Tofacitinib in early active axial spondyloarthritis: a prospective, randomized, double-blind, placebo-controlled multicentre study - FASTLANE

Prior treatment

• Current or previous treatment with any biologic or targeted synthetic disease modifying antirheumatic drug (bDMARD or tsDMARD, respectively) including but not limited to TNF inhibitors, IL-17 inhibitors, IL-23 inhibitors, JAK inhibitors, and TYK inhibitors, PDE4 inhibitors, thalidomide (including previous use) and other prohibited concomitant medications.
• Significant trauma or surgery procedure within 4 weeks prior to baseline or any pre-planned elective surgery during the study period.
• Any subject who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks after the last dose of study drug.
• Any other conditions making the patient unsuitable in the opinion of the investigator for the participation in the current study or treatment with tofacitinib and/or naproxen.
• Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or within 4 weeks following the last dose of study drug.
• History of infections requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the 3 months prior to the first dose of study medication.
• 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 marijuana.
• Treatments with conventional synthetic DMARDs (csDMARDs) other than methotrexate, sulfasalazine, or mesalazine (e.g., Leflunomide, Hydroxychloroquine, Azathioprine, etc.) within 4 weeks prior to baseline (in case of Leflunomide either 8 weeks or 4 weeks with a standard cholestyramine wash-out).
• Concomitant treatment with strong inductors or inhibitors of cytochrome CYP3A4 (e.g. ketoconazole, itraconazole, rifampicin, clarithromycin, St-John´s-wort), or any combination of products resulting on simultaneous inhibition of CYP2C19 and moderate inhibition of CYP3A inhibitor and strong CYP2C19 inhibitor (e.g. fluconazole).
• Treatment with intravenous, intramuscular, intraarticular/periarticular, or epidural glucocorticoids within 2 weeks prior to baseline visit; treatment with oral or intra-rectal glucocorticoids in a dose of >10 mg prednisolone equivalent per day within 2 weeks prior to baseline visit.
• Current participation in another interventional study. If subjects participated in another study of any investigational drug, there must be an appropriate wash-out period prior to baseline visit.

Other illness

• Current malignancy or history of malignancies except adequately treated or excised basal cell or squamous cell carcinoma or cervical carcinoma in situ.
• A subject with any condition possibly affecting oral drug absorption, e.g. gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass. Procedures such as gastric banding, that simply divides the stomach into separate chambers, are NOT exclusionary.
• Any significant acute or chronic infection (at the discretion of the investigator).
• Patients with a history of a severe psychiatric illness, which might interfere with the patient’s ability to understand the requirements of the study and assessment and may interfere with the interpretation of study results.
• Patients with contraindications for the MRI including but not limited to: claustrophobia, seizure disorders, presence of an implanted electronic device (e.g., heart pacemaker, insulin pump, etc.) or metal implants not known to be MRI safe and metal foreign bodies in the patient’s body suspected to be ferromagnetic, tattoos performed with metal-containing paints or tattoos of large skin areas.
• 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.
• Current clinical signs and symptoms suggestive for tuberculosis.
• Chronic infection with Hepatitis B virus. At screening HBs-Ag and anti-HBc will be tested. Patients who are HBs-Ag positive will be excluded. In case of HBs-Ag negativity, but anti-HBc positivity, participation in the study is possible if HBV-DNA is negative and liver function tests are not meeting exclusion criterion 24e.
• Chronic infection with Hepatitis C (HCV), or history of Human Immunodeficiency Virus (HIV) infection. Subjects who are Hepatitis C Virus Antibody Positive (HCV Ab+) must undergo further testing for Hepatitis C Virus Ribonucleic Acid (HCV RNA). Subjects who are HCV RNA- may enroll.
• History of known or suspected complete ankylosis of the spine.
• 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.
• Subjects with chronic inflammatory articular disease (other than axSpA, e.g., rheumatoid arthritis), or any other systemic autoimmune diseases (e.g. systemic lupus erythematosus, Sjögren´s syndrome, etc.), chronic fatigue syndrome, or fibromyalgia. Subjects with a diagnosis of EMM in axSpA (i.e. inflammatory bowel disease, uveitis or psoriasis) are allowed to enter the study provided if they are not excluded by other criteria (e.g. prohibited medications, glucocorticoid use).
• A subject that is considered at risk for GI perforation by the investigator or Sponsor.
• Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities which may affect subject safety (e.g., pattern of acute myocardial infarction, acute ischemia, or serious arrhythmia) or interpretation of study results (e.g., continuously paced ventricular rhythm or complete left bundle branch block).
• History of allergies or hypersensitivity to any component of tofacitinib tablets (including lactose) or to naproxen. Subjects with acquired lactose intolerance should be considered by the investigator whether this is sufficiently concerning so as to preclude participation.
• History of an infected joint prosthesis at any time, with the prosthesis still in situ.

Lab values

• Evidence of other severe uncontrolled gastrointestinal, hepatic (serum albumin <25 mg/l or Child-Pugh-Score >10), renal, pulmonary, cardiovascular, nervous or endocrine disorders.
• Any of the following lab abnormalities detected at screening: a. Hemoglobin <10g/dl; b. Absolute neutrophil count <1.0 x 109/L (<1000/mm3); c. Absolute lymphocyte count <1.0 x 109/L (<750/mm3); d. Platelet count <100 x 109/L (<100,000/mm3); e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) >1.5times upper limit of normal; f. Creatinine-Clearance < 40 ml/min. One re-testing of a laboratory-acceptable specimen (e.g., 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). Documentation in the source of the typical results to allow a repeat lab is required. Re-test must be completed within the screening period.
• Positive tuberculosis Interferon Gamma Release Assay (IGRA) serum test and abnormal chest x-ray (positive x-ray) suggestive of past or present tuberculosis (both at screening or performed within 3 months prior to screening). Patients with a positive Tuberculosis IGRA serum test but negative chest x-ray and without clinical symptoms suggestive for tuberculosis may participate in the study after initiation of standard prophylactic anti-tuberculous treatment according to the current local treatment guidelines. Rifampicin should be avoided due to interaction with tofacitinib.
• Any prior treatment with non-B cell specific lymphocyte depleting agents/therapies (e.g., alemtuzamab, efalizumab), alkylating agents (e.g., cyclophosphamide or chlorambucil), or total lymphoid irradiation.

Other

• Patients who are defined as vulnerable patients according to Art. 10 REGULATION (EU) No 536/2014: patients who are institutionalized due to regulatory or juridical order; patients who are an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site; family members of the employees or the investigator.
• Primary or secondary immunodeficiency, or a first degree relative with a hereditary immunodeficiency.

• Subject ≥18 and ≤ 45 years of age at the screening visit.
• Subjects who are regularly taking NSAIDs or analgesics as part of their SpA therapy are required to be on a stable dose/dose regimen for at least 2 weeks prior to the baseline visit.
• Subjects taking oral corticosteroids must be on an average daily dose of ≤10mg/day prednisone or equivalent for at least 2 weeks prior to the baseline visit.
• Subjects taking Methotrexate (≤25 mg /week), Sulfasalazine (up to 3g/day) or Mesalazine (≤ 4.5g/day) are allowed to continue their medication if started at least 12 weeks prior to baseline, with a stable dose for at least 4 weeks before randomization. Subjects on methotrexate should be on an adequate and stable dose of folate supplementation by local standards (not less than 5 mg weekly, 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 methotrexate and not be expected to require evaluation for possible methotrexate toxicity (eg, require a liver biopsy for methotrexate toxicity) during the study.
• The subject is able and willing to give written informed consent and comply with the requirements of the study protocol. Only patients who give written informed consent will be included in the trial.
• Clinical diagnosis of axSpA by their treating rheumatologist.
• Fulfilment of the ASAS classification criteria for axSpA: a) Back pain for at least 3 months; b) Onset before 45 years of age; c) Sacroiliitis on imaging (x-rays or MRI) with ≥ 1 SpA feature OR HLA-B27 positive with ≥ 2 SpA features; i. Sacroiliitis on imaging defined as by x-rays as definite radiographic sacroiliitis grad II bilaterally or grade 3-4 unilaterally; according to the mNY criteria 1984; or as by MRI as active (acute) inflammation of SIJ on MRI, highly suggestive of sacroiliitis associated with SpA.”; ii. SpA features are considered: inflammatory back pain; extra-spinal manifestations (arthritis, enthesitis (heel), anterior acute uveitis, psoriasis, inflammatory bowel disease); good response to NSAIDs; family history of SpA; HLA-B27 positivity; elevated CRP or ESR.
• Symptom (back pain) duration for ≤ 2 years, according to the recently defined “early axial SpA” by ASAS.
• Active disease activity as defined by: a) BASDAI ≥4 and Back pain score (BASDAI Question 2) of ≥4 (on a 0-10 NRS) at screening and baseline.; AND b) Objective signs of inflammation at screening, evident by: i. MRI with SIJ inflammation (assessed by two central readers); AND/OR ii. Elevated serum CRP levels (>5mg/l)
• History of an inadequate response to at least one NSAID, other than naproxen. An inadequate response to a previous NSAID is defined as a lack of sufficient clinical response to the maximum recommended or tolerated daily dose for a minimum of 2 weeks based on a clinical judgment or based on a related adverse event PLUS the presence of active disease. This will be documented on the relevant case report form (CRF). Concerning patients who have received naproxen prior to screening visit: those who have had an inadequate response as per description above will be excluded. Only patients who have had naproxen but do not fulfill the abovementioned definition for inadequate responder will be considered for inclusion (e.g. patients with well-tolerated naproxen at doses below the maximum recommended dose).
• If female: either unable to bear children (postmenopausal for at least 1 year or surgically sterile) or is willing and able to practice a reliable method of contraception (preferably with low user dependency) throughout the study and 4 weeks after the last dose of study drug. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Reliable methods of contraception are: 1) (with low user dependency): intrauterine devices (IUD), implantable progestogen-only hormone contraception associated with inhibition of ovulation, intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (at least 1 year prior to enrolment); 2) (user dependent): combined (estrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal or injectable), progesterone-only hormone contraception with inhibition of ovulation (oral or injectable), complete sexual abstinence (in accordance with the usual and preferred lifestyle of the patient).. In questionable cases of menopausal status, a blood sample with simultaneous levels of follicle stimulating hormone (FSH) above 40 U/l and estradiol below 30 pg/ml is confirmatory. The results of the pregnancy test performed at Screening and Baseline must be negative.
• If male: either not of child-bearing potential (surgically sterilized, e.g. vasectomy at least 1 year prior to enrolment) or is willing and able to practice a reliable method of contraception throughout the study and 4 weeks after the last drug application.