Primary Endpoint Of Non-inferiority Research Articles

Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine

ABSTRACT Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis

Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies. To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis. The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively. In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks. Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood. Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified. Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity. ClinicalTrials.gov Identifier: NCT03818035.

Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial

Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. For the Mandarin translation of the abstract see Supplementary Materials section.

Tislelizumab versus Sorafenib in First-Line Treatment of Unresectable Hepatocellular Carcinoma: Impact on Health-Related Quality of Life in RATIONALE-301 Study

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy-naive adults with HCC were randomized 1:1 to receive tislelizumab (n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key-prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change difference in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR: 0.68; 95% CI: 0.49–0.94), QLQ-C30 physical functioning (HR: 0.45; 95% CI: 0.32–0.63) and fatigue (HR: 0.47; 95% CI: 0.36–0.61), QLQ-HCC18 symptom index (HR: 0.52; 95% CI: 0.34–0.81), and HCC-specific fatigue (HR: 0.59; 95% CI: 0.45–0.79). For pain, both arms had similar risk of deterioration (HR: 0.78; 95% CI: 0.56–1.09). At cycles 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had favorable HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

806-P: Once Weekly (QW) Basal Insulin Fc (BIF) and Daily Degludec (DEG) Achieve Comparable Glycemic Control in Three Patient Populations Studied during Phase 2—Clinical Insights from CGM Assessments

BIF is a fusion protein combining a novel single chain insulin variant with a human IgG Fc domain. Three randomized, open-label, treat-to-target phase 2 studies of 26 or 32 week duration assessed 912 people with T2D previously treated with basal insulin (T2D-Switch) or new to insulin therapy (T2D-Naïve), or T1D on multiple daily injections (T1D). Studies assessed QW BIF vs once daily DEG. Key results were previously disclosed and met the primary endpoint of non-inferiority in HbA1c change from baseline (non-inferiority margin=0.4%). Two studies had CGM during entire study and T2D-Naïve had blinded, intermittent CGM using 14-day sessions. Patients had baseline HbA1c of 8.1, 8.0, and 7.5% for T2D-Switch, T2D-Naïve, and T1D respectively. Figure shows average hourly mean glucose at endpoint and time in range (inset). Glucose profiles appeared comparable between treatments with 24-hour average glucose for BIF vs DEG in T2D-Naïve: 137 vs 127 mg/dL p=.042 and T1D: 175 vs 169 p=.075 (T2D-Switch not available). Average duration of hypoglycemia, &amp;lt;70mg/dL (min) per patient for BIF vs DEG: T2D-Switch 31 vs 35 p=NS, T2D-Naïve 51 vs 91 p&amp;lt;.001, and T1D 35 vs 35 p=NS. QW BIF achieved similar glycemic control vs DEG as seen in several CGM derived measures providing useful and reassuring insights into the use of QW BIF in these patient populations. Disclosure C.M.Kazda: Employee; Eli Lilly and Company. J.M.Bue-valleskey: Employee; Eli Lilly and Company. Q.Zhang: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. D.Dahl: Research Support; Lilly, Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim Inc., Amgen Inc. Funding Eli Lilly and Company

Rationale and design of a randomized study comparing the Watchman FLX device to DOACs in patients with atrial fibrillation

Percutaneous left atrial appendage (LAA) closure (LAAC) was developed as a non-pharmacological alternative to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) who are at an increased risk for stroke or systemic embolism. The Watchman device permanently seals off the LAA to prevent thrombi from escaping into the circulation. Previous randomized trials have established the safety and efficacy of LAAC compared to warfarin. However, direct OACs (DOACs) have become the preferred pharmacological strategy for stroke prevention in patients with AF, and there is limited data comparing Watchman FLX to DOACs in a broad AF patient population. CHAMPION-AF is designed to prospectively determine whether LAAC with Watchman FLX is a reasonable first-line alternative to DOACs in patients with AF who are indicated for OAC therapy. A total of 3000 patients with a CHA2DS2-VASc score ≥2 (men) or ≥3 (women) were randomized to Watchman FLX or DOAC in a 1:1 allocation at 142 global clinical sites. Patients in the device arm were to be treated with DOAC and aspirin, DOAC alone, or DAPT for at least 3 months post-implant followed by aspirin or P2Y12 inhibitor for 1-year. Control patients were required to take an approved DOAC for the duration of the trial. Clinical follow-up visits are scheduled at 3- and 12-months, and then annually through 5 years; LAA imaging is required at 4 months in the device group. Two primary endpoints will be evaluated at 3 years: (i) composite of stroke (ischemic/hemorrhagic), cardiovascular death, and systemic embolism compared for non-inferiority, and (ii) non-procedural bleeding (International Society on Thrombosis and Haemostasis [ISTH] major and clinically relevant non-major bleeding) tested for superiority in the device arm against DOACs. The third primary non-inferiority endpoint is the composite of ischemic stroke and systemic embolism at 5 years. Secondary endpoints include 3- and 5-year rates of (i) ISTH-defined major bleeding and (ii) the composite of cardiovascular death, all stroke, systemic embolism, and non-procedural ISTH bleeding. This study will prospectively evaluate whether LAAC with the Watchman FLX device is a reasonable alternative to DOACs in patients with AF.

083 Prolonged Q16W treatment interval of guselkumab is non-inferior to Q8W dosing for maintaining disease control in super responders: primary results from GUIDE at Week 68 in patients with psoriasis

The Phase IIIb, double-blind GUIDE study evaluates the impact of early intervention and prolonged treatment intervals with guselkumab (GUS) on disease course in super responder (SRe) patients (pts) with moderate–severe psoriasis (PSO). SRes (PASI=0 at Weeks [W] 20+28 with GUS 100 mg Q8W [every 8W] treatment) were randomized to continue GUS Q8W or extend to Q16W, stratified by disease duration (short [SDD], ≤2 years [y]; or long [LDD], >2 y). The primary endpoint was the proportion of SRes achieving PASI <3 at W68. A non-inferiority margin of 10% was allowed for comparing GUS Q16W vs Q8W. Of 880 pts enrolled, 297 (33.8%) SRes were randomized at W28. Baseline demographic data (median values) for the GUS Q8W/Q16W groups were balanced: BMI 26.7/26.2 kg/m2, age 36.5/37.0 y, disease duration 2.1/2.0 y, PASI 16.7/16.7, and prior biologic therapy 4.7/9.4% pts. In the intent-to-treat (ITT) population, PASI <3 at W68 was achieved by 137/148 (92.6%) and 137/149 (91.9%) GUS Q8W and Q16W pts, respectively, meeting the primary endpoint of non-inferiority (P=0.001) for GUS Q16W vs Q8W. Subgroup analyses of SDD pts also showed non-inferiority (nominal P=0.005) for achievement of PASI <3 at W68 (90.7% GUS Q8W, 93.4% GUS Q16W pts). Corresponding rates in LDD pts were 94.5% and 90.4%, respectively; non-inferiority was not met (nominal P=0.104). In the ITT set, the PASI=0 rate at W68 was significantly different (nominal P=0.016) in GUS Q8W (120/148 [81.1%]) and GUS Q16W (103/149 [69.1%]) pts. GUS Q16W for SRes is non-inferior to Q8W in achieving PASI<3 at W68, indicating the potential for dose-interval flexibility for maintenance of PSO disease control and pt-tailored therapeutic strategies for GUS in SRes.

A Prospective, Randomized Trial Examining the Use of G-CSF Versus No G-CSF in Patients Post-Autologous Transplantation

Contemporary, prospective data regarding the impact of granulocyte-colony stimulating factor (G-CSF) on outcomes after autologous hematopoietic stem cell transplantation (Auto-HSCT) in an era when stem cell grafts are more qualitatively robust are limited. Recent retrospective analyses have not supported a beneficial effect of post-transplantation G-CSF use on major outcomes after Auto-HSCT leading to strategies to delay or eliminate the use of G-CSF altogether in this context. To test the hypothesis that the infusion of consistently higher doses of stem cells (defined as ≥4 × 106/kg) in Auto-HSCT will obviate the need for post-transplantation G-CSF. If so, the impact of withholding G-CSF will be noninferior to the use of G-CSF in terms of length of stay (LOS). The specific objectives were to conduct a prospective, randomized clinical trial primarily examining the impact of post-transplantation G-CSF on LOS, and secondarily on engraftment, infectious complications, antibiotic usage, and incidence of engraftment syndrome after Auto-HSCT in patients receiving versus not receiving G-CSF after Auto-HSCT. Patients with multiple myeloma or non-Hodgkin lymphoma (NHL) who underwent Pegfilgrastim plus Plerixafor-primed stem cell collection followed by Auto-HSCT were randomized to the G-CSF group (receive G-CSF starting at day 3 after Auto-HSCT) or the no G-CSF group (G-CSF withheld after Auto-HSCT). Seventy patients per arm were planned to demonstrate the primary endpoint of noninferiority in LOS between the G-CSF and the no G-CSF groups. Patient outcomes in the two groups were followed up and compared after Auto-HSCT, and an interim analysis for futility was planned when accrual reached 50%.The primary finding of this study was that despite only a 2-day longer median absolute neutrophil count (ANC) recovery in the no G-CSF arm (median 11 versus 13 days; P = .001), LOS was 4 days longer in patients not treated with G-CSF (median 11 days versus 15 days; P = .001). G-CSF use was associated with more robust incremental daily increases in ANC once recovered (P = .001), fewer days of febrile neutropenia (P = .001), and fewer days on antibiotics (P = .001), potentially contributing to this disproportionate finding. Inferiority in LOS in the no G-CSF group was demonstrated on the interim analysis, and the study was closed at the half-way point. There were no significant group differences in platelet recovery, documented infections, hospital readmissions, or overall survival at 1 year. Engraftment syndrome occurred in 54.3% of patients and was not related to G-CSF use. These results suggest that the increased LOS associated with the omission of G-CSF is largely due to concerns regarding the potential for infection in patients without a stable, recovered ANC in a hospital setting. Engraftment syndrome represented a significant source of febrile neutropenia further contributing to patient safety concerns and requires strategies to decrease its incidence. Infectious complications and death were not affected by the omission of G-CSF supporting a carefully monitored outpatient approach to Auto-HSCT in which white blood cell growth factor is eliminated or given as needed for documented infection.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Review of efficacy of ciclesonide for the treatment of asthma in children.

Background: Ciclesonide (CIC) is an inhaled corticosteroid (ICS) approved for the maintenance treatment of asthma in patients ages ≥ 12 years. The prodrug aspect of CIC is associated with a safety profile that may make it ideal for children. Objective: The objective was to summarize efficacy results from the eight phase III, randomized, double-blind, controlled trials in children with asthma conducted during CIC clinical development. Methods: Four trials compared CIC 40, 80, or 160 µg/day with placebo. Two trials compared CIC 160 µg/day with fluticasone propionate 200 µg/day, one trial compared CIC 80 or 160 µg/day with fluticasone 200 µg/day, and one trial compared CIC 160 µg/day with budesonide 400 µg/day. Results: The primary end point was met by at least two CIC doses versus placebo in the trials in which the primary end point was the change from baseline in lung function outcome (forced expiratory volume in 1 second [FEV1] % predicted or morning peak expiratory flow [PEF]). A trial that compared CIC with placebo did not meet the primary end point of superiority in time-to-first severe wheeze exacerbation or lack of improvement. The primary end point of noninferiority to the active control (fluticasone or budesonide) in the change from baseline in a lung function outcome (FEV1, morning PEF, evening PEF) was met with the CIC 160-µg dose in all active control trials. CIC generally demonstrated statistically significant improvements in forced expiratory flow at 25%-75% of forced vital capacity, asthma symptoms, rescue medication use, and asthma control when compared with placebo and noninferiority for these outcomes compared with fluticasone or budesonide. Conclusion: In children with asthma, once-daily CIC significantly improved large and small airway function, asthma symptoms, and asthma control, and reduced rescue medication use compared with placebo. CIC was comparable with other ICS used to treat asthma in children, which demonstrated its worth for the pediatric population.

The cost effectiveness of lenvatinib versus atezolizumab and bevacizumab or sorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in Canada.

4098 Background: Hepatocellular carcinoma (HCC) represents 72% of liver cancers in Canada. In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in overall survival (OS) versus sorafenib and demonstrated superiority in secondary endpoints of progression free-survival (PFS), time to progression and objective response rate. Based on the REFLECT trial, lenvatinib has become the standard of care in the treatment of Canadian patients with unresectable HCC (uHCC). In the Phase III IMbrave150 trial, the use of the combination of atezolizumab and bevacizumab (atezo+bev) resulted in statistically significant improvement in OS and PFS versus sorafenib for patients with uHCC. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus atezo+bev or sorafenib as first-line treatment for patients with uHCC from the perspective of Ministry of Health in Canada. Methods: A cost-utility analysis was conducted using a partitioned survival analysis. Health state membership for lenvatinib and sorafenib were estimated based on patient level data and clinical inputs from REFLECT and extrapolated using parametric survival models. Relative efficacy for atezo+bev was estimated from a de novo network meta-analysis. In the base-case analysis, estimates from REFLECT used in the NMA were adjusted for imbalances in baseline characteristics. Sensitivity analyses included the use of alternative approaches to determine relative efficacy. Health state utility values were determined with EQ-5D data collected in REFLECT. Drug acquisition costs were obtained from publicly available sources and medical resource utilization was based on a survey of Canadian clinicians. The time horizon was 10 years. Results of the incremental analysis were calculated sequentially. Results: In the base case lenvatinib was associated with cost savings of CAD$4,640 and CAD$120,095 and a QALY difference of 0.15 and -0.28 vs sorafenib and atezo+bev, respectively. The base case deterministic analysis resulted in lenvatinib being dominant over sorafenib and cost-effective vs. atezo+bev (sequential ICER for atezo+bev was CAD$425,754 per QALY). Results of the probabilistic sensitivity analysis (PSA) were consistent with the base case findings with lenvatinib being the optimal treatment strategy in &gt;99% of iterations. Conclusions: Results of this analysis demonstrate that lenvatinib represents the optimal use of healthcare resources as a first-line treatment for uHCC in Canada.

The comparative efficacy of atezolizumab and bevacizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC).

e16151 Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, comprising 90% of all cases. In the phase III IMbrave150 trial, combination of atezolizumab and bevacizumab (atezo+bev) resulted in improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib for patients with unresectable hepatocellular carcinoma (uHCC). In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in OS versus sorafenib, and demonstrated superiority in secondary endpoints; PFS, time to progression and objective response rate (ORR). Furthermore, post-hoc analyses strongly suggest that the original non-inferiority trial likely underestimated the true effect of lenvatinib on OS due to imbalances in baseline prognostic covariates and the comparatively greater use of post-treatment anti-cancer therapies in the sorafenib arm. In the absence of a head-to-head comparison between atezo+bev and lenvatinib, the objective of this analysis was to estimate their comparative efficacy as first-line treatments for patients with uHCC. Methods: A network meta-analysis (NMA) was conducted based on a de novo systematic literature review which identified evidence for licensed therapies in first-line uHCC. This was supplemented with data from the extended IMbrave150 study findings (clinical cut-off on 31 August 2020). Median hazard ratios (HR) with corresponding 95% credible intervals (CrI) were estimated for OS and PFS. HRs for OS and PFS from REFLECT were taken from multivariable analyses which adjusted imbalances in baseline prognostic covariates. All analyses were conducted in a Bayesian generalised linear model framework. Model selection was based on deviance information criterion (DIC). Results: Four eligible phase III studies (REFLECT, SHARP, Asia-Pac and IMbrave150) were included. Using a fixed-effects model, the estimated median HRs for atezo+bev compared with lenvatinib were 0.81 (95%CrI: 0.61, 1.08; posterior p=0.078) and 0.99 (95%CrI: 0.76, 1.28; posterior p=0.454) for OS and PFS, respectively. The results obtained were similar to those observed by Vogel et al, who reported an OS HR of 0.63 (95% CI: 0.32, 1.25), and a PFS HR of 0.91 (95% CI: 0.23, 3.65). Conclusions: While the NMA respects the randomization of the included studies, it does not represent direct evidence and should therefore be considered exploratory in nature. The results of this NMA suggest that the benefit of atezo+bev is not statistically significant compared to lenvatinib, as the differences between atezo+bev and lenvatinib fell within the Bayesian range of equivalence (upper limit of Crl ≥ 1 for OS and PFS) and were subject to a high degree of uncertainty. The results of the NMA were consistent for all the publicly available data cuts from IMbrave150.

Phase 3 Study Evaluating Once Weekly Somatrogon Compared to Daily Genotropin in Japanese Patients With Pediatric Growth Hormone Deficiency (pGHD)

Abstract Objectives: Somatrogon is a long-acting recombinant human growth hormone consisting of the amino acid sequence of human growth hormone and three copies of the carboxy-terminal peptide of human chorionic gonadotropin. Somatrogon is being developed as a once weekly treatment for children with pGHD. A Phase 3 trial was designed to compare the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in Japanese patients with pGHD (ClinicalTrials. gov: NCT03874013). Methods: 44 Japanese pGHD patients (age 3-11 years) were randomized in a 1:1 ratio to receive either once weekly somatrogon (0.66 mg/kg/week) or once daily Genotropin (0.025 mg/kg/day) subcutaneously for 12 months. Somatrogon-treated patients had a pharmacokinetic assessment in the first 6 weeks with dose escalation occurring in 3 steps, at 0.25, 0.48, and 0.66 mg/kg/week, for 2 weeks at each dose. For the remaining 46 weeks, patients in the somatrogon treatment group continued to receive somatrogon at a dose of 0.66 mg/kg/week. The primary endpoint of the study was annualized height velocity (HV) at 12 months. Results: Baseline characteristics were balanced and comparable between the two treatment groups. The least square means of HV at month 12 were 9.65 cm/year in the somatrogon group (n=22) and 7.87 cm/year in the Genotropin group (n=22), with a point estimate treatment difference of 1.79 cm/year (95% confidence interval: 0.97, 2.60) in favour of somatrogon. The point estimate was greater than the pre-established mean treatment difference of -1.8 cm/year, which was the non-inferiority margin met in the global Phase 3 study (n=224) with somatrogon (0.66 mg/kg/week) and Genotropin (0.034mg/kg/day) (ClinicalTrials. gov: NCT02968004). Most of the adverse events were mild to moderate in severity and somatrogon was generally well-tolerated with no notable difference in safety between the two treatment groups. Injection site pain was more common in the somatrogon group (somatrogon: 72.7%, Genotropin: 13.6%). Conclusions: The Japanese Phase 3 trial in patients with pGHD demonstrated that once weekly somatrogon was comparable to daily Genotropin. The annual HV after 12 months of treatment was higher in the somatrogon group than the Genotropin group. Somatrogon administration was generally well tolerated in patients with pGHD. The results of this Japanese Phase 3 study are consistent with the results previously reported from the global Phase 3 study that met its primary endpoint of noninferiority to daily Genotropin.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease

This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n= 59 [CT-P13 SC]; n= 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial

Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Abstract PS9-59: Pooled efficacy analysis from two phase 3 studies in patients receiving eflapegrastim, a novel, long-acting granulocyte-colony stimulating factor, following TC for early-stage breast cancer

Abstract Background: Eflapegrastim (Rolontis®, Efla) represents the first novel, long-acting granulocyte-colony stimulating factor (G-CSF) to be introduced in more than 15 years. Efla consists of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a polyethylene glycol linker. Preclinical, clinical, and pharmacodynamic/pharmacokinetic data have shown increased potency for Efla versus pegfilgrastim (Peg). Both independent, randomized Phase 3 studies comparing Efla and Peg for prophylaxis of chemotherapy-induced neutropenia in patients with early-stage breast cancer (ESBC) met the primary endpoint of non-inferiority in duration of severe neutropenia (SN; ANC&amp;lt;0.5 × 109/L) (p&amp;lt;0.001) for Efla vs Peg in all 4 treatment cycles. Additionally, one of the studies exhibited a statistically significant reduction in the relative risk of SN in Cycle 1 with Efla. Here we provide a pooled analysis across the two pivotal studies comparing Efla vs Peg for SN in various subgroups. Methods: Patients with ESBC, who were candidates for adjuvant or neoadjuvant chemotherapy, were randomized 1:1 in two open-label Phase 3 studies to fixed-dose Efla (3.6 mg G-CSF) or standard Peg (6 mg G-CSF) administered on Day 2 following TC (docetaxel/cyclophosphamide) for a total of 4 cycles. ANCs were collected daily in Cycle 1 and 5 times in Cycles 2-4. SN was evaluated between treatment groups in Cycle 1 using Fisher’s exact test at 5% level of significance and was analyzed using multivariate logistic and Cox proportional hazards regression models. Results: A total of 643 patients who received either Efla (n=314) or Peg (n=329) were included in the analysis. The two treatment groups were well balanced for demographics and baseline characteristics. The mean age was 59 years, 38% were ≥65 years old, and 54% weighed &amp;gt;75kg. The safety profiles, including AEs and discontinuations, for Efla and Peg were comparable, and &amp;gt;99% of all patients received full dose of TC on schedule. The majority (67%) of patients with SN experienced a 1 day duration, occurring between Days 7 and 8 after TC. Mean duration of SN for Efla was statistically lower than for Peg (0.24 vs. 0.36 days; p=0.029). The above statistical significance was maintained for Efla after adjusting for demographic and baseline characteristics, namely age, weight, enrolling geographical region, and treatment setting in a multivariate model. Similarly, the incidence of SN for Efla was statistically lower than Peg in Cycle 1 (17.5% vs 24%; relative risk reduction [RRR]=27%; p=0.043). Univariate analysis of the incidence of SN showed a significant risk reduction in favor of Efla (8.6% vs 14.1%; p=0.034) for patients weighing &amp;gt;75kg (p=0.034). Multivariate analysis of SN showed significant odds ratio of SN for age ≥65 years and baseline ANC &amp;gt;6 × 109/L in favor of Efla (OR=0.42 and 0.39, respectively). The incidence of SN in Cycles 2-4 was comparable between treatment groups. Also, the incidence of febrile neutropenia and neutropenic complications was similar with &amp;lt;5% in each treatment group. No leukocytosis, splenic rupture, or anaphylaxis was reported in any patient receiving Efla or Peg. Conclusion: A pooled analysis of two, randomized Phase 3 studies evaluating Efla vs Peg, administered once-per-cycle for prophylaxis of SN, showed Efla and Peg had similar safety profiles with Efla demonstrating a statistically significant risk reduction in SN overall and in patients weighing &amp;gt;75kg. Eflapegrastim is a novel, long-acting and potent recombinant human G-CSF which may provide an attractive option in supporting patients at risk for SN-related complications. Citation Format: Lee S Schwartzberg, Gajanan Bhat, Alvaro Restrepo, Osama Hlalah, Inderjit Mehmi, Yong Wha Moon, Seungjae Baek, Shanta Chawla, Francois Lebel, Patrick Wayne Cobb. Pooled efficacy analysis from two phase 3 studies in patients receiving eflapegrastim, a novel, long-acting granulocyte-colony stimulating factor, following TC for early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-59.

Long-Term Efficacy and Safety of Ultra Rapid Lispro (URLi) in Adults with Type1 Diabetes: The PRONTO-T1D Extension.

IntroductionThe PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi.MethodsIn this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety.ResultsHbA1c increased marginally during the long-term maintenance period (week 26–52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of − 0.06% (− 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments.ConclusionOverall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi.Trial RegistrationClinicalTrials.gov, NCT03214367.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-020-00987-8.

Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE)

Abstract Background Little is known about the impacts of sodium glucose co-transporter 2 inhibitors on cardiac functional parameters, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). Purpose To compare the effect of canagliflozin with glimepiride, based on changes in N-terminal pro-brain natriuretic peptide (NT-proBNP), in that patient population. Methods This trial was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint trial at 34 centers in Japan. Patients with T2D and clinically stable CHF excluding NYHA class IV, randomized to receive canagliflozin 100 mg or glimepiride (starting dose: 0.5 mg), were examined using the primary endpoint of non-inferiority of canagliflozin versus glimepiride, defined as a margin of 1.1 in the upper-limit of the 2-sided 95% confidence interval (95% CI) for the group ratio of percentage change in NT-proBNP at 24 weeks. Results Data analysis of 233 patients (mean age 68.6±10.1 yrs; 75% male) showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6±14.6%, with 71% of patients having a preserved LVEF (≥50%). The ratio of NT-proBNP percentage change was 0.48 (95% CI, −0.13 to 1.59, P=0.226), and therefore did not meet the prespecified non-inferiority margin. However, data stratified according to baseline NT-proBNP levels showed a trend that canagliflozin treatment reduced NT-proBNP levels to a greater extent than in subgroups with elevated levels of NT-proBNP (Figure A). Furthermore, NT-proBNP levels in the canagliflozin group did show a nonsignificant trend lower in the subgroup with preserved LVEF (Figure B), but not in the subgroup with reduced LVEF (Figure C). Additionally, the changes in the NYHA class were comparable between groups (P=0.061) in the overall cohort, whereas in the subgroup with a preserved LVEF canagliflozin caused a significant improvement in NYHA classes compared to that found for glimepiride treatment (P=0.027). Conclusions This trial did not meet the predefined primary endpoint of changes in NT-proBNP levels, with 24 weeks of treatment with canagliflozin relative to glimepiride which together with other recent studies would question the value of continuing to monitor NT-proBNP levels after the initial diagnosis of heart failure. Nevertheless, in a subgroup with preserved LVEF, there was a non-significant trend for canagliflozin treatment to reduce NT-proBNP levels and improve symptoms even in stable HF patients. Further research is therefore warranted to determine whether patients with preserved LVEF, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors. Changes in NT-proBNP Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Mitsubishi Tanabe Pharma Corporation

Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials

Seasonal influenza remains a substantial public health threat despite the availability of egg-derived and other vaccines. Plant-based manufacturing might address some of the limitations of current vaccines. We describe two phase 3 efficacy studies of a recombinant quadrivalent virus-like particle (QVLP) influenza vaccine manufactured in plants, one in adults aged 18-64 years (the 18-64 study) and one in older people aged 65 years and older (the 65-plus study). We did two randomised, observer-blind, multinational studies in the northern hemisphere in the 2017-18 (the 18-64 study) and 2018-19 (the 65-plus study) influenza seasons. The 18-64 study was done at 73 sites and the 65-plus study was done at 104 sites, both across Asia, Europe, and North America. In the 18-64 study, inclusion criteria were body-mass index less than 40 kg/m2; age 18-64 years at screening visit; and good health. In the 65-plus study, inclusion criteria were body-mass index of maximum 35 kg/m2; aged 65 years or older at screening visit; not living in a rehabilitation centre or care home; and no acute or evolving medical problems. Participants in the 18-64 study were randomly assigned (1:1) to receive either QVLP vaccine (30 μg haemagglutinin per strain) or placebo. Participants in the 65-plus study were randomly assigned (1:1) to receive QVLP vaccine (30 μg haemagglutinin per strain) or quadrivalent inactivated vaccine (QIV; 15 μg haemagglutinin per strain). The primary outcome in the 18-64 study was absolute vaccine efficacy to prevent laboratory-confirmed, respiratory illness caused by antigenically matched influenza strains. The primary outcome in the 65-plus study was relative vaccine efficacy to prevent laboratory-confirmed influenza-like illness caused by any influenza strain. The primary analyses were done in the per-protocol population and safety was assessed in all participants who received the assigned treatment. These studies are registered with ClinicalTrials.gov (18-64 study NCT03301051; 65-plus study NCT03739112). In the 18-64 study, between Aug 30, 2017, and Jan 15, 2018, 10 160 participants were randomly assigned to receive either QVLP vaccine (5077 participants) or placebo (5083 participants). The per-protocol population consisted of 4814 participants in the QVLP group and 4812 in the placebo group. The study did not meet its primary endpoint of 70% absolute vaccine efficacy for the QVLP vaccine (35·1% [95% CI 17·9 to 48·7]) against respiratory illness caused by matched strains. 55 (1·1%) of 5064 participants in the QVLP group versus 51 (1·0%) of 5072 in the placebo group had a serious adverse event. Four (0·1%) and six [0·1%] participants had severe treatment-related treatment-emergent adverse events. In the 65-plus study, between Sept 18, 2018, and Feb 22, 2019, 12 794 participants were randomly assigned to receive either QVLP vaccine (6396 participants) or QIV (6398 participants). The per-protocol population consisted of 5996 participants in the QVLP group and 6026 in the QIV group. The study met its primary non-inferiority endpoint with a relative vaccine efficacy of the QVLP vaccine for the prevention of influenza-like illness caused by any strain of 8·8% (-16·7 to 28·7). 263 (4·1%) of 6352 participants in the QVLP group versus 266 (4·2%) of 6366 in the QIV group had serious adverse events (one [<0·1%] vs two [<0·1%] were considered treatment-related); one (<0·1%) versus three (<0·1%) participants had severe treatment-related treatment-emergent adverse events. These efficacy studies are the first large-scale studies of any plant-derived human vaccine. Together, they show that the plant-derived QVLP vaccine can provide substantial protection against respiratory illness and influenza-like illness caused by influenza viruses in adults. QVLP vaccine was well tolerated and no major safety signal arose in participants who received QVLP vaccine across the two studies. Medicago.

APEX: a phase II randomised clinical trial evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular degeneration

PurposeThe safety and efficacy of X-82, an orally administered inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor, was investigated for treatment of wet age-related macular degeneration (AMD)...

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1)

To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-μg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. Study eyes received bimatoprost implant 10 μg (n= 198) or 15 μg (n= 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n= 198). Intraocular pressure was measured at hours 0 and 2 at each visit. Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-μg implant, 15-μg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-μg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-μg implant) and 21.8% (15-μg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-μg implant over the 15-μg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.