Approval Probability
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Adjusted LOA
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omecamtiv mecarbil · 8 trials · 5 indications
Efficacy of omecamtiv mecarbil compared with placebo on the risk of HF outcomes in patients with symptomatic HFrEF and severely reduced ejection fraction in the setting of guideline-directed medical therapy per local standard of care.
The effect of treatment on exercise capacity, as assessed by peak oxygen uptake, was assessed during cardiopulmonary exercise testing (CPET) with gas-exchange analysis. Cycle ergometry was the preferred modality for exercise testing; treadmill exercise testing was an acceptable alternative. Participants were to use the same testing modality for all exercise tests during the study. Whenever possible, CPET was administered by the same study personnel using the same equipment throughout the study.
The primary outcome was a composite of a heart-failure (HF) event or cardiovascular (CV) death, whichever occurred first, in a time-to-event analysis. A heart-failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. All deaths and HF events were adjudicated by an independent external clinical events committee (CEC) at the Duke Clinical Research Institute, using standardized definitions based on the recent American College of Cardiology/American Heart Association (ACC/AHA) standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death or first HF event was analyzed using Kaplan-Meier (KM) methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported.
Continuous 12-lead digital ECG recording was performed on day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after OM dosing minus adjusted mean ΔQTcF after placebo. If the upper bound of the confidence interval of ΔΔQTcF was \< 10 ms for all post-dose time points, OM was to be concluded to not have a significant effect on QT interval prolongation.
Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12)
Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12).
The highest infusion rate tolerated by at least eight subjects. A dose was intolerable if: 1) the pattern of intolerance clearly distinguished active drug from placebo, or 2) the number of subjects intolerant of the dose level in question was at least 3 more than the number of subjects intolerant of placebo.
| Arm | Type | Description |
|---|---|---|
| Omecamtiv Mecarbil | EXPERIMENTAL | Participants randomized to omecamtiv mecarbil will be dosed based on their omecamtiv mecarbil plasma concentration at 25, 37.5 or 50 mg twice daily until at least 850 participants experience a HF event or CV death, whichever comes first. |
| Placebo | PLACEBO_COMPARATOR | Participants randomized to placebo will receive placebo twice daily until at least 850 participants experience a HF event or CV death, whichever comes first. |
| Placebo BID | PLACEBO_COMPARATOR | Participants will receive placebo BID. |
| 25 mg Omecamtiv Mecarbil BID | EXPERIMENTAL | Participants will receive 25 mg omecamtiv mecarbil BID. |
| 37.5 mg Omecamtiv Mecarbil BID Target Dose | EXPERIMENTAL | Participants will receive omecamtiv mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 37.5 mg BID after Week 4 or Week 8, based on Week 2 PK. |
| 50 mg Omecamtiv Mecarbil BID Target Dose | EXPERIMENTAL | Participants will receive Omecamtiv Mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 50 mg BID after Week 4 or Week 8, based on Week 2 PK. |
| Part A | EXPERIMENTAL | After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1. |
| Part B | EXPERIMENTAL | Participants with a maximum observed plasma OM concentration ≤ 350 ng/mL in Part A were randomly assigned to receive a single dose of each the following 3 treatments in one of six treatment sequences: * Placebo * 50 mg omecamtiv mecarbil * 400 mg moxifloxacin Each treatment was separated by a washout of at least 7 days. |
| Omecamtiv mecarbil 25 mg / 37.5 mg | EXPERIMENTAL | Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was \< 200 ng/mL, participants received 37.5 mg BID; if day 8 Cpredose was ≥ 200 ng/mL or a day 8 PK value was not available participants continued to receive 25 mg BID. |
| Omecamtiv mecarbil 25 mg / 50 mg | EXPERIMENTAL | Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was \< 200 ng/mL, participants received 50 mg BID; if day 8 Cpredose was ≥ 200 ng/mL or a day 8 PK value was not available participants continued to receive 25 mg BID. |
| Dose-escalation Cohort 1 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 2 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 3 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 4 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Name | Type | Description |
|---|---|---|
| Omecamtiv Mecarbil (OM) | DRUG | Oral Tablet |
| Placebo | DRUG | Oral Tablet |
| Omecamtiv Mecarbil | DRUG | Oral omecamtiv mecarbil twice daily for up to 20 weeks with dose level determined by periodic blood testing |
| Standard of Care | DRUG | Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated. |
| 25 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| 37.5 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| 50 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| Moxifloxacin | DRUG | 400 mg moxifloxacin oral tablet |
Inclusion Criteria: Adult patients who meet all the following criteria at screening may be included in the study: * Are between ≥ 18 years and ≤ 85 years at the signing of informed consent * Have a history of chronic HFrEF, defined as requiring treatment for HF for a minimum of 3 months prior to s...
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