The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Study Number: 116197 Title: A Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting with Acute Coronary Syndrome Treated with Compared to (PM1116197) (Short title: LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and modify outcomes after an acute coronary syndrome [(LATITUDE)-TIMI 60] Rationale: This Phase III outcomes trial compared the effects of losmapimod 7.5 mg twice daily (BID) for 12 weeks versus placebo when added to standard of care on the incidence of major adverse cardiovascular events (MACE) in subjects with acute coronary syndrome (ACS) (non-st-segment elevation myocardial infarction [NSTEMI] and ST-segment elevation myocardial infarction [STEMI]). Phase: Phase III Study Period: 03 Jun 2014-08 Dec 2015 Study Design: This was a randomized, placebo-controlled, double-blind, parallel-group, multicenter international study which was designed to be conducted in two parts. The entire trial was planned to include approximately 25,500 subjects presenting with NSTEMI or STEMI. Subjects were to be randomized 1:1 to receive either oral losmapimod or matching placebo BID for 12 weeks in addition to standard of care. They were to be followed for an additional 12 weeks after completing treatment, for a total study duration of 24 weeks. An independent data monitoring committee (IDMC) had study oversight to ensure scientific integrity of the data and subject safety, and an independent Clinical Events Committee (CEC) blinded to treatment adjudicated outcome events. The study was planned in two parts (Part A and Part B): Part A: A leading cohort of 3,500 subjects was randomized to provide an initial assessment of safety and exploratory efficacy (~200 adjudicated primary endpoint events) before progressing to Part B. Efficacy data from this stage of the study was not planned to be used in the primary efficacy analysis of the trial. Part B: The main cohort was planned to be event driven with approximately 22,000 subjects randomized to provide the main assessment of efficacy with an event target of 1,400 adjudicated primary endpoint events and 1,000 1,200 adjudicated cardiovascular (CV) death and myocardial infarction (MI) events. As prespecified in the protocol, upon completion of the treatment phase of Part A summary level unblinded efficacy and safety data from Part A were reviewed by a limited group involved in study conduct (comprising trial leadership from the Sponsor and the Thrombolysis in Myocardial Infarction (TIMI) Study Group) in order to determine whether to progress to Part B of the trial. A decision was made not to progress to Part B of the study, based on lack of efficacy on the primary endpoint, with acceptable safety profile. The trial was completed at the end of Part A. Centres: Argentina 6, Australia 10, Belgium 10, Bulgaria 7, Canada 9, Chile 4, Czech Republic 11, Denmark 4, Estonia 3, France 10, Germany 24, Greece 6, Hong Kong 3, Hungary 5, Israel 5, Italy 7, Republic of Korea 8, Mexico 2, Netherlands 14, New Zealand 6, Norway 5, Philippines 4, Poland 13, Romania 3, Russian Federation 20, Slovakia 4, South Africa 7, Spain 12, Sweden 8, Taiwan 5, Thailand 4, Ukraine 7, United Kingdom 6, United States 70 Indication: Acute coronary syndrome Treatment: : 7.5 mg/tablet/oral; 1 tablet within 2 hours after randomization (and subsequently 1 tablet every 12 hours) for 12 weeks duration. : 0 mg/tablet/oral; 1 tablet within 2 hours after randomization (and subsequently 1 tablet every 12 hours) for 12 weeks duration. Objectives: The primary objective was to evaluate the efficacy of oral losmapimod compared to placebo when added to standard of care in subjects with ACS on the time to first occurrence of adjudicated MACE (defined as cardiovascular [CV] death, myocardial infarction [MI], or severe recurrent ischemia requiring urgent coronary revascularization [SRI-UR]) through 12 weeks of therapy. Primary Outcome (Endpoints)/Efficacy: The primary efficacy endpoint was the composite measure of adjudicated MACE that includes the time to first occurrence of CV death, MI, or SRI-UR. 1
Secondary Outcome (Endpoints)/Efficacy: Principal Secondary Endpoint: The principal secondary endpoint was the time to first occurrence of the composite of adjudicated CV death or MI. Additional Secondary Endpoints: The composite of CV death, MI, or hospitalization for heart failure (HF). The expanded composite of arterial CV events, defined as CV death, MI, SRI-UR, or stroke. The composite of coronary events (defined as coronary heart disease [CHD] death, MI, SRI-UR, or any unplanned coronary artery revascularization). Planned coronary artery revascularizations are those initial or staged interventions performed based on the initial qualifying ACS. The composite of CV death or hospitalization for HF. The composite of CV death, MI or stroke. The composite of CV death, MI, SRI-UR, stroke or hospitalisation for HF. The primary and principal secondary endpoints were evaluated replacing CV death separately with CHD death ( Coronary MACE ) and all-cause death. The primary and principal secondary endpoints were evaluated replacing all MI with Type 1 (spontaneous) MI. Individual components of the composite endpoints (including all-cause mortality). Definite or probable stent thrombosis. Any re-hospitalization within 30 days of discharge. For the primary and each of the secondary endpoints, the principal analysis was through 12 weeks, with additional analyses through 4 and 24 weeks unless otherwise stated. In addition, a recurrent event analysis (i.e. accounting for subjects who experienced multiple events) was conducted for each composite endpoint. Statistical Methods: In total, approximately 25,500 ACS subjects were planned to be recruited, comprising 3,500 subjects in a leading cohort (Part A) used to provide an initial assessment of safety and exploratory efficacy with approximately 200 MACE (defined as CV death, MI, or SRI-UR), followed by a main cohort of approximately 22,000 subjects (event target of 1,400 MACE and 1,000 1,200 CV death or MI). The pivotal and powered assessment of efficacy would have been provided by Part B of the study, with Part A providing an exploratory assessment to support continuation to Part B. Whilst an exploratory cohort could not be appropriately powered for formal assessment of efficacy, the precision with which the MACE effect size could be estimated from Part A was considered. Given the limitations on precision that would be expected in an exploratory context, the decision not to progress to Part B was multifaceted. The principal efficacy evaluation occurred through Week 12 with additional evaluations of efficacy through Weeks 4 and Week 24. The primary analysis of MACE at 12 weeks was based on a stratified log-rank test with a stratified Coxregression model used to estimate the hazard ratio (HR) and its 95% confidence interval (CI) (both analyses stratified by NSTEMI/STEMI). Key secondary endpoints were assessed using the same methods as the primary endpoint. The primary population for all analyses of MACE, secondary time-to-event outcomes, and other efficacy assessments was the All Randomized (Intent-to-Treat [ITT]) Population. Subjects were analysed according to the treatment to which they were randomized. The primary population for evaluation of safety was based on all randomized subjects who received at least one dose of investigational product (IP). Subjects were analysed according to the treatment which they actually received. Study Population: Subjects were eligible for enrollment if they were aged 35 years or older; had been hospitalized with a presumed spontaneous (type 1) MI, including NSTEMI within 24 hours of ischemic symptoms or STEMI within 12 hours of onset; and had at least 1 additional predictor of cardiovascular risk. Study drug was to be administered as early as possible during hospitalization and prior to coronary revascularization or reperfusion. Relevant exclusion criteria at study entry included clinical instability, known acute or chronic liver disease, current life-threatening or opportunistic infection, severe renal impairment (estimated glomerular filtration rate <30 ml/min/1.73 m2), or New York Heart Association class III or IV or Killip class III or IV heart failure at randomization. 2
Part A Total Number of Subjects: Planned, N - - 3500 Randomised, N 1765 1738 3503 Excluded from analysis 1 7 7 14 ITT population, N 1758 1731 3489 Completed as planned, n (%) 1512 (86.0) 1456 (84.1) 2968 (85.1) Never received IP, n (%) 6 (0.3) 7 (0.4) 13 (0.4) Discontinued study treatment, n (%) 240 (13.7) 268 (15.5) 508 (14.6) Withdrawn due to adverse events (AEs), n (%) 66 (3.8) 73 (4.2) 139 (4.0) Withdrawn for other reasons, n (%) 174 (9.9) 195 (11.3) 369 (10.6) Demographics N (ITT) 1758 1731 3489 Females: Males 532: 1226 500: 1231 1032: 2457 Mean age, years (SD) 66.5 (9.72) 66.7 (10.00) 66.6 (9.86) Mean body mass index, kg/m 2 (SD) 28.52 (5.069) 28.60 (5.118) 28.56 (5.093) Race, n (%) Black 25 (1.4) 20 (1.2) 45 (1.3) Central/South/South East Asian 30 (1.7) 34 (2.0) 64 (1.8) East Asian/Japanese 68 (3.9) 71 (4.1) 139 (4.0) White 1614 (92.0) 1585 (91.6) 3199 (91.8) Other 18 (1.0) 21 (1.2) 39 (1.1) Ethnicity, n (%) Hispanic or Latino 75 (4.3) 71 (4.1) 146 (4.2) Not Hispanic or Latino 1682 (95.7) 1660 (95.9) 3342 (95.8) 1. Subjects excluded from analysis due to data integrity issues. Primary Efficacy Results: Time to First Occurrence of MACE Through Week 12 (Day 84) and Week 24 (Day 182) (ITT Population) 1 N=1758 N=1731 n (%) n (%) Week 12 First occurrence MACE 123 (7.0) 139 (8.0) Hazard ratio for losmapimod: placebo 2 1.16 95% CI 2 (0.91, 1.47) P-value 2 0.239 Cardiovascular death 34 (1.9) 31 (1.8) Myocardial infarction 74 (4.2) 90 (5.2) SRI-UR 15 (0.9) 18 (1.0) Week 24 First occurrence MACE, n (%) 162 (9.2) 176 (10.2) Hazard ratio for losmapimod: placebo 2 1.11 95% CI 2 (0.90, 1.38) P-value 2 0.329 Cardiovascular Death 45 (2.6) 38 (2.2) Myocardial infarction 98 (5.6) 117 (6.8) SRI-UR 19 (1.1) 21 (1.2) 1. Analysis was not performed for Week 4 and recurrent analysis was not performed because this was planned for the full study and not for Part A alone. 2. Hazard ratio and CI were estimated using a Cox proportional hazard regression model stratified by baseline STEMI/NSTEMI status with treatment as the only covariate. A hazard ratio <1 indicates a lower risk with the treatment compared with placebo. 3
Secondary Outcome Results: Summary of Composite Secondary Efficacy Endpoints Through Week 12 and Week 24 (ITT Population) 1 N=1758 N=1731 Hazard ratio First Occurrence of Time point n (%) n (%) [95% CI] 2 P-value Principal secondary endpoint: CV Week 12 110 (6.3) 122 (7.0) 1.13 [0.88,1.47] 0.338 death or MI Week 24 145 (8.2) 156 (9.0) 1.10 [0.88, 1.38] 0.410 CV death, MI or hospitalization Week 12 131 (7.5) 140 (8.1) 1.09 [0.86, 1.38] 0.472 for HF Week 24 169 (9.6) 178 (10.3) ND Arterial CV events: CV death, MI, Week 12 135 (7.7) 151 (8.7) 1.14 [0.91, 1.44] 0.255 SRI-UR, or stroke Week 24 174 (9.9) 190 (11.0) ND CV death or hospitalization for Week 12 72 (4.1) 64 (3.7) 0.90 [0.64, 1.26] 0.536 HF Week 24 94 (5.3) 86 (5.0) 0.92 (0.69, 1.24) 0.060 CV death, MI or stroke Week 12 122 (6.9) 134 (7.7) 1.12 [0.88, 1.43] 0.356 Week 24 157 (8.9) 170 (9.8) ND CV death, MI, SRI-UR, stroke, or Week 12 155 (8.8) 169 (9.8) 1.11 [0.90, 139] 0.329 Hosp for HF Week 24 197 (11.2) 212 (12.2) ND Coronary events: CHD death, MI, Week 12 144 (8.2) 152 (8.8) 1.08 [0.86, 1.36] 0.505 SRI-UR or any unplanned Week 24 186 (10.6) 194 (11.2) ND coronary artery revascularization CHD death, MI SRI-UR Week 12 119 (6.8) 133 (7.7) 1.14 [0.89, 1.47] 0.285 Week 24 152 (8.6) 167 (9.6) ND CHD death or MI Week 12 106 (6.0) 116 (6.7) 1.12 [0.86, 1.46] 0.401 Week 24 135 (7.7) 147 (8.5) ND All cause death, MI SRI-UR Week 12 128 (7.3) 142 (7.7) 1.14 [0.89, 1.47] 0.285 Week 24 169 (9.6) 185 (10.7) ND All cause death, MI Week 12 115 (6.5) 125 (7.2) 1.11 [0.86, 1.43] 0.412 Week 24 152 (8.6) 165 (9.5) ND CV death, Type I (spontaneous) Week 12 86 (4.9) 94 (5.4) 1.11 [0.83, 1.49] 0.469 MI or SRI-UR Week 24 122 (6.9) 127 (7.3) ND CV death, Type I (spontaneous) Week 12 73 (4.2) 77 (4.4) 1.07 [0.78, 1.48] 0.664 MI Week 24 104 (5.9) 106 (6.1) ND All cause mortality Week 12 49 (2.8) 39 (2.3) 0.80 [0.53, 1.22] 0.309 Week 24 68 (3.9) 57 (3.3) ND CV death Week 12 44 (2.5) 36 (2.1) 0.83 [0.53, 1.28] 0.398 Week 24 59 (3.4) 47 (2.7) 0.80 (0.55, 1.18) 0.264 CHD death Week 12 40 (2.5) 30 (2.1) 0.76 [0.47, 1.22] 0.251 Week 24 49 (2.8) 37 (2.1) ND Myocardial infarction (fatal and Week 12 75 (4.3) 90 (5.2) 1.23 [0.91, 1.67] 0.182 non-fatal) Week 24 99 (5.6) 117 (6.8) 1.21 (0.93, 1.58) 0.158 Type 1 MI Week 12 32 (1.8) 42 (2.4) 1.34 [0.85, 2.12] 0.210 Week 24 51 (2.9) 62 (3.6) ND SRI-UR Week 12 16 (0.9) 18 (1.0) 1.14 [0.85, 2.24] 0.697 Week 24 22 (1.3) 22 (1.3) ND Hospitalization for HF Week 12 42 (2.4) 35(2.0) 0.84 [0.54, 1.32] 0.457 Week 24 53 (3.0) 49 (2.8) 0.94 (0.63,1.38) 0.736 Stroke Week 12 15 (0.9) 14 (0.8) 0.95 [0.46, 1.96] 0.883 Week 24 19 (1.1) 18 (1.0) ND Any unplanned revascularization Week 12 57 (3.2) 62 (3.6) 1.11 [0.77, 1.59] 0.581 Week 24 75 (4.3) 87 (5.0) ND Definite or probable stent thrombosis Week 12 19 (1.5) 11 (0.8) 0.57 [0.27, 1.19] 0.130 Week 24 21 (1.6) 12 (0.9) ND 4
N=1758 N=1731 Odds ratio Time point n (%) n (%) [95% CI] 3 P-value Re-hospitalization or died within 30 days of discharge NA 42 (2.4) 36 (2.1) 1.03 [0.84, 1.27] 0.744 NA: not applicable. ND: not determined (not tested). 1. Analysis was not performed for Week 4 and recurrent analysis was not performed because this was planned for the full study and not for Part A alone. 2. Hazard ratio and CI were estimated using a Cox proportional hazard regression model stratified by baseline STEMI/NSTEMI status with treatment as the only covariate. A hazard ratio <1 indicates a lower risk with the treatment compared with placebo. 3. Odds ratio and CI were estimated using a logistic regression model stratified by baseline STEMI/NSTEMI status with treatment as the only covariate. An odds ratio <1 indicates a lower risk with the treatment compared with placebo. Safety Results: Non-serious adverse events (AEs) were collected from the time of the first dose of IP until the Week 12 visit (+2 weeks). Adverse events of special interest were collected from the time of first dose until the Week 24 visit (+/- 2 weeks). Serious adverse events (SAEs) were collected from the time of screening until the Week 24 visit (+/-2 weeks). Summary of On-treatment AEs Excluding Positively CEC-Adjudicated Events (Safety Population) N=1752 N=1724 n (%) n (%) Subjects with any AE on-treatment 972 (55.5) 972 (56.4) Most frequent 10 AEs in each treatment group by Preferred Term: Atrial fibrillation 61 (3.5) 76 (4.4) Angina pectoris 29 (1.7) 48 (2.8) Non-cardiac chest pain 37 (2.1) 46 (2.7) Dyspnoea 54 (3.1) 41 (2.4) Diarrhoea 38 (2.2) 41 (2.4) Cough 31 (1.8) 40 (2.3) Hypotension 32 (1.8) 33 (1.9) Anaemia 28 (1.6) 32 (1.9) Troponin increased 48 (2.7) 31 (1.8) Hypertension 48 (2.7) 30 (1.7) Angina unstable 30 (1.7) 28 (1.6) Headache 29 (1.7) 28 (1.6) Dizziness 29 (1.7) 26 (1.5) On-treatment AEs include those events that occurred on or after the treatment start date and on or before the treatment stop date +3 days, including AEs that occurred during temporary interruptions. 5
Summary of SAEs (Fatal and Non-Fatal) Excluding Positively CEC-Adjudicated Events Through Week 24 (Safety Population) N=1752 N=1724 n (%) [related] n (%) [related] Subjects with any SAE through Week 24 (fatal and non-fatal events) 323 (18.4) [15] 363 (21.1) [12] Most frequent 10 SAEs in each group by preferred term: Angina unstable 24 (1.4) [0] 26 (1.5) [0] Angina pectoris 14 (0.8) [0] 24 (1.4) [0] Atrial fibrillation 14 (0.8) [0] 19 (1.1) [0] Pneumonia 12 (0.7) [0] 16 (0.9) [0] Non-cardiac chest pain 19 (1.1) [0] 15 (0.9) [0] Musculoskeletal chest pain 4 (0.2) [0] 14 (0.8) [0] Acute kidney injury 9 (0.5) [0] 13 (0.8) [0] Acute myocardial infarction 7 (0.4) [0] 13 (0.8) [1] Cardiac failure 6 (0.3) [0] 10 (0.6) [0] Troponin increased 11 (0.6) [0] 9 (0.5) [0] Pleural effusion 6 (0.3) [0] 9 (0.5) [0] Cardiac failure congestive 5 (0.3) [0] 8 (0.5) [0] Summary of Fatal SAEs Excluding Positively CEC-Adjudicated Events During Entire Study (Safety Population) N=1752 N=1724 n (%) [related] n (%) [related] Subjects with any fatal SAE during total study 10 (0.6) [0] 13 (0.8) [0] Fatal SAEs by preferred term: Death 1 (<0.1) [0] 3 (0.2) [0] Pneumonia 1 (<0.1) [0] 1 (<0.1) [0] Septic shock 1 (<0.1) [0] 1 (<0.1) [0] Colitis 0 (0.0) [0] 1 (<0.1) [0] Injury 0 (0.0) [0] 1 (<0.1) [0] Injury 0 (0.0) [0] 1 (<0.1) [0] Obstructive airways disorder 0 (0.0) [0] 1 (<0.1) [0] Pancreatic carcinoma metastatic 0 (0.0) [0] 1 (<0.1) [0] Pulmonary embolism 0 (0.0) [0] 1 (<0.1) [0] Sepsis 0 (0.0) [0] 1 (<0.1) [0] Urosepsis 0 (0.0) [0] 1 (<0.1) [0] Ventricular tachycardia 0 (0.0) [0] 1 (<0.1) [0] 1 Chronic obstructive pulmonary disease 2 (0.1) [0] 0 (0.0) [0] Colon cancer metastatic 1 (<0.1) [0] 0 (0.0) [0] Gastrointestinal haemorrhage 1 (<0.1) [0] 0 (0.0) [0] Multi organ failure 1 (<0.1) [0] 0 (0.0) [0] Pericarditis 1 (<0.1) [0] 0 (0.0) [0] Pneumonia aspiration 1 (<0.1) [0] 0 (0.0) [0] 1. This subject had 2 SAEs linked to the death. One event was adjudicated as an efficacy endpoint and the other event (ventricular tachycardia) was not. Therefore, this subject is counted in the CEC-adjudicated endpoint of CV death as well as in this summary, which excludes positively CEC adjudicated events. 6
Conclusion: A decision was made not to proceed to the second part of the study (Part B) due to lack of efficacy in Part A. Part A analyses revealed the following: The primary endpoint of MACE (CV death, MI, or SRI-UR) occurred by 12 weeks in 123 (7.0%) subjects in the placebo group and 139 (8.1%) subjects in the losmapimod group (hazard ratio [HR]: 1.16; 95% CI: 0.91, 1.47; p=0.24). Results were similar at Week 24 in the overall cohort, with the primary end point having occurred in 10.3% of subjects in the losmapimod group and 9.7% of subjects in the placebo group (HR: 1.11; 95% CI: 0.9, 1.38). Because there was no evidence for efficacy for the primary outcome, all additional analyses were considered exploratory. The time to first occurrence of the key secondary endpoint of cardiovascular death or MI through Week 12 was not significantly different between the 2 treatment groups (HR: 1.13; 95% CI: 0.88, 1.47). None of the other secondary endpoints revealed any effect of losmapimod. On-treatment AEs (excluding CEC-adjudicated cardiovascular events) were reported for 55.5% (972/1752) of subjects on placebo and 56.4% (972/1724) of subjects on losmapimod. Fatal and non-fatal SAEs (excluding CEC-adjudicated cardiovascular events) through Week 24 were reported for 18.4% (323/1752) of subjects in the placebo group and 21.1% (363/1724) of subjects in the losmapimod group. Fatal SAEs (excluding CEC-adjudicated cardiovascular events) were reported for 0.6% (10/1752) of subjects in the placebo group and 0.8% (13/1724) of subjects in the losmapimod group. 7