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Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

ABSTRACT: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (?1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ?1.5×), as well as opportunistic infections and gastrointestinal perforations (?2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

SUBMITTER: Curtis JR

PROVIDER: S-EPMC5323490 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

Curtis Jeffrey R JR Zhang Richard R Krishnaswami Sriram S Anisfeld Andrew A Chen Yan Y Strengholt Sander S Chen Connie C Geier Jamie J

Clinical rheumatology 20160728 3

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well ...[more]

PMID: 27470086

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Project description:BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies.MethodsORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ?1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout.ResultsORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population.ConclusionsTofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population.Clinical trial identifierNCT00856544 and NCT00413699.

Project description:IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta.ObjectiveThe objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting.MethodsPregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up.ResultsOut of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up.ConclusionsThe pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.

Project description:IntroductionIn Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies.MethodsData were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study.ResultsAcross phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population.ConclusionsIn Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ≥ 60 months' treatment.FundingPfizer Inc. TRIAL REGISTRATION NUMBERS (ALL CLINICALTRIALS.GOV): NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699.

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Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

Publications

Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

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