25)

16.46 (18.98, 13.93)

1.32 (4.88, 2.23)

24.71 (27.82, 21.60)

23.61(26.73, 20.49)

1.09 (5.84, 3.30)

1.48 (1.35, 1.61)

0.08 (0.26, 0.10)

1.56 (1.43, 1.69)

1.71 (1.83, 1.59)

1.62 (1.74, 1.50)

0.09 (0.25, 0.08)

18.41 (21.33, 15.50)

17.55 (20.46, 14.65)

0.86 (4.96, 3.24)

1.39 (1.25, 1.53)

1.49 (1.35, 1.64)

0.10 (0.30, 0.10)

32.8% (39/119)

24.4% (29/119)

8.40 (3.07, 19.79)

25.2% (30/119)

23.5% (28/119)

1.68 (9.19, 12.58)

35.3% (42/119)

26.1% (31/119)

9.24 (2.52, 20.82)

LS ¼ Least Square; VAS ¼ Visual Analog Scale; WOMAC VA 3.0 ¼ Western Ontario and McMaster Universities Arthritis Index Version 3.0.

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(95% CI: 9.19, 12.58). The rate of response for the secondary endpoint of PGAD was 35.3% of patients in the etoricoxib 30 mg treatment group and 26.1% of patients in the celecoxib 200 mg treatment group; treatment difference in responder rates was 9.24% (95% CI: 2.52,

Pain Subscale (mm) Time-Weighted Average Change From Baseline (LS Mean ± SE)

0 −5 −10 −15 −20 −25 Etoricoxib 30 mg Celecoxib 200 mg S

R

S = Screening Visit R = Randomization Visit

2 6 Weeks Postrandomization

12

Time-Weighted Average Over 12 Weeks

Figure 2. Longitudinal plots of least-squares means of change from baseline in WOMAC VA 3.0 pain subscale (VAS) at weeks 2, 6, and 12. The change from Screening to Randomization illustrates symptom flare after withdrawal from previous treatments with analgesics. ITT ¼ Intentionto-Treat; LS ¼ Least Square; SE ¼ Standard Error.

100%

Cumulative Percent of Responders

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Overall, at least one AE was reported for 71 of the 238 (29.8%) treated patients: 37.8% of patients in the etoricoxib 30 mg treatment group and 21.8% of patients in the celecoxib 200 mg treatment group. The difference in incidences (etoricoxib versus celecoxib) was 15.8% with 95% CI (4.4, 27.3). The percentage of patients with drugrelated AEs was 6.7% in the etoricoxib group, 2.5% in the celecoxib group. The difference in incidences was 4.2% with 95% CI (1.3, 10.5). The 95% CIs suggest a significant difference in overall AEs, but not in the drugrelated AEs. The difference in the rate of AEs was due to greater numbers of etoricoxib patients with arthralgia, urticaria, and edema-related AEs. All AEs were mild or moderate in intensity. The rates of serious AEs and discontinuations were low and similar between groups (Table 3).

Modified ITT Population (B)

(A) Cumulative Percent of Responders

Etoricoxib 30 mg Celecoxib 200 mg

90% 80% 70% 60% 50% 40% 30% 20% 10%

Etoricoxib 30 mg Celecoxib 200 mg

0% −60% −40% −20%

0%

20%

40%

60%

80% 100%

−60% −40% −20%

% Improvement From Baseline

(C) Cumulative Percent of Responders

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5

−35

20.82). Responder curves illustrating different levels of improvement are shown in Figure 3 for the primary and key secondary endpoints.

Safety

Modified ITT Population

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0%

20%

40%

60%

80% 100%

% Improvement From Baseline

100% 90% 80% 70% 60% 50% 40% 30% 20% 10%

Etoricoxib 30 mg Celecoxib 200 mg

0% −100%−75% −50% −25% 0%

25% 50% 75% 100%

% Improvement From Baseline

Figure 3. Responder curves showing cumulative percentage of responders versus percentage of improvement from baseline to time-weighted average value in primary and key secondary endpoints. (A) WOMAC VA 3.0 Pain Subscale. (B) WOMAC VA 3.0 Physical Function Subscale. (C) Patient Global Assessment of Disease Status. ITT ¼ Intention-to-Treat.

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Table 3. Summary of safety. Etoricoxib 30 mg N ¼ 119 n (%)

Celecoxib 200 mg N ¼ 119 n (%)

Total N ¼ 238 n (%)

26 (21.8) 3 (2.5) 1 (0.8) 0 (0)

71 (29.8) 11 (4.6) 1 (0.4) 3 (1.3)

1 (0.8) 0 (0)

5 (2.1) 3 (1.3)

5 (4.2) 3 (2.5) 0 (0)

8 (3.4) 15 (6.3) 5 (1.7)

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With one or more AEs 45 (37.8) Drug-related AEs 8 (6.7) Serious AEs 0 (0) Discontinuation due to AEs 3 (2.5) AEs of special interest Edema-related AEs 4 (3.4) Discontinuation due to edema-related AEs 3 (2.5) Most common AEs (43% incidence within a treatment group) Nasopharyngitis 3 (2.5) Arthralgia 12 (10.1) Urticaria 4 (3.4) AE ¼ Adverse Event.

Discussion The results of this study demonstrate that the COX-2 selective NSAIDs etoricoxib 30 mg and celecoxib 200 mg provided analgesic and functional efficacy in a population of Korean patients with OA. There were primarily three different aspects of OA investigated in this trial that affect patients: pain levels, patients’ physical function, and physician-assessed disease status. An analysis of responder rates for the primary and key secondary endpoints were done to complement the mean value results in order to show individual variability in response and to better illustrate the levels of improvement associated with the study medications. These mean results and responder rates demonstrated that the levels of analgesic and functional efficacy observed in this trial are consistent with levels associated with clinically important improvement in OA symptoms, demonstrating that etoricoxib and celecoxib provided meaningful benefits for the patients who participated in this trial17. The primary hypothesis of the trial was met showing that etoricoxib 30 mg was non-inferior to celecoxib 200 mg. Etoricoxib had previously demonstrated efficacy in OA at the dose of 60 mg18. Subsequent studies have shown clinically important efficacy with the lower dose of 30 mg as well. In particular, there were two trials that compared etoricoxib 30 mg and celecoxib 200 mg in Western populations of patients with OA13. The results of those studies also showed that etoricoxib 30 mg was non-inferior to celecoxib 200 mg and that both were statistically superior to placebo (p50.001) with regard to the same primary and key secondary endpoints used in this trial. Therefore ethnic factors, including genetic and nutritional factors that may differ from previously studied populations, did not seem to affect the efficacy of etoricoxib in this population of Asian OA patients. Both etoricoxib and celecoxib were generally well tolerated in this study. Importantly, the number of serious AEs and AEs leading to discontinuation were relatively low as were AEs that 2406

Etoricoxib 30 mg in Korean osteoarthritis patients Yoo et al.

were determined by the investigators to be related to study medication. There were a higher number of patients in the etoricoxib group who had AEs compared with celecoxib. However, it should be noted that this is partially due to the capture of the AE of arthralgia in etoricoxib patients, which reflects the reporting of pain in the arthritic study joint that was the subject of study in this trial. Further, the AEs were all mild to moderate in intensity, and the majority resolved by the end of the study. In addition, it should be noted that there were edema-related AEs reported with etoricoxib while none were reported with celecoxib. Previous research has shown reports of renovascular AEs such as hypertension and edema-related AEs with etoricoxib19. Prostaglandins have a role in the regulation of renal homeostasis20; therefore, renovascular AEs should be monitored with the use of etoricoxib as well as all NSAIDs, which inhibit the synthesis of prostaglandins. This study was limited because it was not designed or powered to adequately capture and evaluate GI or thrombotic CV AEs. These are AEs of special interest for NSAIDs due to previous research showing that these agents affect prostaglandin-dependent gastric protection (primarily through inhibition of COX-1) as well as previous research showing an increase in thrombotic CV AEs with COX-2 selective inhibitors and most traditional NSAIDs9,11,12,21. There were no gastrointestinal (GI) or thrombotic cardiovascular (CV) AEs in this study. This trial was also limited in that the patients were all Korean, which may limit definitive extrapolation of these results to other Asian populations.

Conclusion In summary, etoricoxib 30 mg administered once daily in Korean patients with knee OA demonstrated non-inferior clinical efficacy to celecoxib 200 mg over 12 weeks of treatment as assessed by all primary and secondary www.cmrojournal.com ! 2014 Informa UK Ltd

Current Medical Research & Opinion Volume 30, Number 12

outcomes (i.e., WOMAC Pain Subscale, WOMAC Physical Function Subscale and PGAD). Etoricoxib 30 mg qd and celecoxib 200 mg qd were generally safe and well tolerated.

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Transparency Declaration of funding This study was funded by Merck & Co. Inc., Whitehouse Station, NJ, USA. Author contributions: M.C.Y. conceived and designed the study collected data, supervised analyses, interpreted results, critically reviewed, and provided substantive suggestions on the manuscript. W.H.Y. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. S.B.K. conceived and designed the study collected data, supervised analyses, interpreted results, critically reviewed, and provided substantive suggestions on the manuscript. Y.-W.P. collected or assembled data, supervised analyses, critically reviewed the manuscript, and provided substantive suggestions. SSK collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. K.H.M. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. Y.W.S. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. B.W.M. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. Y.J.C. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. S.-H.M. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. S.-I.B. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. H.-J.B. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. S.C.S. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. S.W.L. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. D.H.Y. collected or assembled data, critically reviewed the manuscript, and provided substantive suggestions. A.M.:interpreted results, wrote sections of the initial manuscript draft, critically reviewed the manuscript, and provided substantive suggestions. A.S. performed analyses, interpreted the results, critically reviewed the manuscript, and provided substantive suggestions. D.M.C. performed analyses, interpreted the results, critically reviewed the manuscript, and provided substantive suggestions. K.V. performed analyses, interpreted the results, critically reviewed the manuscript, and provided substantive suggestions. L.Y. conceived the study, assembled data, supervised analyses, interpreted results, wrote sections of the initial draft, critically reviewed the manuscript, and provided substantive suggestions. All authors read and approved the final manuscript. Declaration of financial/other relationships A.M., A.S., D.M.C., K.V., and L.Y. have disclosed that they are current or former employees of Merck & Co. Inc., the sponsor of this study. Y.J.C. has disclosed that she/he has received research grants from MSD Korea. D.H.Y. has disclosed that she/he has

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December 2014

received research grants and consulting and speakers’ fees from Celltrion. M.C.Y., W.H.Y., S.B.K., Y.-W.P., S.S.K., K.H.M., Y.W.S., B.W.M., S.-H.M., S.-I.B., H.-J.B., S.C.S., and S.W.L. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose. Acknowledgments This study was previously presented at the Asia Pacific League of Associations for Rheumatology (APLAR) meeting in April 2014. The authors take full responsibility for the content of the paper. The authors thank Sheila Erespe (Merck & Co. Inc., Whitehouse Station, NJ, USA) for editorial and administrative assistance and Ji Young Park (MSD Korea, Seoul, Republic of Korea) for logistic and administrative support.

References 1. Breedveld FC. Osteoarthritis – the impact of a serious disease. Rheumatology (Oxford) 2004;43(Suppl 1):i4-8 2. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health 1994;84:351-8 3. Fransen M, Bridgett L, March L, et al. The epidemiology of osteoarthritis in Asia. Int J Rheum Dis 2011;14:113-21 4. Kim I, Kim HA, Seo YI, et al. The prevalence of knee osteoarthritis in elderly community residents in Korea. J Korean Med Sci 2010;25:293-8 5. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology. Arthritis Rheum 1995;38:1535-40 6. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part II. Osteoarthritis of the knee. American College of Rheumatology. Arthritis Rheum 1995;38:1541-6 7. Yiannakopoulou E. Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. Eur J Clin Pharmacol 2013;69:1369-73 8. Peloso PM, Gammaitoni A, Smugar SS, et al. Longitudinal numbers-neededto-treat (NNT) for achieving various levels of analgesic response and improvement with etoricoxib, naproxen, and placebo in ankylosing spondylitis. BMC Musculoskelet Disord 2011;12:165-12 9. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-8 10. Laine L, Goldkind L, Curtis SP, et al. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol 2009;104:356-62 11. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-102 12. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352:1081-91 13. Bingham III CO, Sebba AI, Rubin BR, et al. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology (Oxford) 2007;46:496-507

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18. Leung AT, Malmstrom K, Gallacher AE, et al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: a randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin 2002;18:49-58 19. Combe B, Swergold G, McLay J, et al. Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study). Rheumatology (Oxford) 2009;48:425-32 20. Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of COX-2-selective inhibitors. Am J Nephrol 2001;21:1-15 21. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-8, 2

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14. Daniels SE, Bandy DP, Christensen SE, et al. Evaluation of the dose range of etoricoxib in an acute pain setting using the postoperative dental pain model. Clin J Pain 2011;27:1-8 15. Rawal N, Viscusi E, Peloso PM, et al. Evaluation of etoricoxib in patients undergoing total knee replacement surgery in a double-blind, randomized controlled trial. BMC Musculoskelet Disord 2013;14:300-14 16. Viscusi ER, Frenkl TL, Hartrick CT, et al. Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study. Curr Med Res Opin 2012;28:1323-35 17. Tubach F, Ravaud P, Baron G, et al. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis 2005;64:29-33

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www.cmrojournal.com ! 2014 Informa UK Ltd

Etoricoxib in the treatment of Korean patients with osteoarthritis in a double-blind, randomized controlled trial.

We evaluated the COX-2 inhibitors, etoricoxib and celecoxib, in Korean patients with osteoarthritis (OA)...
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