Open-label Long-term Extension Research Articles

Deucravacitinib in plaque psoriasis: 2-year laboratory results from the phase 3 POETYK PSO program

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In the phase 3 POETYK PSO-1 and PSO-2 trials, deucravacitinib was significantly more efficacious than placebo and apremilast and was well tolerated in moderate to severe plaque psoriasis. PSO-1 and PSO-2 completers could enroll in the ongoing open-label POETYK long-term extension (LTE) trial. Changes in blood laboratory parameters with deucravacitinib in the PSO-1, PSO-2, and LTE trials were compared with signature changes seen with JAK 1/2/3 inhibitors.
 Methods: The 52-week, double-blind PSO-1 (NCT03624127) and PSO-2 (NCT03611751) trials randomized adults with moderate to severe plaque psoriasis 2:1:1 to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily. At Week 52, eligible patients enrolled in POETYK LTE (NCT04036435) and received deucravacitinib. Changes from baseline in hematologic parameters (lymphocytes, neutrophils, platelets, hemoglobin) and lipid and chemistry parameters (cholesterol, creatinine, CPK, ALT) were assessed through Week 100 (LTE Week 48). CTCAE grade ≥3 laboratory abnormalities and treatment discontinuations due to laboratory abnormalities were evaluated.
 Results: 1519 patients received ≥1 dose of deucravacitinib in all 3 trials. In total, 1179 (77.6%) and 584 (38.4%) patients had ≥52 and ≥104 weeks, respectively, of continuous deucravacitinib exposure; median duration of exposure was 682.0 days (97 weeks). No trends in clinically meaningful changes from baseline were observed in these parameters from Weeks 0–52 or in the LTE. Grade 3 or 4 abnormalities over 100 weeks of deucravacitinib treatment were rare, with incidence rates comparable to placebo and apremilast through Week 52; no increases were seen in the LTE. Two patients discontinued deucravacitinib due to lymphopenia and abnormal hepatic function.
 Conclusion: No trends in clinically meaningful changes from baseline were observed with deucravacitinib in laboratory parameters, including signature changes associated with JAK 1/2/3 inhibitors. Treatment discontinuations and grade 3 or 4 laboratory abnormalities were rare and comparable to incidence rates seen with placebo and apremilast. These results suggest laboratory monitoring is not warranted with deucravacitinib.

Matching-adjusted indirect comparison (MAIC) of deucravacitinib versus adalimumab for the treatment of patients with moderate to severe plaque psoriasis over 2 years

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved in the US for the treatment of adults with moderate to severe plaque psoriasis (PsO). A previous indirect treatment study showed comparable efficacy between deucravacitinib and first-generation biologics at week 52. The objective of this study was to compare the long-term efficacy of deucravacitinib to that of adalimumab based on long-term extension (LTE) trials, after adjusting for differences in patient characteristics at baseline. 
 Methods: Open-label LTE trials that were feasible for indirect treatment comparison were identified for each treatment (deucravacitinib: POETYK PSO-LTE [NCT04036435]; adalimumab: REVEAL extension [NCT00195676]). Patients who were initially randomized to placebo and switched to continuous active treatment after Week 16 were selected as cohorts due to the comparability of study design and outcomes of interest. Patients with prior adalimumab were excluded from the deucravacitinib cohort. The primary outcome was PASI 75 at Week 112 since randomization and secondary outcomes were PASI 75 at Week 52 and PASI 90 at Weeks 52 and 112; missing PASI data was imputed using the last observation carried forward (LOCF) method. Matching-adjusted indirect comparison was conducted where individual patient-level data from POETYK PSO-LTE were reweighted to achieve balance with the summary baseline characteristics in the REVEAL extension trial: age, sex, race, weight, duration of psoriasis, body surface area affected, prior treatment history, baseline PASI and placebo PASI 75/90 responses at Week 16. Sensitivity analyses explored the effect of adjusting for prior treatment or not as well as history of psoriatic arthritis and patient's overall severity of disease.
 Results: Patients from POETYK PSO-LTE (N=329) were on average older, with lower weight, but with more prior systemic treatment exposure, higher baseline PASI score and higher placebo PASI 75/90 response at Week 16 than those in REVEAL (N=345). After adjustment, baseline differences between the two trials were mitigated. Results showed adjusted PASI 75 and PASI 90 response rate at Week 112 since randomization was higher for patients who were treated with deucravacitinib compared to those who were treated with adalimumab after 16 weeks of placebo: PASI 75= 67.2% vs 54% (mean difference [95% CI]= 13.2% [4, 22.5]); PASI 90= 41.3% vs 34% (7.3% [-2, 16.7]). Adjusted PASI 75 and PASI 90 at Week 52 were similar between the two cohorts. Results from the sensitivity analyses confirmed the base case findings.
 Conclusion: This indirect comparison analysis suggests that patients with moderate to severe plaque psoriasis with continuous active treatment on deucravacitinib had better long-term response than adalimumab and highlights the therapeutic role of deucravacitinib.

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD. ClinicalTrials.gov identifierNCT03395353

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

33006 Long-term improvement of patient-reported outcomes in adult patients with atopic dermatitis treated with baricitinib in the US and Canada

Objective: To evaluate long-term patient-reported outcome (PRO) improvements in patients with atopic dermatitis (AD) treated with baricitinib, a Janus kinase (JAK)1/JAK2 inhibitor. Methods: Data were derived from 2 phase 3 studies: double-blind placebo-controlled BREEZE-AD5 (NCT03435081) and long-term open-label extension BREEZE-AD6 (NCT03559270) through 52 weeks of treatment. Low-potency topical corticosteroids were permitted after Week 16 in BREEZE-AD5 and throughout BREEZE-AD6. PROs [Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), and Hospital Anxiety Depression Scale (HADS-anxiety and HADS-depression)] were assessed to Week 52 using descriptive statistics with missing data imputed by last observation carried forward. Results: In 146 patients receiving baricitinib 2 mg, the quality of life measure DLQI (mean ± standard deviation at baseline 15.0 ± 7.6) showed a mean change from baseline of −7.0 ± 8.2 at Weeks 48-52. Patient-reported improvements in skin symptoms as measured by POEM were −7.3 ± 8.8 at Weeks 48-52 from mean baseline value of 21.7 ± 5.4. By Weeks 48-52, 68.9% and 57.6% of patients had achieved a clinically meaningful ≥4-point improvement in DLQI and POEM, respectively. HADS-anxiety and HADS-depression scores were 7.0 ± 4.4 and 5.2 ± 4.3 at baseline, respectively, with patients reporting a change from baseline of −1.9 ± 3.7 and −1.8 ± 3.3 at Weeks 48-52. Conclusion: Patients with moderate to severe AD treated with baricitinib 2 mg experienced clinically meaningful PRO improvements in skin symptoms, quality of life, and anxiety and depression over 52 weeks.

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study

BackgroundRecombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151–202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks.MethodsPatients who completed the randomized PRM-151–202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis).ResultsAll 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, − 6.2% (− 7.7; − 4.6) and − 5.7% (− 8.0; − 3.3) for percent predicted FVC and − 36.3 m (− 65.8; − 6.9) and − 28.9 m (− 54.3; − 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128.ConclusionsLong-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect.Trial registration NCT02550873; EudraCT 2014-004782-24.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial.

To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5mg twice daily and aspirin 100mg once daily during long-term open-label extension (LTOLE). Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Efficacy and Safety of Duloxetine in Children and Adolescents with Major Depressive Disorder in Japan: A Randomized Double-Blind Placebo-Controlled Clinical Trial Followed by an Open-Label Long-Term Extension Trial.

Objective: The goal of this study was to evaluate the efficacy and safety of duloxetine in children and adolescents (9-17 years of age) with major depressive disorder (MDD) in Japan. Methods: This study consists of two clinical trials. First, a 6-week, randomized double-blind placebo-controlled clinical trial (RCT) was conducted. The primary endpoint of RCT was the change in Children's Depression Rating Scale-Revised (CDRS-R) total scores from baseline. Following RCT, an open-label long-term extension trial (OLE) was conducted to investigate the longer-term safety of duloxetine for ∼1 year. Results: In RCT, CDRS-R total score changes from baseline to 6 weeks after the start of administration (primary endpoint) were -21.03 in the duloxetine group (n = 74) and -22.42 in the placebo group (n = 74). No significant difference was observed in the primary endpoint between the groups (p = 0.5587). In addition, no significant difference was observed in secondary endpoints such as CDRS-R response rates. The proportion of patients with ≥1 treatment-emergent adverse event (TEAE) in RCT was significantly higher in the duloxetine group (78.7%) than in the placebo group (62.2%), and most were mild or moderate in severity. Changes in CDRS-R total scores during OLE, in consecutive patients from the duloxetine group in RCT (n = 63), or placebo group (n = 59) in RCT, and newly enrolled patients (n = 28), were -12.1, -11.3, and -17.8, respectively. The proportion of patients with ≥1 TEAE in OLE was 90.5%, 88.1%, and 89.3% in the respective groups, and most of them were mild or moderate in severity. Conclusions: Duloxetine did not show superiority to placebo in efficacy in children and adolescents with MDD in Japan. Overall reported TEAEs were consistent with the currently available duloxetine safety profile and no new safety finding was observed in the two clinical trials.

Systematic Evaluation of the T30 Neurostimulator Treatment for Tinnitus: A Double-Blind Randomised Placebo-Controlled Trial with Open-Label Extension.

Tinnitus is often triggered by cochlear damage and has been linked with aberrant patterns of neuronal activity. Acoustic Coordinated Reset (CR®) Neuromodulation is a sound therapy hypothesised to reduce tinnitus symptoms by desynchronising pathological brain activity using a portable acoustic device (the T30 neurostimulator). We report results of a pivotal trial to test the efficacy of this intervention. This two-centre, double-blind randomised controlled trial with long-term open-label extension, was undertaken between February 2012 and February 2014 in the UK. Participants were 100 adults with tinnitus as a primary complaint, recruited through hearing clinics and media advertisements. Intervention was the device programmed either with the proprietary sound sequence or placebo algorithm, fit by one of five trained audiologists. Minimisation software provided group allocation (1:1 randomisation), with groups matched for age, gender, hearing loss and tinnitus severity. Allocation was masked from participants and assessors during the trial. The primary measure of efficacy was change in tinnitus symptom severity between groups, measured using the Tinnitus Handicap Questionnaire at 12 weeks. Secondary outcomes were other measures of tinnitus symptom severity, health-related quality of life, and perceptual characteristics (pitch, loudness, bandwidth) at 12 weeks, and Tinnitus Handicap Questionnaire at 36 weeks (open-label extension). A statistician blinded to the allocation conducted an intention-to-treat analysis that employed linear regressions on minimisation variables, trial centre and intervention group, with multiple imputations for missing data. The study was registered on clinicaltrials.gov (NCT01541969). We screened 391 individuals and assigned interventions to 100 eligible participants. The primary outcome was not statistically significant between groups (mean group = −0.45, 95% CI −5.25 to 4.35; p = 0.85), nor were any of the secondary outcomes. Four adverse events occurred during the trial. Analysis of tinnitus symptom severity data collected across the 24-week open-label extension showed no statistically significant within-group changes after 12, 24, or 36 weeks treatment with the proprietary sound sequence. While individual participants may benefit from sound therapy, Acoustic CR® Neuromodulation did not lead to group-mean reductions on tinnitus symptom severity or other measures compared to placebo, or over time.

P378 Rectal bleeding and stool frequency improvement with tofacitinib dose escalation to, 10 mg BID in patients with Ulcerative Colitis following loss of response on tofacitinib, 5 mg BID maintenance therapy: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, patients who responded to tofacitinib, 10 mg BID during induction, and experienced treatment failure whilst receiving tofacitinib, 5 mg BID during maintenance (OCTAVE Sustain) and subsequently received tofacitinib, 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the dose escalation subpopulation. The efficacy and safety of tofacitinib in the dose escalation subpopulation have been previously reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the dose escalation subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall dose escalation subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline) and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 57 patients were included in the dose escalation subpopulation, of which, 28 (49.1%) had prior TNFi failure. Overall, at M1 and M6, of OCTAVE Open, 59.6% and, 66.7% of patients had rectal bleeding improvement, respectively (Figure, 1). Corresponding values for stool frequency improvement were, 50.9% and, 64.9%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Patients with a clinical response at M2 had a numerically greater mean decrease from baseline in PMS, RBS and SFS at M1 than those without (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after, 8–52 weeks of treatment with tofacitinib, 5 mg BID (following reduction from induction tofacitinib, 10 mg BID), dose escalation back to, 10 mg BID generally resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Furthermore, early improvement in RBS and/or SFS at M1 may indicate likelihood of recapturing response at M2 with dose escalation from tofacitinib, 5 to, 10 mg BID. Reference 1. Sands BE et al. Aliment Pharmacol Ther, 2020;, 51:, 271–280.

P286 Sustained improvement in health-related quality of life outcomes in patients with Ulcerative Colitis with long-term tofacitinib treatment in the open-label extension study, OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib induction and maintenance therapy has previously been shown to improve health-related quality of life (HRQoL) outcomes. Here, we present HRQoL data from patients (pts) with UC who received tofacitinib 5 or 10 mg twice daily (BID) in the Phase 3 open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), up to Month (M)72. Methods Proportions of pts with an Inflammatory Bowel Disease Questionnaire (IBDQ) total score ≥170, and EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36) scores were analysed up to M72 in 4 subpopulations in the OLE study: ‘maintenance remitters’ completed OCTAVE Sustain in remission and received tofacitinib 5 mg BID in the OLE study; in contrast, ‘maintenance treatment failures’ (induction responders who experienced treatment failure), ‘maintenance non-remitters’ and ‘induction non-responders (IndNR)’ received tofacitinib 10 mg BID in the OLE study (Figure 1). Data were analysed for each subpopulation overall and stratified by prior tumour necrosis factor inhibitor (TNFi) failure, prior immunosuppressant failure and baseline corticosteroid use. Results Baseline demographics and clinical characteristics for each subpopulation are shown in Table 1. Among the 163 maintenance remitters, HRQoL outcomes were maintained up to M72: 80.0% of pts had an IBDQ total score ≥170 (Figure 1); changes from baseline in EQ-5D scores up to M72 and SF-36 scores up to M33 were minimal (eg M72 EQ-5D utility score -0.07 [standard deviation 0.10]; M33 SF-36 physical functioning score -1.3 [8.3]). Among pts continuing long-term tofacitinib treatment, improvement in IBDQ total score was maintained/achieved by M2 (first post-baseline assessment), and was stable up to M72, with maintenance treatment failures and IndNR subpopulations experiencing the largest improvements from baseline (Figure 1). Similar trends were observed for improvement in EQ-5D and SF-36 scores. Improvements in HRQoL outcomes were independent of prior TNFi failure, prior immunosuppressant failure or baseline corticosteroid use, eg in maintenance remitters with prior TNFi failure, 90.9% of pts had IBDQ total score ≥170 at M60 vs 88.9% of pts without prior TNFi failure. Conclusion Sustained beneficial effects in HRQoL were observed among pts continuing long-term tofacitinib treatment in OCTAVE Open. In maintenance remitters, improvements in all HRQoL outcomes were maintained with tofacitinib therapy. In pts who entered the OLE study not in remission and received tofacitinib 10 mg BID, HRQoL improvements were observed within the first 2 months, and were maintained up to M72, regardless of treatment history including prior TNFi failure.

OP38 Tofacitinib for the treatment of Ulcerative Colitis: An integrated summary of safety data from the global OCTAVE and RIVETING clinical trials

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). We report updated tofacitinib safety analyses from the tofacitinib UC clinical programme, with inclusion of a 6-month interim analysis of data from the P3b/4 study, up to 7.8 years of tofacitinib exposure. Methods This analysis included 1157 patients (pts) receiving tofacitinib 5 or 10 mg BID from completed P2/P3/OLE studies, and the ongoing P3b/4 study (as of 20 Feb 2020; Overall+P3b/4 Cohort). Proportions and incidence rates (IRs; unique pts with events/100 pt-years [PY] of exposure) were evaluated for deaths and adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE) and gastrointestinal perforations were adjudicated. Results Table 1 shows demographics and clinical characteristics. In the Overall+P3b/4 Cohort, 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 955 (83%) received a predominant dose of 10 mg BID; 397/1157 (34.3%) pts had received tofacitinib for >4.1 years. Median treatment duration was 623 (range, 1–2850) days (2999.7 PY of exposure). Table 2 shows safety data for AEs of special interest in the Overall+P3b/4 Cohort. IRs (95% confidence intervals) for all tofacitinib doses: deaths, 0.23 (0.09, 0.46); serious infections, 1.69 (1.26, 2.21); herpes zoster (non-serious and serious), 3.30 (2.67, 4.04); OIs, 1.03 (0.70, 1.46); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 (0.55, 1.24); NMSC, 0.73 (0.45, 1.10); MACE, 0.29 (0.13, 0.55); deep vein thrombosis, 0.03 (0.00, 0.18); pulmonary embolism, 0.19 (0.07, 0.42); and gastrointestinal perforations, 0.10 (0.02, 0.28). IRs for AEs of special interest were similar to prior Overall Cohort analyses.1 Conclusion The safety profile of tofacitinib in pts with UC from the tofacitinib UC clinical programme was generally consistent with that of other UC therapies, including biologics, with the exception of herpes zoster.2 IRs for AEs of special interest have remained stable over an extended period of time (up to 7.8 years) with inclusion of final data from the OLE study and an interim analysis of data from the P3b/4 study.1,3

P563 Association between smoking status and the efficacy and safety of tofacitinib in patients with Ulcerative Colitis: Data from the tofacitinib clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme. Methods Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose. Results This analysis included 1156 pts (ever smokers, n=416 [36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%)]; never smokers, n=740 [64.0%]; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer [NMSC]) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers. Conclusion The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2

P477 Rectal bleeding and stool frequency improvement with tofacitinib retreatment in patients with Ulcerative Colitis after treatment interruption: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Patients may require retreatment following treatment interruption for reasons such as adverse events or pregnancy.1 In the tofacitinib UC clinical programme, patients who responded to tofacitinib 10 mg BID during induction, and experienced treatment failure whilst receiving placebo during maintenance (OCTAVE Sustain) and subsequently received tofacitinib 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the retreatment subpopulation. The efficacy and safety of tofacitinib in the retreatment subpopulation have previously been reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the retreatment subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall retreatment subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline), and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 101 patients were included in the retreatment subpopulation, of which 46 (45.5%) had prior TNFi failure. Overall, at M1 and M6 of OCTAVE Open, 83.2% and 76.2% of patients had rectal bleeding improvement, respectively (Figure 1). Corresponding values for stool frequency improvement were 70.3% and 75.2%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Mean decrease from baseline in PMS, RBS and SFS at M1 was similar in patients with and without a clinical response at M2 (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after 8–52 weeks of treatment interruption, retreatment with tofacitinib 10 mg BID resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Reference 1. Panés J et al. J Crohns Colitis 2021. Epub ahead of print.

S777 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 7.8 Years of Safety Data from Global Clinical Trials

S777 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 7.8 Years of Safety Data from Global Clinical Trials

S761 Persistence of Tofacitinib Treatment in Patients With Ulcerative Colitis Who Entered the Open-Label, Long-Term Extension Study, OCTAVE OPEN Without a Clinical Response

Introduction: Drug survival in open-label, long-term extension (OLE) studies may provide information on the long-term efficacy and tolerability of a therapy. Methods: We present data on the persistence of tofacitinib treatment in the OLE study for: (1) delayed responders: induction non-responders (pts who did not achieve a clinical response [CR] after 8 weeks [wks] induction treatment with tofacitinib 10 mg BID) who achieved a CR at Wk 8 (total of 16 wks induction) of the OLE study and continued to receive 10 mg BID;(2) retreatment responders: tofacitinib 10 mg BID induction responders who experienced treatment failure with PBO in OCTAVE Sustain and entered the OLE study and received 10 mg BID, and achieved a CR at Wk 8 of the OLE study;and (3) dose escalation responders: tofacitinib 10 mg BID induction responders who experienced treatment failure with 5 mg BID in OCTAVE Sustain and entered the OLE study and received 10 mg BID, and achieved a CR at Wk 8 of the OLE study (Figure 1). The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19. 3CDAI 50% from baseline (or for subjects with isolated ileal disease and a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by central readers.

EFFICACY OF LONG-TERM TREATMENT WITH VILOXAZINE EXTENDED-RELEASE CAPSULES (QELBREE™) IN CHILDREN AND ADOLESCENTS WITH ADHD: AN OPEN-LABEL EXTENSION STUDY

Viloxazine extended-release capsules (viloxazine ER; Qelbree™) is a novel nonstimulant recently approved for the treatment of ADHD in children and adolescents based on results from 3 pivotal Phase 3 trials. Here, we report efficacy results of the ADHD Rating Scale, 5th Edition (ADHD-RS-5) and Clinical Global Impression-Improvement (CGI-I) assessed during the long-term open-label extension (OLE) safety study of viloxazine ER. The change from baseline (pivotal; CFB) in ADHD-RS-5 Total score, 50% ADHD-RS-5 Responder Rate (percentage of subjects with a ≥50% reduction in their CFB ADHD-RS-5 Total score), and CGI-I Responder Rate (percentage of subjects with a CGI-I score of 1 or 2) were analyzed by visit from pivotal to last visit in an OLE trial. Subjects were grouped based on pivotal trial treatment assignment (pivotal-placebo or pivotal-viloxazine ER). In the OLE trial, subjects aged 6-11 years were dosed at 100 mg/day or titrated up (100 mg/day/week) to optimal dose at or below 400 mg/day, and subjects aged 12-17 years were dosed at 100 mg/day or titrated up (100 or 200 mg/day/week) to optimal dose at or below 600 mg/day. Of the 1170 subjects who completed a pivotal trial, 1100 subjects were dosed in the OLE (323 pivotal-placebo and 777 pivotal-viloxazine ER). The median dose of viloxazine ER was 300 mg in children aged 6-11 years and 400 mg in adolescents aged 12-17 years. ADHD symptoms improved in the first month and continued improving over time during OLE in both pivotal-placebo and pivotal-viloxazine ER subjects. The mean (±SD) CFB in ADHD-RS-5 Total score at last visit during OLE was significantly improved in the pivotal-viloxazine ER group (–19.3 ± 13.22; p < 0.0001) and in the pivotal-placebo group (–18.0 ± 13.17; p < 0.0001). For both groups, ADHD-RS-5 and CGI-I responder rates were above 50% within the first 3 months, remained above 65% after 3 months, and remained above 75% after 18 months of treatment. ADHD symptoms significantly improved and the number of subjects experiencing a clinically meaningful improvement increased over time during long-term viloxazine ER treatment. These data indicate that viloxazine ER treatment can provide sustained efficacy, further improve ADHD symptoms, and increase the responder rates even after 8 weeks of treatment.