|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Ankylosing spondylitis (AS)
|Medical condition in easily understood language
|Type of chronic inflammatory arthritis involving the spine and/or sacroiliac joints.
|Diseases [C] - Immune System Diseases [C20]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10028395 - Musculoskeletal and connective tissue disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|• To compare the efficacy of tofacitinib 5 mg BID versus placebo on the ASAS20 response rate at Week 16 in subjects with active AS that have had an inadequate response to previous treatment.
|Secondary objectives of the trial
|• To compare the efficacy of tofacitinib 5 mg BID versus placebo on the ASAS40 response rate at Week 16 in subjects with active AS that have had an inadequate response to previous treatment.
• To compare the safety and tolerability of tofacitinib 5 mg BID versus placebo in subjects with active AS that have had an inadequate response to previous treatment.
• To compare the efficacy (including health-related quality of life, function, pain and fatigie) of tofacitinib 5 mg BID versus placebo at all time points in subjects with active AS that have had an inadequate response to previous treatment
|Trial contains a sub-study
|Principal inclusion criteria
|1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of and is capable of comprehending all pertinent aspects of the study. 2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Subject is at least 18 years old (or the minimum country-specific age of consent if > 18) at the screening visit.
4. The subject has a diagnosis of AS based on the Modified New York Criteria for Ankylosing Spondylitis (1984).
5. The subject must have a radiograph of the SI joints (AP Pelvis) documenting diagnosis of AS. Previous radiographs (up to 2 years old) can be used if they are accepted by the central reader. Otherwise, a new radiograph will be obtained during the screening period.
6. Subject has active AS Screening and Baseline (Day 1) visits defined as:
• BASDAI score of ≥4; and
• Back pain score (BASDAI Question 2) of ≥4.
7. Subject has active disease despite nonsteroidal anti-inflammatory drug (NSAID) therapy or is intolerant to NSAIDs as defined in the protocol. Subjects who are designated as TNFi-IR must have received at least 1, but not more than 2 approved TNF inhibiting biologic agent that was administered in accordance with its labeling recommendations and was inadequately effective after the minimum treatment times listed below and/or not tolerated after one or more doses.
• At least 3 months of adalimumab treatment;
• At least 3 months of etanercept treatment;
• At least 4 infusions of infliximab;
• At least 3 injections of golimumab;
• At least 3 months of certolizumab treatment.
Intolerance is defined as having experienced a treatment-related AE (eg, infusion/injection reactions, infections, laboratory test changes, etc)
8. Subjects may be receiving the following csDMARDs at the time of the screening visit. These medications should be continued throughout the entire study and doses should remain unchanged. Any other DMARDs require discussion prior to enrollment with the sponsor for washout timeframe.
• Methotrexate (MTX): Maximum dose of 25 mg/week. Minimum duration of therapy 4 months and dose stable for 4 weeks prior to first dose of investigational product. Subjects on MTX should be on an adequate and stable dose of folate supplementation per local standards/regulatory approval (eg, not less than 5 mg weekly based on folic acid, unless such doses would violate the local label guidelines or standard of care) for at least 4 weeks prior to the first dose of investigational product. Subject must not have had previous serious toxicity while on MTX and not be expected to require evaluation for possible methotrexate toxicity (eg, require a liver biopsy for methotrexate toxicity) during the study;
• Sulfasalazine (Azulfidine®, Salazopyrin®): Maximum dose of 3 gm/day. Minimum duration of therapy 2 months and dose stable for 4 weeks prior to first dose of investigational product.
9. Subjects who are already taking oral corticosteroids (not injectables) may participate in the study:
• Oral corticosteroids: Subjects who are already receiving oral corticosteroids must be on a stable dose of ≤10 mg/day of prednisone or equivalent for 1 weeks prior to the first dose of investigational product;
• Injected (eg, intraarticular, intramuscular, epidural or intravenous) corticosteroids must be discontinued 4 weeks prior to the first dose of investigational product;
• Topical and intra-rectal corticosteroids will be allowed during the study.
10. Subject has discontinued all disallowed concomitant medication for the required time prior to the first dose of investigational product.
11. Subjects who are receiving any investigational or marketed treatment for AS, arthritis or back pain not mentioned elsewhere must have that treatment discontinued for 4 weeks or 5 half-lives, whichever is longer.
12. Subjects receiving non-prohibited concomitant medications for any reason must be willing to stay on a stable regimen (doses and frequency) as defined in the protocol.
13. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined in the protocol.
14. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
15. Female subjects of non-childbearing potential must meet at least 1 of the following criteria:
• Achieved post-menopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with/and have a central laboratory confirmation of serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
|Principal exclusion criteria
|1. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. Persons who are dependent upon the sponsor, investigator or the study site are excluded.
2. Participation in other studies involving investigational drug(s) within
4 weeks prior to study entry and/or during study participation
(excluding noninterventional follow-up during the screening period).
3. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
4. History of known or suspected complete ankylosis of the spine.
5. Subjects that have been exposed to or are currently receiving conventional synthetic, targeted synthetic DMARDS (including JAK inhibitors), or those currently on biological DMARDs (ie washout from any current bDMARD required per protocol section 5.8.1), thalidomide (including previous use) and other prohibited concomitant medications.
6. History of allergies, intolerance or hypersensitivity to lactose or tofacitinib (CP-690,550). This includes subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption. The investigators of potential subjects with acquired lactose intolerance should consider whether this is sufficiently concerning so as to preclude participation.
7. Blood dyscrasias at screening or within 3 months prior to the first dose of investigational product including confirmed:
• Hemoglobin <10 g/dL;
• Absolute white blood cell count (WBC) <3.0 x 10^9/L (<3000 mm3);
• Absolute neutrophil count (ANC) <1.5 x 10^9/L (<1500 mm3);
• Absolute lymphocyte count <1.0 x 10^9/L (<1000/mm3);
• Platelet count <100 x 10^9/L (<100,000/mm3).
8. Estimated Creatinine Clearance <40 mL/min based on Cockcroft Gault equation at Screening visit.
9. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal (ULN) at screening visit.
One re-testing of a laboratory-acceptable specimen (eg, appropriately labeled, within stability parameters, not hemolyzed, appropriate type (tube and reagent) and volume) is allowed of any above parameters if the abnormal lab(s) was an uncharacteristic result(s). Re-test must be completed within the screening period.
10. History of any other autoimmune rheumatic disease.
11. History of an infected joint prosthesis at any time, with the prosthesis still in situ. 12. History of any lymphoproliferative disorder, such as Epstein Barr Virus related lymphoproliferative disease (EBV-LPD), history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
13. History of recurrent (more than one episode) herpes zoster or disseminated/multi-dermatomal (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
14. History of infection requiring hospitalization, parenteral
antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the 3 months prior to the first dose of investigational product.
15. History of infection requiring antimicrobial therapy within 2 weeks prior to the first dose of investigational product.
16. Any prior treatment with non-B cell specific lymphocyte depleting agents/therapies (eg, alemtuzamab, efalizumab), alkylating agents (eg, cyclophosphamide or chlorambucil), or total lymphoid irradiation.
17. Any subject who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of investigational product or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks after last dose of investigational product.
18. A subject with any condition possibly affecting oral drug absorption, eg, gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass. Procedures such as gastric banding, that simply divide the stomach into separate chambers, are NOT exclusionary.
19. A subject that is considered at risk for GI perforation by the investigator or Sponsor.
20. History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of investigational product. Subjects currently using marihuana.
|E.5 End points
|Primary end point(s)
|• ASAS20 response at Week 16.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|-ASAS40 response at Week 16;
-Incidence and severity of Adverse Events (AE).
-Clinical laboratory tests, vital signs, physical examination and 12-lead ECG parameters.
-ASAS20 response at all other time points.
-ASAS40 response at all other time points.
-Change from baseline in Ankylosing Spondylitis Disease Activity Score using C-Reactive Protein (ASDASCRP) at all time points.
-Change from baseline in hsCRP at all time points.
-Change from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) at all time points collected.
-Change from baseline in Short-Form-36 Health Survey-Version 2 Acute (SF-36v2) at all time points collected.
-Change from baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) including the 5 components (lateral spine flexion, tragus-to- wall distance, lumbar flexion, maximal intermalleolar distance and cervical rotation) at all time points.
-Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) (3 endpoints: total score, experience domain and impact domain scores) at all time points.
-Change from baseline in Patients Global Assessment of Disease (PGA) at all time points collected.
-Change from baseline in Patient's Assessment of Spinal Pain (Total Back Pain, Nocturnal Spinal Pain) at all time points collected.
-Change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at all time points.
-Change from baseline in inflammation (mean of the answers to questions 5 and 6 of the BASDAI) at all time points collected.
-ASAS 5/6 response at all time points.
-ASAS partial remission criteria at all time points.
-Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at all time points.
-BASDAI50 response at all time points.
-ASDAS clinically important improvement, ASDAS major improvement and ASDAS inactive disease at all time points.
-Change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at all time points collected.
-Change from baseline in extra-articular Involvement (Specific Medical History and peripheral articular involvement [as assessed by change from baseline in swollen joint count]) at all time points collected.
-Change from baseline in spinal mobility at all time points collected.
-Change from baseline in EuroQol EQ-5D Health State Profile 3 level
(EQ-5D-3L) and Your own health state today (EQ-VAS), at all time points collected.
-Change from baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Spondyloarthritis at all time points collected.
|Timepoint(s) of evaluation of this end point
|At all timepoints. Please refer to the protocol for additional details
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
|Other trial design description
|Open label treatment phase from Week 16 - 48
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|End of trial in a Member State of the EU is defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days