Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ⩾6 Years with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Clinical Trial.

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).

Safety and clinical activity of atacicept in the long-term extension of the phase 2b ADDRESS II study in systemic lupus erythematosus.

OBJECTIVES: Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. METHODS: In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. RESULTS: In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. CONCLUSION: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

Points to consider for analyzing efficacy outcomes in long-term extension clinical trials.

This article focuses on 2 objectives in the analysis of efficacy in long-term extension studies of chronic diseases: (1) defining and discussing estimands of interest in such studies and (2) evaluating the performance of several multiple imputation methods that may be useful in estimating some of these estimands. Specifically, 4 estimands are defined and their clinical utility and inferential ramifications discussed. The performance of several multiple imputation methods and approaches were evaluated using simulated data. Results suggested that when interest is in a binary outcome derived from an underlying continuous measurement, it is preferable to impute the underlying continuous value that is subsequently dichotomized rather than to directly impute the binary outcome. Results also demonstrated that multivariate Gaussian models with Markov chain Monte Carlo imputation and sequential regression have minimal bias and the anticipated confidence interval coverage, even in settings with ordinal data where departures from normality are a concern. These approaches are further illustrated using a long-term extension study in psoriasis.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

BACKGROUND AND AIMS: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.

Safety and Effectiveness of Peficitinib (ASP015K) in Patients with Rheumatoid Arthritis: Final Results (32 Months of Mean Peficitinib Treatment) From a Long-Term, Open-Label Extension Study in Japan, Korea, and Taiwan.

INTRODUCTION: This final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA). METHODS: Patients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY). RESULTS: Overall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug. CONCLUSIONS: Improvements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months' duration. TRIAL REGISTRATION: ClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013 .

Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan.

BACKGROUND: Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52 weeks' duration. However, safety and effectiveness after long-term treatment have not been assessed. METHODS: This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12 weeks) and phase 3 (RAJ3 and RAJ4; 52 weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n = 843) received oral peficitinib once daily (100 mg, or 50 mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150 mg) or reduced (to 50 mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). RESULTS: Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7 months and the maximum dose was 100 mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6 - 3.1), herpes zoster-related disease 6.8 (95% CI, 5.6 - 8.3), and malignancies 1.1 (95% CI, 0.7 - 1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively. CONCLUSIONS: The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6 years was well tolerated in Asian patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer.

BACKGROUND: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2-positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study. METHODS: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS. RESULTS: A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26-0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS. CONCLUSION: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02771795 (EudraCT 2015-005663-17).