Permanent Study Drug Discontinuation Research Articles

Clinical significance of new-onset atrial fibrillation in patients with coronary artery or peripheral artery disease: results from the COMPASS trial

Abstract Background The COMPASS trial enrolled patients with coronary artery or peripheral artery disease, but excluded patients requiring oral anticoagulation. Compared to aspirin alone, rivaroxaban in addition to aspirin reduced a composite of cardiovascular death, stroke or myocardial infarction. Purpose This study aimed to explore the clinical significance of a new diagnosis of atrial fibrillation (AF) during follow-up. Methods New AF was identified from unplanned hospitalization, study drug discontinuation and adverse event reports. The associations between new-onset AF, clinical characteristics and outcomes in COMPASS participants were studied using time-updated regression modeling. Event rates were reported as per 100 patient-years (following a new diagnosis of AF vs. from randomization until the end-follow-up or new AF, whichever came first). Results During a mean follow-up of 23 months, 655 of 27,395 participants (2.4%) were newly diagnosed with AF. Advanced age, male sex, white race, higher body mass index, higher systolic blood pressure, heart failure and prior myocardial infarction were independently associated with new-onset AF. The rates of permanent discontinuation of study drug were 83.8% following a new diagnosis of AF, compared to 17.5% in participants without/before new AF. Compared to participants without/before a new diagnosis of AF, participants with new-onset AF were at increased risk of a composite of cardiovascular death, stroke or myocardial infarction (8.9 vs. 2.5 per 100 patient-years, hazard ratio [HR] 4.49, 95% confidence interval [CI] 3.37-6.00) (Figure 1). Risk increases with new-onset AF were also observed for hospitalization for heart failure (9.1 vs. 1.1 per 100 patient-years, HR 6.35, 95% CI 4.59-8.80) (Figure 2) and major bleeding (4.1 vs. 1.3 per 100 patient-years, HR 2.93, 95% CI 1.99-4.33). Conclusion In COMPASS, a new diagnosis of AF during trial follow-up was associated with a marked increase in risk of adverse outcomes.Composite outcome after new-onset AFHeart failure after new-onset AF

Abstract 14628: Residual Stroke Risk Among Atrial Fibrillation Patients Treated With Warfarin or Novel Oral Anticoagulants: A Patient Level Meta-Analysis From Combine AF

Introduction: Despite oral anticoagulation treatment atrial fibrillation (AF) patients have residual risk of ischemic stroke and systemic embolism (SE) which could potentially be mitigated. Methods: Harmonized individual patient data from five landmark trials testing direct oral anticoagulants (DOAC) were pooled in the COMBINE-AF dataset, which we used to calculate annual rate of ischemic stroke/SE according to CHA 2 DS 2 -Vasc score, history of stroke, and AF type. Results: We included 71,794 subjects (median age 72 IQR 65-78 years 61.3% male) with CHA 2 DS 2 -Vasc scores≥2 randomized to either standard- or lower-dose DOAC or warfarin, and followed for a median of 2.1 (IQR 1.5-2.7) years. The median CHA 2 DS 2 -VASc score was 4 (IQR 3-5), and 18.8% had a history of stroke and 76.4% had non-paroxysmal AF. The overall annual stroke/SE rate was 1.33%/year (95%CI 1.27-1.39%). Subjects with non-paroxysmal AF had higher stroke/SE rates, 1.38%/year (95%CI 1.31-1.45%) compared to 1.15%/year (95%CI 1.05-1.27%) with paroxysmal AF. The rate increased by a RR 1.36 (95%CI 1.32-1.41%) per CHA 2 DS 2 -VASc point; in subjects with CHA 2 DS 2 -VASc≥4, the stroke/SE rate was 1.67%/year (95%CI 1.59-1.75%). Annual stroke/SE rates were higher in subjects with a prior stroke, 2.51%/year (95%CI 2.33-2.71%), and increased with higher CHA 2 DS 2 -VaSc score; RR 1.11 (95%CI 1.05-1.18), Figure 1 . After premature permanent discontinuation of study drug, which occurred in 22% of individuals, stroke/SE rates were 3.6%/year (95%CI 3.4-3.9%) overall; 6.5%/year (95%CI 5.7-7.4%) in those with prior stroke. During follow-up 8.9% of subjects died. Conclusions: Despite treatment with oral anticoagulation in a clinical trial setting, there remains an 8.4% risk of stroke/SE over five years in subjects with CHA 2 DS 2 -Vasc≥4, and 12.5% over five years in subjects with a prior stroke. Permanent discontinuation is common, and associated with stroke/SE risks of almost 20% over five years.

P64 Efficacy of baricitinib in patients with different degrees of severe alopecia areata: 52-week results from BRAVE-AA1 and BRAVE-AA2

Abstract Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, demonstrated efficacy in adults with severe alopecia areata (AA) over 36 weeks in two phase III, randomized, double-blind, placebo-controlled trials, BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259). Using integrated data from the long-term extension periods of both trials, we report treatment response to baricitinib by the AA severity subgroup based on the Severity of Alopecia Tool (SALT) score over 52 weeks. Patients randomized to baricitinib at baseline (n = 855) retained their treatment allocation (2 mg/4 mg) through to week 52 in both trials and were included in week 52 analyses; placebo nonresponders were rescued at week 36. Severity of AA at baseline was defined as severe (SALT score 50–94) or very severe (SALT score 95–100). Key inclusion criteria were SALT score ≥ 50, current AA episode lasting > 6 months to < 8 years without spontaneous improvement within 6 months prior to screening, and no previous inadequate response to oral JAK inhibitors. Efficacy endpoints included the proportion of patients achieving a SALT score ≤ 20 and the proportion of patients achieving Clinician-Reported Outcome (ClinRO) Measure for Eyebrow/Eyelash Hair Loss™ 0,1 (no, minimal gaps) with ≥ 2-point improvement from baseline among patients with baseline scores 2,3 (significant gaps, no notable eyebrows/eyelashes). Analyses were presented descriptively for each subgroup up to week 52. Nonresponder imputation was used for missing data. Data collected after permanent study drug discontinuation or at remote visits due to the COVID-19 pandemic were excluded. In total, 1200 patients were enrolled (BRAVE-AA1, n = 654; BRAVE-AA2, n = 546). At baseline, the overall mean (SD) age was 37.5 (12.9) years; 60.7% were female and 46.8% and 53.2% of patients had severe and very severe AA, respectively. At week 52, a SALT score ≤ 20 was achieved by 36.1% and 51.2% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with severe AA and 12.4% and 27.7% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with very severe AA. Eyebrow/Eyelash Hair Loss™ scores 0,1 with ≥ 2-point improvement from baseline at week 52 were achieved by 19.4% and 26.0% (baricitinib 2 mg) and 37.5% and 38.5% (baricitinib 4 mg) of patients with severe AA and 24.3% and 25.3% (baricitinib 2 mg) and 47.6% and 48.1% (baricitinib 4 mg) of patients with very severe AA. Following 52 weeks of treatment with both baricitinib doses, clinical responses of SALT score ≤ 20 were observed both in patients with severe and very severe AA. Proportions of patients achieving full coverage or minimal gaps in eyebrows and eyelashes were similar at week 52, regardless of scalp hair-loss severity. Funding sources: Eli Lilly and Company.

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0-10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Outcomes of patients with atrial fibrillation and ischemic stroke while on oral anticoagulation.

The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of patients following a stroke event while on oral anticoagulation. Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke [cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%-8.7%]. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%-14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%-7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%-8.9%). Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need.

Longer-term safety of alirocumab with 24,610 patient-years of placebo-controlled observation: further insights from the ODYSSEY OUTCOMES trial

Abstract Background In the ODYSSEY OUTCOMES trial (NCT01663402), alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowered low-density lipoprotein cholesterol from ∼2.3 mmol/L to ∼1.0 mmol/L at 4 months, reduced the risk of major adverse cardiovascular events (MACE: coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization), and was associated with fewer deaths compared with placebo in 18924 patients (pts) with recent acute coronary syndrome followed for up to 5 years (yrs). Purpose In the ODYSSEY OUTCOMES trial, the overall safety of alirocumab and placebo was similar, except for an excess of local injection-site reactions with alirocumab. However, the safety among pts eligible for longer follow-up has not been fully explored. Methods The present post hoc analyses describe the efficacy and safety of alirocumab in a pre-specified subgroup (for efficacy) of pts eligible for a minimum of 3 and up to 5 yrs of follow-up. Results There were 8242 pts (43.5%) eligible for ≥3 yrs follow-up, of whom 8228 received at least one dose of study medication, comprising 24,610 pt-years of observation with a median follow-up of 3.3 yrs; 6651 pts were eligible for 3 up to 4 yrs, and 1574 patients were eligible for 4–5 yrs, follow-up. As previously reported in a pre-specified analysis of this subgroup, alirocumab significantly reduced death (4.7% vs. 5.9%; p=0.01) compared with placebo. In the present post hoc analysis, alirocumab also significantly reduced MACE vs. placebo (12.0% vs. 14.2%; Hazard Ratio 0.83 [95% CI 0.74 to 0.94]; p=0.003). In a safety analysis, 3217 (78.3%) vs. 3303 (80.2%) pts in the alirocumab vs. placebo group had at least one adverse event (AE) of whom 27.5% vs. 29.4% had a serious AE (Fig. 1). The frequency of permanent discontinuation of study drug due to AEs, incident diabetes, diabetes worsening or complications, neurocognitive events, elevations of ALT&amp;gt;3, AST&amp;gt;3, bilirubin&amp;gt;2, and creatine phosphokinase&amp;gt;10 times the upper limit of normal, were similar with alirocumab vs. placebo (Fig. 1). While pt-reported local injection-site reactions occurred more frequently with alirocumab, the Kaplan-Meier cumulative incidence for time to first local injection site reaction in the longer-term follow-up subgroup was &amp;lt;5% over ∼4 yrs, with most occurring within the first 6 months (Fig. 2). Conclusions In an 8228-pt subgroup of the ODYSSEY OUTCOMES trial eligible for at least 3, and up to 5 yrs follow-up, the safety of alirocumab was similar to placebo except for an excess of local injection site reactions. This subgroup also derived significant benefit from reduced MACE and death. Thus, alirocumab appears to be both a safe and effective lipid-modifying treatment when used for up to 5 yrs. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi and Regeneron

Understanding Study Drug Discontinuation Through EUCLID

IntroductionDisparities in the care and outcomes of peripheral artery disease (PAD) have been well-established. In part this is due to disparities in enrollment of PAD trial cohorts. However, less attention has been paid to non-random protocol non-adherence after enrollment, which may lead to inaccurate estimates of treatment effects and reduce generalizability of study results. We aimed to ascertain characteristics associated with premature study drug discontinuation in a PAD cohort.MethodsUsing data from EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease), factors associated with study drug discontinuation were assessed using univariable and multivariable Cox proportional hazards models with time to study drug discontinuation as the outcome of interest. Relationships between study drug discontinuation and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, ischemic stroke), major adverse limb events (MALE; acute limb ischemia, major amputation, and lower extremity revascularization), and all-cause hospitalization were assessed.ResultsOf 13,842 eligible EUCLID participants, 3,886 (28.1%) prematurely and permanently discontinued study drug over a maximum follow-up of 42 months (annualized rate of 13.2 discontinuations per 100 patient-years). In a multivariable model, premature study drug discontinuation was associated with older age (aHR 1.16, 95%CI 1.14–1.19), eligibility based on prior lower extremity revascularization rather than ABI/TBI criteria (aHR 1.14, 95%CI 1.06–1.23), CLI status (aHR 1.23, 95%CI 1.06–1.42), COPD (aHR 1.36, 95%CI 1.24–1.49), and geographic region. In a multivariable analysis, study drug discontinuation was significantly associated with MACE (aHR 3.27, 95%CI 2.90–3.67, p < 0.001), MALE (aHR 1.84, 95%CI 1.63–2.07, p < 0.001), and all-cause hospitalization (aHR 2.37, 95%CI 2.21–2.54) following study drug discontinuation.ConclusionsThis analysis of EUCLID demonstrates that premature, permanent discontinuation of study drug is relatively common in more than a quarter of PAD patients, is unevenly distributed based on geography and other baseline characteristics, and is associated with worse outcomes in a clinical trial context. Study teams leading future PAD trials may want to address the possibility of study drug discontinuation prospectively, as a proactive approach may help investigators to maintain study cohort diversity and representativeness without sacrificing power and precision.

DARolutamide ObservationaL (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

e17029 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that significantly increased median metastasis-free survival by ̃2 years and improved overall survival with a 31% reduction in risk of death vs placebo in men with nmCRPC in ARAMIS (NCT02200614), with a favorable tolerability profile. DARO significantly improved survival in men with metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS. The ongoing DAROL trial (NCT04122976) is designed to support results from the phase 3 ARAMIS study and to provide insight into the safety and effectiveness of DARO and the management of nmCRPC in the real-world setting. We report results of the first prespecified interim analysis. Methods: DAROL is an international, single-arm, non-interventional study. Eligible patients (pts) are DARO naïve, ≥18 years of age, with confirmed nmCRPC, for whom the decision to treat with DARO was made before enrollment. Treatment dose and duration are per investigator’s routine practice. The primary endpoint is safety, including treatment-emergent adverse events (TEAEs). Prostate-specific antigen (PSA) response was an exploratory objective. Descriptive statistics are reported for the first prespecified interim analysis (cut-off: September 23, 2021) performed after ̃100 pts (from US, Canada, Japan) completed ≥6 months of treatment or discontinued treatment. Results: All 100 pts were evaluable for safety: median age 78.0 years; White/Black/Asian/other/not reported, 59%/11%/27%/1%/2%; North America/Asia Pacific, 79%/21%; baseline ECOG performance status 0–1/2–4/not reported, 72%/5%/23%; median (Q1–Q3) time from initial diagnosis to castration-resistant, 89.1 mo (39.1–130.6 mo); Gleason score at initial diagnosis ≤6/7/8–10, 15.8%/38.9%/45.3%; baseline PSA ≤10/ &gt; 10 ng/mL, 75.3%/24.7%; PSA doubling time ≤6/ &gt; 6 mo, 58.2%/41.8%. Median (Q1–Q3) duration of treatment was 11.3 mo (8.4–14.4 mo); median (Q1–Q3) follow-up time was 12.3 mo (9.6–15.6 mo). Median starting dose and daily treatment dose was 1200 mg daily. 28% of pts had TEAEs of any grade, with 3% grade 3; no grade ≥4. 2% of pts had serious adverse events (AEs). Incidence rates of AEs were generally low, consistent with the safety profile observed in ARAMIS, and those that occurred in ≥2% of pts were fatigue (5%), diarrhea (5%), asthenia (2%), muscle weakness (2%), anemia (2%), and rash (including rash pruritic, 2%). TEAEs led to permanent study drug discontinuation in 7% of pts. Of 93 pts evaluable for efficacy, the percentage with a PSA response of ≥30%, ≥50%, and ≥90% at any time during follow-up was 81.7%, 77.4% and 52.7%, respectively. Conclusions: At the first interim analysis of the DAROL observational study in the real-world setting, the safety and tolerability of DARO was consistent with the favorable tolerability profile observed in the randomized ARAMIS trial. Clinical trial information: NCT04122976.

Epistaxis in anticoagulated patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial

Abstract Background Epistaxis is common with antithrombotic therapy yet under-investigated in cardiovascular clinical trials and observational studies. These bleeding events are often troublesome to patients and may lead to anticoagulant discontinuation. Purpose To describe the frequency, severity, and outcomes of epistaxis in patients with atrial fibrillation (AF) randomized to edoxaban vs warfarin. Methods ENGAGE AF-TIMI 48 randomized 21,105 patients with AF and CHADS2 ≥2 to a higher-dose edoxaban regimen (HDER; 60mg daily), a lower-dose edoxaban regimen (LDER; 30mg daily), or warfarin, with edoxaban doses reduced by 50% in patients meeting dose-reduction criteria. Location and severity of bleeding were adjudicated by a blinded Clinical Events Committee using ISTH criteria. Patients with intracranial hemorrhage were excluded from this analysis. Patients with more than one bleeding event were categorized according to the most severe event. The safety cohort with interval censoring during study drug interruption was analyzed. Proportions were compared using a Pearson's chi-squared test and treatment arms were compared using a Cox proportional hazards model. Results 5,247 patients with a bleeding event were included in this analysis, including 1,008 (19.2%) with epistaxis and 4,239 (80.8%) with exclusively non-epistaxis bleeding. Baseline characteristics were similar for patients with epistaxis as compared to non-epistaxis bleeding. Epistaxis events were overall less severe than non-epistaxis bleeds (ISTH major: 3.2% vs 20.7%; CRNM: 64.7% vs 60.1%; minor: 32.1% vs 19.2%; p&amp;lt;0.001; Fig. 1, Panel A). Two life-threatening and no fatal epistaxis bleeds occurred. Permanent study drug discontinuation was similar following epistaxis vs non-epistaxis bleeding in patients with major (59.4% vs 53.6%; p=0.52) or CRNM bleeding (32.5% vs 33.3%; p=0.70), but was significantly higher after minor epistaxis versus minor bleeding at other sites (33.3% vs 23.9%; p=0.001; Fig. 1, Panel B). Compared to warfarin, hazard ratios (HR) for epistaxis bleeding were: 1) major: HDER 0.47 (0.19–1.15), LDER 0.65 (0.29–1.45); 2) major/CRNM: HDER 1.00 (0.84–1.19), LDER 0.70 (0.58–0.85); 3) major/CRNM/minor: HDER 1.09 (0.95–1.26), LDER 0.73 (0.62–0.86) (Fig. 1, Panel C). Conclusion Epistaxis was frequent in patients with atrial fibrillation on anticoagulation. When compared to warfarin, LDER reduced the risk of epistaxis by 27–30% while HDER neither increased nor decreased these events. There were significantly higher rates of permanent drug discontinuation following minor epistaxis as compared to minor bleeding at other sites. These findings suggest that epistaxis is symptomatically important, may cause disproportionate interruption in antithrombotic therapy, and deserves increased attention in cardiovascular studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Pharma Development Figure 1

Efficacy and Safety of Dulaglutide in Older Patients: A post hoc Analysis of the REWIND trial.

ContextDulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed.ObjectiveThis work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years).MethodsA post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes).ResultsThere were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant.ConclusionDulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.

Older participant perspectives on permanent study drug discontinuation in an ongoing primary prevention trial of statins.

Study drug discontinuation is commonplace in clinical trials of older populations. Little is known about why older participants discontinue the study drug. This qualitative study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥ 70years within an ongoing primary prevention trial of statins by exploring their experiences and perceptions. Trial participants who had permanently discontinued the study drug within 2years of randomisation were purposively sampled by age (< 75 and ≥ 75years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analysed thematically. Thirty participants were interviewed (21 females; mean age, 77years), and three themes were identified from the data. Perceived adverse events (AEs) and their effect on daily living (mobility, functional capacity, quality of life) were identified as the major factors leading to the participants permanently discontinuing their study drug, despite an ambiguity about the cause of the AE. For some, concurrent challenging life circumstances further lowered their tolerance to perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. GP advice, unrelated illness). Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry, as well as offering timely medical assistance and support when AEs occur, may be useful to reduce drug discontinuation rates.

Abstract 15140: Older Participant Perspectives on Permanent Study Drug Discontinuation in an Ongoing Primary Prevention Trial of Statins: A Qualitative Study

Introduction: Study drug discontinuation is commonplace in clinical trials of older populations and poses a major challenge to trial investigators. Little is known about why older participants discontinue the study drug. This study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥70 years within an ongoing primary prevention trial of statins by tapping into their experiences and perceptions. Methods: Trial participants who had permanently discontinued the study drug within 2 years of randomization were purposively sampled based on age (&lt;75 and ≥75 years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analyzed thematically. Results: Thirty participants took part (21 females; mean age, 77 years) and three themes were identified from the data. Perceived adverse events (AEs) and their impact on daily living (mobility, functional capacity, quality of life, etc.) were identified as the major factors leading to the participants permanently discontinuing their study drug. Muscle symptoms were the most commonly reported AE. Selected participant quotes which describe symptoms and their impact are presented in Table. For some, a challenging life circumstance further lowered their tolerance to the perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. concerns about possible side effects, GP advice, unrelated illness). Conclusion: Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry and offering timely medical assistance and support when AEs occur may be useful to reduce drug discontinuation rates.

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation

AimsThe ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought...

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

BackgroundPeficitinib (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.MethodsThis 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).ResultsResults 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.ConclusionsThe 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 registrationClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

Deferred treatment with a fixed‐dose combination of sofosbuvir‐velpatasvir for chronic hepatitis C virus genotype 1, 2, 4 and 6 infection

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100mg) once daily for 12weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.

Long-Term Safety in the Open-Label Period of a Phase 2a Study of Brazikumab, an Antibody Against Interleukin-23

Introduction: Brazikumab (MEDI2070), a human monoclonal antibody that is an anti-p19 subunit inhibitor of interleukin-23, was shown to be effective over 8 weeks of treatment for patients with moderate-to-severe active Crohn's disease.[1] Here, we report the long-term safety and tolerability of brazikumab. Methods: The Phase 2a study (NCT01714726) consisted of a 12-week double-blind induction period with randomization to intravenous brazikumab (700 mg) or placebo, followed by the open-label (OL) period where all patients were administered subcutaneous brazikumab (210 mg) every 4 weeks. Patients were aged 18-65 years, had a ≥6-month history of moderate-to-severe active Crohn's disease, had failed on or were intolerant to ≥1 anti-tumor necrosis factor alpha (TNFa) agent, successfully completed the double-blind period, and signed consent for inclusion in the OL period. Adverse events (AEs) and vital signs were recorded every 4 weeks until patients discontinued or completed the study at 100 weeks. Results: 104 patients entered (n=52 from placebo to brazikumab and n=52 from brazikumab to brazikumab) and 57 (54.8%) patients completed the OL period. Overall, 87 (83.7%) patients experienced ≥1 treatment-emergent AE (TEAE); 12 (11.5%) experienced ≥1 TEAE leading to permanent discontinuation of study drug and 20 (19.2%) experienced ≥1 serious AE (SAE). The most common TEAEs were headache (22.1%), nasopharyngitis (22.1%), abdominal pain (18.3%), and Crohn's disease (16.3%) [Table]. Half of the SAEs observed were gastrointestinal disorders associated with Crohn's disease. Five SAEs of infection were reported, none of which were opportunistic, such as herpes zoster or tuberculosis; all resolved and the investigational product was permanently discontinued for only one patient. No cases of cancer were reported. The AE profile was similar between patients who completed a previous 12-week course of either placebo or brazikumab treatment. Conclusion: In this 100-week OL period, brazikumab was well tolerated in patients with moderate-tosevere active Crohn's disease, warranting future studies in larger patient populations.590 Figure 1. Treatment-emergent adverse events in the 100-week open-label period

Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study

BackgroundChronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection.MethodsChinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing.ResultsAll 206 enrolled patients achieved SVR12 (100%; 95% CI 98–100%), including 106 treatment-naive patients (100%; 95% CI 97–100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported.ConclusionLedipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.

Abstract GS6-07: EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation

Abstract Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that inhibits the PARP enzyme and effectively traps PARP on single-stranded DNA breaks, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent physician's choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). The primary objective was PFS assessed by blinded independent central review (BICR). Secondary objectives: OS, ORR, CBR at 24 weeks (CBR24), and safety. Exploratory objectives: patient-reported QoL and DOR. Eligibility criteria: age ≥ 18 years; HER2-negative aBC; deleterious or suspected deleterious gBRCAmut; ≤ 3 prior cytotoxic regimens for aBC; and ECOG PS ≤ 2. Prior platinum was allowed. Patients were randomized 2:1 and stratified by receptor status, extent of prior therapy, and CNS metastases (NCT01945775). Results: 431 patients were randomized (median age 46 years; 54% hormone-receptor [HR]+ BC; 45% BRCA1+ and 55% BRCA2+; 55% ECOG PS = 0; 38% chemo-naïve for aBC; 18% prior platinum; 15% CNS metastases); 287 were assigned to TALA and 144 to PCT (1 TALA, 18 PCT patients were not treated). Median duration of exposure was 6.1 and 3.9 months, respectively; TALA had a relative dose intensity of 87%. At 62% PFS data maturity: TALAPCTHazard Ratio/Odds Ratio (P value)PFS by BICR, mo (95% CI)8.6 (7.2-9.3); n = 2875.6 (4.2-6.7); n = 1440.542 (&amp;lt; 0.0001)OS [interim], mo (95% CI)22.3 (18.1-26.2); n = 28719.5 (16.3-22.4); n = 1440.761 (0.105)ORR by INV, % (95% CI)62.6% (55.8-69.0); n = 21927.2% (19.3-36.3); n = 1144.99 (&amp;lt; 0.0001)DOR by INV, mo (IQR)5.4 (2.8-11.2); n = 1373.1 (2.4-6.7); n = 310.431 (0.0005)*CBR24 by INV, % (95% CI)68.6% (62.9-74.0); n = 28736.1% (28.3-44.5); n = 1444.28 (≤0.0001) INV, investigator. *Not a randomized subset. Improved clinical benefit was seen in all subsets including those with HR+ BC (HR 0.47; 95% CI 0.32-0.71) and CNS metastasis (HR 0.32; 95% CI 0.15-0.88). There was a significant delay in the time to deterioration in global health status (GHS)/QoL for TALA vs PCT (HR 0.38; 95% CI 0.26-0.55; P &amp;lt; 0.0001]. Grade 3-4 hematologic adverse events (AEs) occurred in 55% TALA (mainly anemia)/39% PCT (mainly neutropenia). Grade 3-4 non-hematologic AEs were seen in 32% TALA/38% PCT; TALA was associated with fewer gastrointestinal disorders (5.6% vs 11.9%) and skin/subcutaneous tissue disorders (0.7% vs 5.6%) than PCT. Grade 3-4 serious AEs were observed in 26% TALA/25% PCT. AEs associated with permanent study drug discontinuation occurred in 8% TALA/10% PCT. AE resulting in death occurred in 2.1% TALA/3.2% PCT.Conclusions: Single-agent TALA significantly prolonged PFS by BICR in HER2-negative aBC patients with a gBRCAmut compared to PCT; all key secondary efficacy endpoints demonstrated benefit with TALA, with a significant delay in time to deterioration in GHS/QoL. TALA was generally well tolerated with minimal non-hematologic toxicity and few AEs associated with treatment discontinuations. Citation Format: Litton J, Rugo HS, Ettl J, Hurvitz S, Gonçalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im Y-H, Quek RGW, Tudor IC, Hannah AL, Eiermann W, Blum JL. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-07.

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial

Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. GlaxoSmithKline.