Long Term Safety and Efficacy of Baricitinib in Patients with RA
Research type
Research Study
Full title
A Phase 3, Multicenter Study to Evaluate the Long-Term Safety and Efficacy of Baricitinib in Patients with Rheumatoid Arthritis
IRAS ID
123180
Contact name
Bruce Kirkham
Contact email
Sponsor organisation
Eli Lilly and Company
Eudract number
2012-003686-17
ISRCTN Number
Not provided
Clinicaltrials.gov Identifier
Not provided
Research summary
Research Summary
Participants may be required to undergo procedures for this study which they would not ordinarily be subjected to, some of which the participant may find uncomfortable. The study staff will try to reassure participants at all times throughout the study and make them as comfortable as possible.The main ethical issues posed by this study are the potential for adverse events. The full adverse event profile of the study drug components has been fully explained in the Patient Information Sheet and participants will have the opportunity to discuss these with the study doctor at any time. The doses of study medication intended to be administered in this study are of a reasonable level and as such the adverse event profile should be well managed. The site will take every precaution to ensure the safety of study participants. Participants will be provided with a contact telephone number for the site and the sponsor for use both during normal hours and out of hours.
Participants are required to attend the clinic more frequently than for normal routine care. The expectations and requirements of this trial are clearly indicated in the Patient Information Sheet to allow participants to consider the commitment needed before they enter the trial. Should the frequency of visits or assessments conducted become too much for the participant, they are free to withdraw from the study at any time.
Participant study data will be captured using an electronic data capture system. Confidentiality will be maintained through only allowing the authorised personnel at the research sites to access the information through a password protected system.
This study was designed according to ICH/GCP and with due thought given to potential ethical dilemmas. It is not anticipated that any significant ethical issues will now arise.
Summary of Results
Study JADY was a Phase 3, multicenter, long term extension study. The primary objective of the study was to evaluate the long-term safety and tolerability of baricitinib in patients who completed an originating study. The secondary objective was to evaluate the efficacy of long-term baricitinib treatment on clinical signs and symptoms improvement, disease activity control, physical function improvement, patient-reported outcomes, and radiographic progression. The study enrolled 2877 patients from the originating clinical studies (JADV, JADW, JADX, JADZ, JAGS, and JADA) who were originally exposed to baricitinib 1, 2, 4, 8, and 16 mg; placebo; or methotrexate.
Patients (2876) were exposed to either baricitinib 4 mg or 2 mg QD, contributing to a total 12,468 patient-years
(PYs) of exposure, 32.2% had at least 1 SAE with an exposure-adjusted incidence rate of 7.25/100 PYs, and 17.1% permanently discontinued the study due to AEs. Safety data are more thoroughly assessed in the context of integrated data, in which the data from originating studies are included. The long-term safety data were analyzed in a 5YSU report and were consistent with the known safety profile of baricitinib. There was no increase in the occurrence of overall TEAEs, SAEs, or events of interest associated with longer durations of baricitinib.
Maintenance of efficacy was demonstrated in the JADY patients. Across all originating study treatment groups, ˃55% of patients who achieved the response of ACR20, ACR50, ACR70, DAS28-hsCRP ≤3.2, DAS28 ESR ≤3.2, CDAI ≤10, or SDAI ≤11 at Study JADY baseline maintained these disease control measures at least 1 year later.
The overall maintenance of response was lower in patients from JADW (tumor-necrosis-factor-incomplete responders), while better response rates were seen in patients from Study JADZ (methotrexate-naïve patients). This was seen particularly for maintenance of ACR20, DAS28-hpCRP ≤3.2, DAS28-hpCRP <2.6, ACR/EULAR, and HAQ DI improvement. At least 40% and 70% of patients did not present radiographic progression as measured by ∆mTSS ≤0 and smallest detectable change (SDC), respectively, at year 3 (JAGS) or year 5 (all other studies) from baseline of the originating studies. Across all originating study treatment groups, at least 65% of patients who achieved a physical function improvement, as measured HAQ-DI improvement ≥0.22, at Study JADY baseline, maintained a HAQ-DI improvement ≥0.22 at least 1 year later. Across all originating study treatment groups, patients reported an improvement in morning stiffness or EQ-5D-5L score when assessed from baseline of the originating study to year 5 and beyond. These extended benefits for clinical signs and symptoms improvement, disease activity control, physical function improvement, and patient-reported outcomes were consistent with the previously published Study JADY data (van der Heijde et al. 2018; Emery et al. 2021; Smolen et al. 2021; Wells et al. 2021).
Patients originally from Studies JADV, JADW, JADX, and JAGS who achieved sustained (CDAI ≤10) or from Study JADZ who achieved sustained remission (CDAI ≤2.8) after at least 15 months of treatment with baricitinib 4 mg QD were rerandomized 1:1 in a double-blind manner to continue 4 mg QD or reduce the dose to 2 mg QD. At least 60% of the patients rerandomized to 2 mg in JADY from originating Studies JADV, JADW, JADX, and JAGS were observed to have maintained LDA up to 2 years post-rerandomization. At least 53% of the patients from Study JADZ maintained remission from rerandomization to 2 mg up to year 2. The proportions of LDA or remission were numerically higher at all time points up to year 2 for patients randomized to 4 mg compared to those randomized to
2 mg. The sustained remission up to Week 96 was an extension of the previous sustained effect up to Week 48 (Takeuchi et al. 2019).
Conclusions:
Safety conclusions
The findings of the safety update report, which includes the integrated safety dataset including Study JADY and the feeder studies, were in line with the known safety profile of baricitinib.
Study JADY met its primary objective, demonstrating acceptable and consistent long-term safety and tolerability with baricitinib treatment.
Efficacy conclusions
Efficacy achieved at the beginning of Study JADY was maintained for at least 1 year in the majority of JADY patients in signs and symptom improvement, disease activity control, and physical function improvement.
Improvements in patient quality of life and morning stiffness were consistently observed from the originating study baseline to year 5. The majority of patients remained free from SDC in radiographic progression from the beginning of the originating study up to year 5. Maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was achieved in both the 4-mg and 2-mg groups up to Week 96.
Altogether, the long-term JADY data support the previously established benefit-risk balance of baricitinib for treating adult patients with moderately to severely active RA.
References:
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London - Brighton & Sussex Research Ethics Committee
REC reference
13/LO/1199
Date of REC Opinion
24 Oct 2013
REC opinion
Further Information Favourable Opinion