Dose-Ranging Study Of Tofacitinib In Adults With Active Ankylosing Spondylitis

Study Overview
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Brief Summary
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This is the first study of oral tofacitinib in adults with active ankylosing spondylitis. It is designed to obtain information on the efficacy and safety of 3 different doses of tofacitinib.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study Of The Efficacy And Safety Of Tofacitinib In Subjects With Active Ankylosing Spondylitis (as)

Conditions
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Ankylosing Spondylitis

Intervention / Treatment
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* Drug: Tofacitinib 2 mg
* Drug: Tofacitinib 5 mg
* Drug: Tofacitinib 10 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of Ankylosing Spondylitis Has active disease despite concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) treatment or is intolerant to NSAIDs Exclusion Criteria: Pregnant or lactating females Currently receiving or previous use of a Tumor Necrosis Factor (TNF) inhibitor or any biological agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofacitinib 2 mg<br> | Drug: Tofacitinib 2 mg<br>* 4 blinded tablets (two 1 mg tablets of tofacitinib along with two 5 mg matching placebo tablets) will be administered orally twice a day (in the AM and PM) for 12 weeks<br>|
| Experimental: Tofacitinib 5 mg<br> | Drug: Tofacitinib 5 mg<br>* 4 blinded tablets (one 5 mg tablet of tofacitinib, one 5 mg and two 1 mg matching placebo tablets) will be administered orally twice a day (in the AM and PM) for 12 weeks<br>|
| Experimental: Tofacitinib 10 mg<br> | Drug: Tofacitinib 10 mg<br>* 4 blinded tablets (two 5 mg tablets of tofacitinib and two 1 mg matching placebo tablets) will be administered orally twice a day (in the AM and PM) for 12 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 4 blinded tablets (two 1 mg and two 5 mg matching placebo tablets) will be administered orally twice a day (in the AM and PM) for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 20 Percent (%) Improvement in Assessment of SpondyloArthritis International Society (ASAS) Score (ASAS 20) at Week 12 | The primary analysis of this outcome measure was performed using the Emax model. Clinical response to treatment was assessed according to ASAS20 criteria. ASAS20 responder had improvement of greater than or equal to (≥) 20% and ≥1 unit in at least 3 domains (on a scale of 0 [least] to 10 [worst]) and no worsening of ≥20% and less than or equal to (≤)1 unit in the remaining domain. The domains are: Patient's Global Assessment of Disease Activity, spinal pain, function and inflammation (from Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]). Missing data were handled by nonresponsive (NRI)/ last observation carried forward (LOCF). Missing values due to a subject dropping out from the study were handled by setting the ASAS20 value to NRI. The LOCF approach was applied to missing components, if just some of the components of the ASAS20 were missing. | Week 12 | 
| Percentage of Participants Achieving ASAS20 at Week 12 | The supportive analysis of this outcome measure was performed using the normal approximation for two proportions. Clinical response to treatment was assessed according to ASAS20 criteria. ASAS20 responder had improvement of ≥ 20% and ≥1 unit in at least 3 domains (on a scale of 0 [least] to 10 [worst]) and no worsening of ≥20% and ≤1 unit in the remaining domain. The domains are: Patient's Global Assessment of Disease Activity, spinal pain, function and inflammation (from Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]). Missing data were handled by NRI/LOCF. Missing values due to a subject dropping out from the study were handled by setting the ASAS20 value to NRI. The LOCF approach was applied to missing components, if just some of the components of the ASAS20 were missing. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in BASDAI Total Score at Week 2, 4, 8 and 12 | BASDAI is a validated self-assessment tool used to determine disease activity in participant with Ankylosing Spondylitis. Utilizing a Numerical Rating Scale (NRS) of 0-10 (0 = none and 10 = very severe) participant's answered 6 questions measuring discomfort, pain and fatigue. The BASDAI score is calculated by computing the mean of questions 5 and 6 and adding it to the sum of questions (Q)1-4. This score is then divided by 5. BASDAI=Q1+Q2+Q3+Q4+[Q5+Q6/2]/5. The final BASDAI score averages the individual assessments for a final score range of 0-10. Negative values indicate improvement. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants Achieving a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 Response at Weeks 2, 4, 8 and 12 | BASDAI is a validated self-assessment tool used to determine disease activity in participant with Ankylosing Spondylitis. Utilizing a Numerical Rating Scale (NRS) of 0-10 (0 = none and 10 = very severe) participant's answered 6 questions measuring discomfort, pain and fatigue. The BASDAI score is calculated by computing the mean of questions 5 and 6 and adding it to the sum of questions (Q)1-4. This score is then divided by 5. The final BASDAI score range from 0-10. A positive response was defined as a 50% improvement in the BASDAI from baseline. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Weeks 2, 4, 8 and 12 | BASFI is a validated self-assessment tool that determines the degree of physical functional limitation in Ankylosing Spondylitis. Utilizing a Numerical Rating Scale (NRS) of 0-10 (0=easy, 10=impossible), participants answered 10 questions assessing their ability in completing normal daily activities or physically demanding activities. The BASFI score is a mean score of the 10 questions with lower scores indicating better physical function. The higher the negative value the better the improvement. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Weeks 2, 4, 8 and 12 | BASMI is an objective measure of spinal mobility and was completed by a blinded assessor. The BASMI score is composed of 5 clinical measures: cervical rotation, intermalleolar distance, modified Schober's test, lateral flexion and tragus to wall distance. The derived score used the average of the 5 assessments on a scale of 0-10 scale with higher scores indicating more impairment of spinal mobility. BASMI was analyzed using the linear function method. The higher the negative value the better the improvement. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Weeks 4, 8 and 12 | Assessment of enthesitis of 13 sites was performed in the following, 1st costochondral joint left and right, 7th costochondral joint left and right, posterior superior iliac spine left and right, anterior superior iliac spine left and right, iliac crest left and right, 5th lumbar spinous process and proximal insertion of Achilles tendon left and right. Each site was graded for the presence (1) and absence (0) of tenderness yielding total MASES ranging from 0 (no tenderness) to 13 (worst possible score; severe tenderness). | Baseline, Week 4, Week 8, Week 12 | 
| Extra-Articular Involvement From Specific Ankylosing Spondylitis Medical History | Participants were assessed at Baseline, Week 12 and Week 16 (Follow-up) to determine if they had specific Ankylosing Spondylitis medical history or changes in specific Ankylosing Spondylitis medical history which included: Inflammatory Bowel Disease (IBD), Peripheral Articular Involvement (PAI; as assessed by swollen joint count), psoriasis (PSO) and uveitis (UVE). | Baseline, Week 12 and Follow-up | 
| Change From Baseline of Total Swollen Joint Count at Weeks 2, 4 8 and 12 | This assessment was performed by the blinded assessor using the following scale: Present/Absent/Not Done/Not Applicable (to be used for artificial or missing joints) for determination of the total number of swollen joints. Forty-four joints were assessed for swelling on left and right side and included the following: sternoclaviculars, acromioclaviculars, shoulders, elbows, wrists, metacarpophalangeals (I, II, III, IV, V), thumb interphalangeal, proximal interphalangeals (II, III, IV, V), knees, ankles, and metatarsophalangeals (I, II, III, IV, V). Artificial joints were not assessed. A negative change means improvement. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline of Mean Spinal Mobility (Chest Expansion) at Week 2, 4, 8 and 12 | Chest expansion, measured in centimeters (cm), is defined as the difference in the thoracic circumference during full expiration versus full inspiration. This was measured at the 4th intercostal space. The difference between maximal inspiration and expiration of the two attempts was recorded. The better of the two attempts was used to calculate chest expansion. Missing data at Week 12 were imputed by LOCF if data at an early visit (discontinuation visit) were available. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline to Week 12 in Short-Form-36 Health Survey (SF-36) Physical and Mental Health Scores at Week 12 | SF-36 is a standardized survey evaluating 8 aspects of functional health and wellbeing: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (0=no functioning, 100=highest level of functioning). Missing data at Week 12 were imputed by LOCF if data at an early visit (discontinuation visit) were available. | Baseline, Week 12 | 
| Change From Baseline in EuroQol EQ-5D Health State Profile (EQ-5D) Utility Score at Week 12 | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of single utility score. Health state profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression; Scale range 1 to 3 (1=better health state [no problems], 3=worst health state [confined to bed]). | Baseline, Week 12 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 2, 4, 8 and 12 | FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants Achieving 20% Improvement in ASAS Score at Weeks 2, 4 and 8 | Clinical response to treatment was assessed according to ASAS20 criteria. ASAS20 responder had improvement of ≥ 20% and ≥1 unit in at least 3 domains (on a scale of 0 [least] to 10 [worst]) and no worsening of ≥20% and ≤1 unit in the remaining domain. The domains are: Patient's Global Assessment of Disease Activity, spinal pain, function and inflammation (from Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]). Missing data were handled by NRI/LOCF. Missing values due to a subject dropping out from the study were handled by setting the ASAS20 value to NRI. The LOCF approach was applied to missing components, if just some of the components of the ASAS20 were missing. | Baseline, Week 2, Week 4, Week 8 | 
| Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) Index of Disease Activity Score of the Sacroiliac (SI) Joints at Week 12 | SPARCC scoring consists of assessing six SI joint MRI image coronal slices representing the largest proportion of the synovial compartment of the SI joints for edema. The maximum score per slice was 2 and 12 for all 6 slices. The total minimum and maximum score for all SI joints across 6 slices is 0 to 72 and higher scores indicate more inflammation. A negative change from baseline indicates improvement. Missing data at Week 12 were imputed by LOCF if data at an early visit (discontinuation visit) were available. | Baseline, Week 12 | 
| Change From Baseline in SPARCC MRI Index of Disease Activity Score of the Spine at Week 12 | SPARCC scoring of the magnetic resonance imaging (MRI) of the spine consists of assessing six disco-vertebral units (DVU) with 3 consecutive sagittal slices at each DVU. The minimum and maximum SPARCC score for all 6 DVUs is 0 to 108, with higher scores indicating more damage. A negative change from baseline indicates improvement. Missing data at Week 12 were imputed by LOCF if data at an early visit (discontinuation visit) were available. | Baseline, Week 12 | 
| Change From Baseline in Modified Berlin Ankylosing Spondylitis Spine Magnetic Resonance Imaging Activity Score (ASspiMRI) of the Spine at Week 12 | Berlin modification of the ASspiMRI is a measure of acute lesion as determined by short-tau inversion recovery (STIR) sequences. All 23 disco-vertebral units (DVU) of the spine (from C2 to S1), defined as the region between 2 virtual lines through the middle of each vertebra, were scored in a single dimension, which is represented the highest level of inflammation in that particular DVU. Total spine ASspiMRI scores can range from 0-69 with higher scores indicating more disease activity. A negative change from baseline indicates improvement. Missing data at Week 12 were imputed by LOCF if data at an early visit (discontinuation visit) were available. | Baseline, Week 12 | 
| Percentage of Participants Achieving 40% Improvement in ASAS Score at Weeks 2, 4, 8 and 12 | ASAS 40 is defined as ≥40% and absolute change of ≥2 units in at least 3 domains on a 0-10 scale (0=no disease activity, 10=high disease activity), and no worsening in the remaining domain. Missing data were handled by NRI/LOCF. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants Achieving ASAS5/6 Response at Weeks 2, 4, 8 and 12 | ASAS5/6 consists of 6 domains: the 4 used in ASAS20 (Patient's Global Assessment of Disease Activity, spinal pain, function, inflammation plus spinal mobility and an acute phase reactant, C Reactive Protein (CRP). ASAS 5/6 is defined as ≥20% improvement in at least 5 domains and no worsening in the remaining domain. Missing data were handled by NRI/LOCF. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Change From Baseline of Ankylosing Spondylitis Disease Activity Score Using C-Reactive Protein ASDAS(CRP) at Weeks 2, 4, 8 and 12 | The ASDAS(CRP) is a derived score that uses back pain, duration of morning stiffness, Patient's Global Assessment of their disease and peripheral pain/swelling. The formula used for calculating the ASDAS (CRP)is: 0.12 x Back Pain + 0.06 x Duration of Morning Stiffness + 0.11 x Patient Global + 0.07 x Peripheral Pain/Swelling + 0.58 x Ln(CRP+1). The calculated score can be from 0 to no defined upper limit. A negative number indicates a reduction in the score which indicates decrease in disease activity. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants With ASDAS Clinically Important Improvement at Weeks 2, 4, 8 and 12 | The ASDAS clinically important improvement was calculated from the ASDAS data. The ASDAS clinically important improvement is defined as change (decrease) from baseline of ≥1.1 units. Missing data were handled by NRI/LOCF. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants With ASDAS Major Improvement at Weeks 2, 4, 8 and 12 | The ASDAS major improvement was calculated from the ASDAS data. The ASDAS major improvement was defined as change (decrease) from baseline of ≥2.0 units. Missing data were handled by NRI/LOCF. | Baseline, Week 2, Week 4, Week 8, Week 12 | 
| Percentage of Participants Achieving ASDAS Inactive Disease at Weeks 2, 4, 8 and 12 | The ASDAS inactive disease was calculated from the ASDAS data. The ASDAS inactive disease was defined as ASDAS <1.3 units. Missing data were handled by NRI/LOCF. | Baseline, Week 2, Week 4, Week 8, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ankylosing Spondylitis, Spondylitis, Ankylosing, Spondyloarthritis, Spondyloarthropathy, Oral preparation