Arthritis, Rheumatoid
Conditions
Brief summary
This is a 2-part (6 weeks duration for each part), randomized, double-blind, placebo-controlled study in participants with rheumatoid arthritis. The hypothesis is that etoricoxib (60 mg and 90 mg) administration will demonstrate superior efficacy compared to placebo after 6 weeks of treatment, as measured by the greater mean improvement from baseline in the Disease Activity Score C-Reactive Protein (DAS-28 CRP), and by the greater mean improvement in Patient Global Assessment of Pain (PGAP) from baseline over 6 weeks of treatment. Additionally, the added benefit of increasing the dose of etoricoxib from 60 mg to 90 mg will be assessed in the second part of the study.
Interventions
DRUGEtoricoxib 60 mg
One tablet orally once daily for 6 weeks.
DRUGEtoricoxib 90 mg
One tablet orally once daily for 6 weeks.
DRUGPlacebo to Etoricoxib 60 mg
One tablet orally once daily for 6 weeks.
DRUGPlacebo to Etoricoxib 90 mg
One tablet orally once daily for 6 weeks
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is male or female ≥ 18 years of age in general good health (other than RA) * Has an American College of Rheumatology Rheumatoid Clinical Response Criteria (ACR) Functional Class I, II, or III * Has a diagnosis of RA at least 6 months ago and was at least 16 years of age when diagnosed * Has a history of positive therapeutic benefit with nonsteroidal anti-inflammatory drugs (NSAIDs) and is taking an NSAID on a regular basis and at a therapeutic dose level and is not anticipated to undergo a change during the study
Exclusion criteria
* Has a concurrent medical/arthritic disease that could confound or interfere with evaluation of efficacy * Has a history of gastric or biliary surgery (including gastric bypass surgery) or small intestine surgery that causes clinical malabsorption * Has an active peptic (gastric or duodenal) ulcer or history of inflammatory bowel disease * Has a confirmed medical diagnosis of ischemic heart disease, cerebrovascular disease, or peripheral artery occlusive disease * Class II-IV congestive heart failure * Has uncontrolled hypertension (systolic \>160 mm Hg or diastolic \> 90 mm Hg) at Visit 1 or Visit 2 * Has a clinical diagnosis of hepatic insufficiency defined as Child-Pugh score ≥5 * Has estimated glomerular filtration rate ≤30 mL/min * Has a history of neoplastic disease within 5 years (exceptions: basal cell carcinoma or carcinoma in situ of the cervix) * Is allergic to etoricoxib; history of a significant clinical or laboratory adverse experience associated with etoricoxib; hypersensitivity to aspirin or NSAIDs; or allergy to acetaminophen/paracetamol * Has a personal or family history of an inherited or acquired bleeding disorder * Requires oral corticosteroid therapy in excess of the equivalent of 10 mg daily of prednisone and/or have not been on a stable dose for at least 4 weeks prior to Visit 1 and/or whose dose is not expected to remain stable during the study * Treated with B-cell depleting therapies within the past 6 months or anticipate this treatment during this trial * Is a recreational or illicit drug use, or history within 5 years of drug or alcohol abuse/dependence; * Is morbidly obese (defined as body mass index ≥40 kg/m\^2) * Is pregnant or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib vs. Placebo) | Baseline and Week 6 | Disease Activity Score Using C-Reactive Protein \[DAS28-CRP\] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56\*square root (sqrt) (tender joint count \[28\])+0.28\*sqrt(swollen joint count \[28\] )+0.36\* ln(crp+1) + 0.014\* Patient Global Assessment of Disease Activity + 0.96. The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. |
| Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo) | Baseline and Week 6 | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. |
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | Up to 112 days | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | Up to Week 12 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | Baseline and Week 6 | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed. |
| Average Change From Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders From Part 1 | Week 6 and Week 10 to Week 12 | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). In those participants who were considered inadequate responders to etoricoxib 60 mg in Part 1 (defined as a participant with \<50% improvement from baseline in PGAP \[VAS\] at Week 6), the incremental benefit of increasing the etoricoxib dose from 60 mg (in Part 1) to 90 mg (in Part 2) compared to remaining on 60 mg in Part 2 was evaluated via average change from Week 6 over Weeks 10 and 12 in Patient Global Assessment of Pain score. Therefore, data for only these 2 arms are displayed. |
| Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | Baseline and Week 6 | Disease Activity Score Using C-Reactive Protein \[DAS28-CRP\] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56\*square root (sqrt) (tender joint count \[28\])+0.28\*sqrt(swollen joint count \[28\] )+0.36\* ln(crp+1) + 0.014\* Patient Global Assessment of Disease Activity + 0.96. The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Etoricoxib 60 mg The etoricoxib 60 mg treatment group received etoricoxib tablets 60 mg administered orally once daily in Part 1 of the study. | 818 |
| Etoricoxib 90 mg The etoricoxib 90 mg treatment sequence received etoricoxib tablets 90 mg administered orally once daily in Part 1 of the study. | 468 |
| Placebo The placebo treatment group received placebo to etoricoxib tablets administered orally once daily in Part 1 of the study. | 118 |
| Total | 1,404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 1 | Adverse Event | 26 | 24 | 0 | 0 | 4 |
| Part 1 | Lack of Efficacy | 37 | 12 | 0 | 0 | 17 |
| Part 1 | Lost to Follow-up | 5 | 3 | 0 | 0 | 1 |
| Part 1 | Non-compliance with study drug | 1 | 1 | 0 | 0 | 0 |
| Part 1 | Physician Decision | 4 | 0 | 0 | 0 | 0 |
| Part 1 | Protocol Violation | 10 | 5 | 0 | 0 | 0 |
| Part 1 | Technical problem | 5 | 0 | 0 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 11 | 10 | 0 | 0 | 0 |
| Part 2 | Adverse Event | 0 | 0 | 6 | 7 | 0 |
| Part 2 | Lack of Efficacy | 0 | 0 | 5 | 7 | 0 |
| Part 2 | Lost to Follow-up | 0 | 0 | 1 | 2 | 0 |
| Part 2 | Non-compliance with study drug | 0 | 0 | 1 | 1 | 0 |
| Part 2 | Physician Decision | 0 | 0 | 1 | 2 | 0 |
| Part 2 | Protocol Violation | 0 | 0 | 1 | 0 | 0 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Etoricoxib 60 mg | Etoricoxib 90 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 11.9 | 54.0 Years STANDARD_DEVIATION 12.3 | 53.6 Years STANDARD_DEVIATION 11 | 53.8 Years STANDARD_DEVIATION 12 |
| Disease Activity Score using C reactive protein (DAS28-CRP) | 5.64 Scores on a scale STANDARD_DEVIATION 0.99 | 5.62 Scores on a scale STANDARD_DEVIATION 1 | 5.65 Scores on a scale STANDARD_DEVIATION 1.12 | 5.63 Scores on a scale STANDARD_DEVIATION 1 |
| Patient Global Assessment of Pain | 70.84 Scores on a scale STANDARD_DEVIATION 15.5 | 70.58 Scores on a scale STANDARD_DEVIATION 15.02 | 74.08 Scores on a scale STANDARD_DEVIATION 14.23 | 71.02 Scores on a scale STANDARD_DEVIATION 15.24 |
| Sex: Female, Male Female | 677 Participants | 395 Participants | 100 Participants | 1172 Participants |
| Sex: Female, Male Male | 141 Participants | 73 Participants | 18 Participants | 232 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 819 | 17 / 467 | 6 / 350 | 6 / 363 | 6 / 118 |
| serious Total, serious adverse events | 7 / 819 | 2 / 467 | 4 / 350 | 5 / 363 | 0 / 118 |
Outcome results
Primary
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure.
Time frame: Up to Week 12
Population: ASaT population defined as all randomized participants who received at least one study drug. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data using the ASaT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etoricoxib 60 mg | Percentage of Participants Who Discontinued Study Drug Due to an AE | 3.3 Percentage of participants |
| Etoricoxib 90 mg | Percentage of Participants Who Discontinued Study Drug Due to an AE | 5.1 Percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Drug Due to an AE | 1.4 Percentage of participants |
| Etoricoxib 60mg/Etoricoxib 90mg - Part 1/2 | Percentage of Participants Who Discontinued Study Drug Due to an AE | 1.9 Percentage of participants |
| Placebo - Part 1 | Percentage of Participants Who Discontinued Study Drug Due to an AE | 3.4 Percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event (AE)
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure.
Time frame: Up to 112 days
Population: All Subjects as Treated (ASaT) population, defined as all randomized participants who received at least one study drug. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data using the ASaT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etoricoxib 60 mg | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 30.3 Percentage of participants |
| Etoricoxib 90 mg | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 36.0 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 19.1 Percentage of participants |
| Etoricoxib 60mg/Etoricoxib 90mg - Part 1/2 | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 24.5 Percentage of participants |
| Placebo - Part 1 | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 25.4 Percentage of participants |
Primary
Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib vs. Placebo)
Disease Activity Score Using C-Reactive Protein \[DAS28-CRP\] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56\*square root (sqrt) (tender joint count \[28\])+0.28\*sqrt(swollen joint count \[28\] )+0.36\* ln(crp+1) + 0.014\* Patient Global Assessment of Disease Activity + 0.96. The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed.
Time frame: Baseline and Week 6
Population: The modified intention-to-treat (mITT) population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for the analysis endpoint that was collected within 3 days after the last dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 60 mg | Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib vs. Placebo) | -1.39 Scores on a scale |
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib vs. Placebo) | -1.37 Scores on a scale |
| Placebo | Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib vs. Placebo) | -1.10 Scores on a scale |
p-value: 0.00495% CI: [-0.49, -0.09]Tukey-Ciminera-Heysetrend test
p-value: 0.03495% CI: [-0.48, -0.06]Tukey-Ciminera-Heysetrend test
Primary
Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo)
A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed.
Time frame: Baseline and Week 6
Population: The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for the analysis endpoint that was collected within 3 days after the last dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 60 mg | Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo) | -28.25 Scores on a scale |
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo) | -30.96 Scores on a scale |
| Placebo | Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo) | -20.26 Scores on a scale |
p-value: <0.00195% CI: [-11.85, -4.13]Tukey-Ciminera-Heyse trend test
p-value: <0.00195% CI: [-14.74, -6.66]Tukey-Ciminera-Heyse trend test
Secondary
Average Change From Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders From Part 1
A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). In those participants who were considered inadequate responders to etoricoxib 60 mg in Part 1 (defined as a participant with \<50% improvement from baseline in PGAP \[VAS\] at Week 6), the incremental benefit of increasing the etoricoxib dose from 60 mg (in Part 1) to 90 mg (in Part 2) compared to remaining on 60 mg in Part 2 was evaluated via average change from Week 6 over Weeks 10 and 12 in Patient Global Assessment of Pain score. Therefore, data for only these 2 arms are displayed.
Time frame: Week 6 and Week 10 to Week 12
Population: This population (a subpopulation of the mITT population) was composed of pain inadequate responder (PIRs) in Part 1. PIRs were defined as participants with \<50% improvement from baseline in Patient Global Assessment of Pain (VAS) at Week 6 and received at least one dose of study medication in Part 2.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 60 mg | Average Change From Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders From Part 1 | -11.96 Scores on a scale |
| Etoricoxib 90 mg | Average Change From Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders From Part 1 | -10.35 Scores on a scale |
p-value: 0.32780% CI: [-0.49, 3.71]covariance model
Secondary
Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)
Disease Activity Score Using C-Reactive Protein \[DAS28-CRP\] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56\*square root (sqrt) (tender joint count \[28\])+0.28\*sqrt(swollen joint count \[28\] )+0.36\* ln(crp+1) + 0.014\* Patient Global Assessment of Disease Activity + 0.96. The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed.
Time frame: Baseline and Week 6
Population: The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for the analysis endpoint that was collected within 3 days after the last dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 60 mg | Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | -1.39 Scores on a scale |
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | -1.37 Scores on a scale |
p-value: 0.7395% CI: [-0.1, 0.14]Tukey-Ciminera-Heysetrend test
Secondary
Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)
A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed.
Time frame: Baseline and Week 6
Population: The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for the analysis endpoint that was collected within 3 days after the last dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 60 mg | Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | -28.25 Scores on a scale |
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | -30.96 Scores on a scale |
p-value: 0.01995% CI: [-4.98, -0.45]Tukey-Ciminera-Heyse trend test