Spondylitis, Ankylosing
Conditions
Brief summary
The purpose of the study is to evaluate the efficacy and tolerability of two doses of etoricoxib compared to naproxen in the treatment of ankylosing spondylitis (AS). The primary objectives are to evaluate the improvement in Spinal Pain Intensity over 6 weeks of treatment with etoricoxib 90 mg or 60 mg compared to naproxen; and to evaluate the improvement in Spinal Pain Intensity over 6 weeks of treatment with etoricoxib 90 mg compared with etoricoxib 60 mg. 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. The primary hypothesis is that the improvement in Spinal Pain Intensity visual analog scale (VAS) as measured by the time-weighted average (TWA) change from baseline over 6 weeks of treatment in Part I for etoricoxib 90 mg or 60 mg once daily is not inferior to naproxen 1000 mg.
Interventions
DRUGPart I - etoricoxib 60 mg
etoricoxib 60 mg oral tablet once daily for 6 weeks
DRUGPart I - etoricoxib 90 mg
etoricoxib 90 mg oral tablet once daily for 6 weeks
DRUGPart I- naproxen 1000 mg
naproxen 500 mg oral tablet twice daily for 6 weeks
DRUGPart I - Placebo to naproxen 500 mg
Placebo to naproxen 500 mg oral tablet twice daily for 6 weeks
DRUGPart II- etoricoxib 60 mg
etoricoxib 60 mg oral tablet once daily for 20 weeks
DRUGPart II- etoricoxib 90 mg
etoricoxib 90 mg oral tablet once daily for 20 weeks
DRUGPart II- naproxen 1000 mg
naproxen 500 mg oral tablet twice daily for 20 weeks
DRUGPart I - Placebo to etoricoxib 60 mg
Placebo to etoricoxib 60 mg oral tablet once daily for 6 weeks.
DRUGPart I - Placebo to etoricoxib 90 mg
Placebo to etoricoxib 90 mg oral tablet once daily for 6 weeks.
DRUGPart II- Placebo to etoricoxib 60 mg
Placebo to etoricoxib 60 mg oral tablet once daily for 20 weeks.
DRUGPart II - Placebo to etoricoxib 90 mg
Placebo to etoricoxib 90 mg oral tablet once daily for 20 weeks.
DRUGPart II- Placebo to naproxen 500 mg
Placebo to naproxen 500 mg orally twice daily for 20 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
* Has a definite diagnosis of Ankylosing Spondylitis (AS) per Modified New York Criteria made at least 6 months prior to screening * Has a history of positive therapeutic benefit with non-steroidal anti-inflammatory drugs (NSAIDs) and regular use of NSAIDS for past 30 days * Has a score on Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 at screening visit that is \<77 mm * Must demonstrate sufficient flare or worsening of AS pain * Is in general good health (other than AS) * Has had approved non-study antirheumatic therapy that has been at stable dosing AND is not anticipated to undergo a change within the first 6 weeks of the protocol
Exclusion criteria
* Has inflammatory arthritis (eg, rheumatoid arthritis, psoriatic arthritis, crystal-induced arthritis, spondyloarthropathy, diffuse idiopathic skeletal hyperostosis \[DISH\]), polymyalgia rheumatica, a history of septic arthritis or intra-articular fracture of the study joint, Wilson's disease, hemachromatosis, ochronosis, or primary osteochondromatosis * Has acute peripheral articular disease (onset within 4 weeks prior to screening) of an active (painful or swollen) peripheral arthritis * Has a history of gastric or biliary surgery, or small intestine surgery that causes clinical malabsorption * Has had an active peptic (gastric or duodenal) ulcer or history of inflammatory bowel disease * Has undergone coronary artery bypass graft surgery (CABG), angioplasty, or has a cerebrovascular accident or transient ischemic attack within the past 6 months or has active ischemic heart disease, cerebrovascular disease, or peripheral vascular disease * Has Class II-IV congestive heart failure * Has uncontrolled hypertension * Has a history of neoplastic disease, except adequately treated basal cell carcinoma or carcinoma in situ of the cervix, or malignancies that have been successfully treated ≥ 5 years prior to screening * Has history of leukemia, lymphoma, malignant melanoma, and myeloproliferative disease * Allergy to etoricoxib or naproxen, or history of a significant clinical or laboratory adverse experience associated with etoricoxib or naproxen * Has a history or family history of an inherited or acquired bleeding disorder * Is considered morbidly obese and demonstrates significant health problems stemming from obesity, which would confound study participation or interpretation of study results * Is pregnant, breast-feeding, or expecting to conceive during the study * Has a clinical diagnosis of hepatic insufficiency defined as Child-Pugh score ≥ 5
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Naproxen | Baseline and up to Week 6 | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. |
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 60 mg vs. Naproxen | Baseline and up to Week 6 | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. |
| Number of Participants Discontinuing Study Treatment Due to an Adverse Event | Up to 26 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Etoricoxib 60 mg | Baseline and up to Week 6 | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. |
| Average Change From Week 6 in the Spinal Pain Intensity Over Weeks 10 and 12 in Study Part 2: Etoricoxib 60/90 mg vs. Etoricoxib 60mg (Non-responders From Part I) | Week 6 to Week 10 and Week 12 | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. Average change from Week 6 in Spinal Pain Intensity (VAS) over Weeks 10 and 12 is calculated as the average Spinal pain Intensity (VAS) value over Weeks 10 and 12 minus the Spinal Pain Intensity (VAS) at Week 6. |
Participant flow
Pre-assignment details
All Patients Randomized
Participants by arm
| Arm | Count |
|---|---|
| Etoricoxib 60 mg Etoricoxib 60 mg oral tablet once daily | 702 |
| Etoricoxib 90 mg Etoricoxib 90 mg once daily | 156 |
| Naproxen 1000 mg Naproxen 500 mg oral tablet twice daily | 157 |
| Total | 1,015 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part I | Adverse Event | 19 | 2 | 6 | 0 | 0 | 0 | 0 |
| Part I | Lack of Efficacy | 21 | 3 | 2 | 0 | 0 | 0 | 0 |
| Part I | Lost to Follow-up | 6 | 1 | 0 | 0 | 0 | 0 | 0 |
| Part I | Non-Compliance With Study Drug | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part I | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Part I | Progressive Disease | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part I | Protocol Violation | 8 | 0 | 2 | 0 | 0 | 0 | 0 |
| Part I | Withdrawal by Subject | 14 | 4 | 4 | 0 | 0 | 0 | 0 |
| Part II | Adverse Event | 0 | 0 | 0 | 5 | 9 | 4 | 2 |
| Part II | Lack of Efficacy | 0 | 0 | 0 | 6 | 4 | 3 | 3 |
| Part II | Lost to Follow-up | 0 | 0 | 0 | 4 | 0 | 2 | 1 |
| Part II | Non-Compliance With Study Drug | 0 | 0 | 0 | 4 | 1 | 1 | 0 |
| Part II | Physician Decision | 0 | 0 | 0 | 1 | 0 | 2 | 0 |
| Part II | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Part II | Technical Problems | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Part II | Withdrawal by Subject | 0 | 0 | 0 | 10 | 9 | 3 | 5 |
Baseline characteristics
| Characteristic | Etoricoxib 60 mg | Etoricoxib 90 mg | Naproxen 1000 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 45.4 Years STANDARD_DEVIATION 12.4 | 45.2 Years STANDARD_DEVIATION 11.3 | 44.5 Years STANDARD_DEVIATION 12.3 | 45.2 Years STANDARD_DEVIATION 12.2 |
| Sex: Female, Male Female | 209 Participants | 45 Participants | 41 Participants | 295 Participants |
| Sex: Female, Male Male | 493 Participants | 111 Participants | 116 Participants | 720 Participants |
| Spinal Pain Intensity | 76.7 mm VAS STANDARD_DEVIATION 14.2 | 76.7 mm VAS STANDARD_DEVIATION 15.2 | 77.0 mm VAS STANDARD_DEVIATION 14 | 76.8 mm VAS STANDARD_DEVIATION 14.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 313 | 50 / 319 | 24 / 145 | 25 / 142 | 18 / 70 | 6 / 10 | 9 / 14 |
| serious Total, serious adverse events | 1 / 313 | 7 / 319 | 6 / 145 | 2 / 142 | 5 / 70 | 0 / 10 | 0 / 14 |
Outcome results
Primary
Number of Participants Discontinuing Study Treatment Due to an Adverse Event
Time frame: Up to 26 weeks
Population: All Patients as Treated Population (APaT) - Participants were included in the treatment group corresponding to the study treatment they actually received. One participant randomized to 60 mg in Part II received 90 mg in Part II, and; therefore, was included in the Etoricoxib 60mg / 90mg (Part II) arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etoricoxib 90 mg | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 22 Participants |
| Naproxen 1000 mg | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 2 Participants |
| Naproxen 1000 mg (Part I) | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 6 Participants |
| Etoricoxib 60 mg / 60 mg (Part II) | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 3 Participants |
| Etoricoxib 60 mg / 90 mg (Part II) | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 9 Participants |
| Etoricoxib 90 mg / 90 mg (Part II) | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 4 Participants |
| Naproxen 1000 mg (Part II) | Number of Participants Discontinuing Study Treatment Due to an Adverse Event | 2 Participants |
Primary
Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 60 mg vs. Naproxen
Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average.
Time frame: Baseline and up to Week 6
Population: Per-Protocol Population - excluded participants due to important protocol deviations that may have had a substantial effect on the result of the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 60 mg vs. Naproxen | -29.00 mm VAS |
| Naproxen 1000 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 60 mg vs. Naproxen | -30.59 mm VAS |
95% CI: [-2.19, 5.37]ANCOVA
Primary
Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Naproxen
Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average.
Time frame: Baseline and up to Week 6
Population: Per-Protocol Population - excluded participants due to important protocol deviations that may have had a substantial effect on the result of the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Naproxen | -31.23 mm VAS |
| Naproxen 1000 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Naproxen | -30.59 mm VAS |
95% CI: [-5.47, 4.19]ANCOVA
Secondary
Average Change From Week 6 in the Spinal Pain Intensity Over Weeks 10 and 12 in Study Part 2: Etoricoxib 60/90 mg vs. Etoricoxib 60mg (Non-responders From Part I)
Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. Average change from Week 6 in Spinal Pain Intensity (VAS) over Weeks 10 and 12 is calculated as the average Spinal pain Intensity (VAS) value over Weeks 10 and 12 minus the Spinal Pain Intensity (VAS) at Week 6.
Time frame: Week 6 to Week 10 and Week 12
Population: Modified Intent-to-Treat (mITT) Population - the mITT population in Part I consisted of all randomized participants who received at least 1 dose of study treatment, had at least 1 measurement of interest post-randomization that was collected within 3 days of the last dose of study medication taken in Part I, and had baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 90 mg | Average Change From Week 6 in the Spinal Pain Intensity Over Weeks 10 and 12 in Study Part 2: Etoricoxib 60/90 mg vs. Etoricoxib 60mg (Non-responders From Part I) | -9.97 mm VAS |
| Naproxen 1000 mg | Average Change From Week 6 in the Spinal Pain Intensity Over Weeks 10 and 12 in Study Part 2: Etoricoxib 60/90 mg vs. Etoricoxib 60mg (Non-responders From Part I) | -7.26 mm VAS |
p-value: 0.11280% CI: [-4.88, -0.52]ANCOVA
Secondary
Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Etoricoxib 60 mg
Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average.
Time frame: Baseline and up to Week 6
Population: Modified Intent-to-Treat (mITT) Population - the mITT population in Part I consisted of all randomized participants who received at least 1 dose of study treatment, had at least 1 measurement of interest post-randomization that was collected within 3 days of the last dose of study medication taken in Part I, and had baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etoricoxib 90 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Etoricoxib 60 mg | -30.51 mm VAS |
| Naproxen 1000 mg | Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Etoricoxib 60 mg | -28.94 mm VAS |
p-value: 0.39680% CI: [-3.96, 0.81]ANCOVA