To Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MYK-224 in Healthy Volunteers
A Phase 1, Blinded, Randomized, Placebo-controlled, Nested Ascending Single Oral Dose and Ascending Multiple Oral Dose Study (with Food Study) to Evaluate Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of MYK-224 in Healthy Volunteers
MyoKardia, Inc.
112 participants
Aug 16, 2019
Interventional
Conditions
Summary
This is a Phase 1, blinded, randomized, placebo-controlled study of the administration of single-ascending doses (SAD) and multiple -ascending doses (MAD) of MYK-224 to healthy participants aged 18–45 years. The SAD and MAD phases of the study are nested. Once the informed consent form (ICF) is signed and eligibility has been established, healthy participants will be enrolled into cohorts of 8 participants randomized 6:2 to MYK-224:Placebo. During the SAD portion and because this is a first in human (FIH) study, a sentinel dosing plan will be employed at each dose level. The first 2 healthy participants of each cohort will be dosed as sentinels. One of the sentinel healthy participants will be randomized to receive MYK-224 and the other will be randomized to receive placebo. Following Safety Review Committee (SRC) review of safety data (including adverse events [AEs], vital signs, electrocardiogram [ECG], and labs [hematology, chemistry, urinalysis, prothrombin time [PT], activated partial thrombin time [aPTT]) 24 to 48 hours after dosing from the sentinel healthy participants, and if deemed appropriate, the remaining 6 healthy participants in the cohort will be dosed. During the food effect (FE) portion, a 2-period crossover design (in which one of the SAD cohorts returns after washout for second administration of the same dose) will be employed to determine the effect of food upon the PK.
Eligibility
Inclusion Criteria8
- Participant is able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study-specific procedure.
- Participant is between the ages of 18 and 45 years, inclusive, at the screening visit.
- Participant has a weight greater than or equal to 50 kg and body mass index between 18 kg/m2 and 32 kg/m2, inclusive, at the screening visit, calculated via the institution’s standard formula.
- Participant is healthy as determined by medical history, physical examination, vital signs, and routine laboratory parameters (chemistry, hematology, and urinalysis) at the screening visit and on day -1. Laboratory values outside the normal range are acceptable if: (1) deemed to be clinically insignificant by the investigator and (2) if transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]), less than 1.5 times the upper limit of the laboratory reference range.
- Participant has documented LVEF greater than or equal to 55% during screening.
- Participant has adequate acoustic windows, in the judgment of the core echo laboratory, to enable accurate transthoracic echocardiography (TTE) measurement of PD endpoints.
- Participant has QT interval with Fridericia Correction (QTcF) less than 450 msec.
- Participant has either a normal 12-lead ECG at Screening, including standard intervals, or one with abnormalities that are considered clinically insignificant by the investigator in consultation with MyoKardia.
Exclusion Criteria9
- Hypersensitivity to any of the components of the MYK-224 formulation or anaphylaxis to any drug, food, animal sting or other substance.
- Any structural abnormalities on screening TTE, in the judgment of the core cardiac laboratory.
- Participant has a history of clinically significant arrhythmia (including, but not limited to, any predominant cardiac rhythm other than normal sinus [including resting heart rate [HR] persistently greater than 100 bpm or less than 50 bpm [repeat measurements permitted to establish or exclude and HR less than 50 and greater than 45 may be included after consultation with the medical monitor] ) the presence of clinically relevant ventricular ectopy [frequent premature ventricular complexes, ventricular bigeminy, couplets or nonsustained ventricular tachycardia], or evidence of clinically important conduction abnormalities), LV systolic dysfunction, or coronary artery disease.
- Participant has a history of malignancy of any type, other than in situ cervical cancer more than 10 years prior to screening or surgically excised nonmelanoma skin cancers more than 2 years prior to Screening.
- Participant has a positive serologic test at Screening for infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).
- Participant has an active infection indicated clinically as determined by the Investigator.
- Participants has a positive test for alcohol or drugs of abuse at Screening or Day -1.
- Participant has used prescription medication within 28 days of Day 1 or over the- counter- medication (including herbal preparations and supplements) within 14 days of Day 1 except for the following exceptions: contraceptive medication is allowed; acetaminophen/paracetamol up to 2 g per day is allowed; and prescription medication may be allowed in this window with Investigator and Sponsor approval, as long as more than 5 half-lives have elapsed since last taking the medication before randomization and the medication is not expected to impact the safety of participants or study procedures.
- Participant has used or ingested alcohol, tobacco and nicotine-containing substances, grapefruit and grapefruit juice, Seville oranges, and quinine (eg, tonic water) within 7 days prior to check-in on Day -1.Seville oranges, and quinine (eg, tonic water) within 7 days prior to check-in on Day -1.
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Interventions
Study consists of single-ascending doses (SAD) and multiple ascending doses (MAD) of MYK-224 to healthy participants aged 18-45 years. This is a first in human (FIH) study, a sentinel dosing plan will be employed at each dose level. The first 2 healthy participants of each cohort will be dosed as sentinels. One of the sentinel healthy participants will be randomized to receive MYK-224 and the other will be randomized to receive placebo. Part A – SAD Cohorts This part will consist of a SAD design, where up to 6 cohorts of 8 healthy men or women will be randomized to MYK-224 or matching placebo in a 6:2 ratio. The starting dose of MYK-224 will be 1.5 mg and subsequent dose levels will be based on a review of the safety, PK and PD (including left ventricular ejection fraction, global longitudinal strain, and left ventricular fractional shortening) data from the previous dose level. The SRC will determine which cohort will participate in the FE portion of the study. That cohort will receive their dose twice in a cross-over fashion (once fasted, once fed); the 2 periods will be separated by a washout period of 35 days (or, after consultation with the Investigator, up to 42 days). Part B – MAD Cohorts This part will consist of a MAD design, where up to 6 cohorts of 8 healthy men or women will be randomized to MYK-224 or its placebo in a 6:2 ratio. This part will be initiated after satisfactory SRC review of safety data from at least 2 cohorts of healthy participants in Part A and SRC approval to initiate the MAD portion. The starting dose will be determined based on data obtained in Part A. Route of administration: Oral suspension Frequency/duration of dosing: SAD cohort: Single dose only; Food Effect -cohort Part 1: 1 Single dose, Part 2: 1 Single dose; MAD cohort: once daily Dose is being conducted under close supervision in a Phase I unit. Syringes containing MYK224 suspension are retained for drug accountability. fasting and fed conditions: In the fasting condition, participants are required to not consume food or liquid (except water) overnight for at least 8 hours prior to drug administration (i.e. pre-dose fast). Participants are then required to fast another four hours after the drug administration (i.e. post-dose fast). In the fed condition, participants are required to consume a high fat, high caloric breakfast containing 800 to 1,000 calories, with about 50% of calories from fat, prior to drug administration. Duration of the wash-out period between the fasted and fed conditions: 35 days after discharge from the CRU (or up to 42 days with approval from the PI) Part A (SAD): up to 64 days; Part A (FE): up to 121 days; Part B (MAD): up to 84 days Overall duration of treatment for part B: One administration of MYK-224 or placebo each day for 28 days; overall confinement period is 35 days with a follow-up visit between days 45 and 56. The starting dose of the MAD cohort is dependent on the data from the SAD cohorts.
Locations(1)
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ACTRN12621000423819