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Trial registered on ANZCTR


Registration number
ACTRN12621000423819
Ethics application status
Approved
Date submitted
8/01/2020
Date registered
16/04/2021
Date last updated
16/04/2021
Date data sharing statement initially provided
16/04/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
To Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MYK-224 in Healthy Volunteers
Scientific title
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
Secondary ID [1] 300053 0
MYK-224-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertrophic Cardiomyopathy 315563 0
Condition category
Condition code
Cardiovascular 313858 313858 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 316322 0
Treatment: Drugs
Comparator / control treatment
Placebo suspension will be prepared with silicon dioxide and titanium dioxide
Control group
Placebo

Outcomes
Primary outcome [1] 322392 0
To asses the safety and tolerability of single and multiple doses of MYK-224 in healthy participants.

Outcome is assessed by any adverse events, Physical examination findings, vital signs, ECG parameters and clinical safety laboratory data.
Timepoint [1] 322392 0
Monitored daily through Screening Visit and 21 days after the last dose of study treatment.
Secondary outcome [1] 378316 0
To characterize PK of single and multiple doses of MYK-224 in healthy participants.

PK parameters will include (but are not limited to) Cmax, tmax, AUC,and t1/2. Additionally, the apparent t1/2z will be calculated.
method of assessment: serum assay and Urinalysis
Timepoint [1] 378316 0
SAD: Plasma PK-
PK samples on Day 1 pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 (Day 2), 48 (Day 3), 60 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6) and 144 hours (Day 7) post-dose, and at the EOS Visit
Urine Pk-
urine sample obtained within 4 hours pre-dose. Pooled postdose urine samples will be obtained for the following intervals: 0 through 8 hours; 8 hours, 1 minute through 24 hours; 24 hours, 1 minute through 48 hours; 48 hours, 1 minute through 72 hours; 72 hours, 1 minute through 96 hours; 96 hours, 1 minute through 120 hours; and 120 hours, 1 minute through 144 hours.

Food Effect Cohort
Part 1- Plasma PK-
PK samples on Day 1 pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 (Day 2), 48, 60 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6) and 144 hours (Day 7) post-dose, and at the EOS Visit.
Urine Pk-
urine sample obtained within 4 hours pre-dose. Pooled postdose urine samples will be obtained for the following intervals: 0 through 8 hours; 8 hours, 1 minute through 24 hours; 24 hours, 1 minute through 48 hours; 48 hours, 1 minute through 72 hours; 72 hours, 1 minute through 96 hours; 96 hours, 1 minute through 120 hours; 120 hours, and 1 minute through 144 hours.

MAD- Plasma PK-
PK samples on Day 1 pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours (pre-dose Day 2), 48 (pre-dose Day 3), 60 hours (Day 3), 72 hours (pre-dose Day 4), 96 hours (pre-dose Day 5), 168 hours (pre-dose Day 8), 240 hours (pre-dose Day 11), 312 hours (pre-dose Day 14), 384 hours (Day 17), 456 hours (Day 20), 492 hours (Day 23), 528 hours (Day 26), 552 hours (Day 27); at Day 28 pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours post-dose; on Days 29, 30, 31, 32, 33, 34, and 35 (same time as pre-dose on Day 28 +/- 20 minutes); and at the EOS Visit.
Urine Pk-
urine sample obtained within 4 hours pre-dose. Pooled Day 1 postdose urine samples will be obtained for the following intervals: 0 through 8 hours; 8 hours, 1 minute through 24 hours; 24 hours, 1 minute through 48 hours; 48 hours, 1 minute through 72 hours; pooled Day 28 postdose urine samples will be obtained for the following intervals: 0 through 8 hours; 8 hours, 1 minute through 24 hours; 24 hours.
Secondary outcome [2] 378317 0
To characterize PD of single and multiple doses of MYK-224 in healthy participants.

Parameters: TTE evaluations of LVEF, LVFS, LV stroke volume (LVSV), LVOT-velocity time integral (VTI), LV global longitudinal strain (GLS), Lateral e’, septal e’, E/e’, and E/A ratio will be PD assessments
Method of assessment: transthoracic echocardiogram
Timepoint [2] 378317 0
SAD Cohort
Screening visit, Day 1 (pre-dose and 1 and 3 hours), 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 144 hours (Day 7) post-dose, and at the EOS Visit

Food Effect
Day 1 (pre-dose and 1 and 3 hours), 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 144 hours (Day 7) post-dose, and at the EOS Visit

MAD Cohort
Screening, Day 1 (pre-dose and 3 hours); on the last day of dosing pre-dose and 3, 24, 48, 96, 144 hours after the last dose; pre-dose on visits Day 2, Day 5, Day 8, Day 11, Day 28-35 (EOS visit) (no specified time)

Eligibility
Key inclusion criteria
1. 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.
2. Participant is between the ages of 18 and 45 years, inclusive, at the screening visit.
3. 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.
4. 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.
5. Participant has documented LVEF greater than or equal to 55% during screening.
6. Participant has adequate acoustic windows, in the judgment of the core echo laboratory, to enable accurate transthoracic echocardiography (TTE) measurement of PD endpoints.
7. Participant has QT interval with Fridericia Correction (QTcF) less than 450 msec.
8. 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.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Hypersensitivity to any of the components of the MYK-224 formulation or anaphylaxis to any drug, food, animal sting or other substance.
2. Any structural abnormalities on screening TTE, in the judgment of the core cardiac laboratory.
3. 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.
4. 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.
5. Participant has a positive serologic test at Screening for infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).
6. Participant has an active infection indicated clinically as determined by the Investigator.
7. Participants has a positive test for alcohol or drugs of abuse at Screening or Day -1.
8. 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.
9. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
16/08/2019
Date of last participant enrolment
Anticipated
31/05/2021
Actual
Date of last data collection
Anticipated
30/06/2021
Actual
Sample size
Target
112
Accrual to date
24
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17433 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 31162 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304505 0
Commercial sector/Industry
Name [1] 304505 0
MyoKardia, Inc.
Country [1] 304505 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
MyoKardia, Inc.
Address
1000 Sierra Point Parkway Brisbane, CA 94005
Country
United States of America
Secondary sponsor category [1] 304773 0
None
Name [1] 304773 0
Address [1] 304773 0
Country [1] 304773 0
Other collaborator category [1] 281121 0
Commercial sector/Industry
Name [1] 281121 0
Novotech (Australia) Pty Limited
Address [1] 281121 0
Level 2, 235 Pyrmont Street, Pyrmont NSW 2009, Australia
Country [1] 281121 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304936 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 304936 0
55 Commercial Rd, Melbourne VIC 3004, Australia
Ethics committee country [1] 304936 0
Australia
Date submitted for ethics approval [1] 304936 0
20/05/2019
Approval date [1] 304936 0
17/07/2019
Ethics approval number [1] 304936 0

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98690 0
Dr Ben Snyder
Address 98690 0
Nucleus Network Pty Ltd, Level 5, Burnet Tower, AMREP Precinct, 89 Commercial Road Melbourne, VIC 3004
Country 98690 0
Australia
Phone 98690 0
+61 3 8593 9838
Fax 98690 0
Email 98690 0
[email protected]
Contact person for public queries
Name 98691 0
Mr Benny Luu
Address 98691 0
MyoKardia, Inc.
Address: 1000 Sierra Point Parkway Brisbane, CA 94005
Country 98691 0
United States of America
Phone 98691 0
+1 6507410900
Fax 98691 0
Email 98691 0
[email protected]
Contact person for scientific queries
Name 98692 0
Mr Benny Luu
Address 98692 0
MyoKardia, Inc.
Address: 1000 Sierra Point Parkway Brisbane, CA 94005
Country 98692 0
United States of America
Phone 98692 0
+1 6507410900
Fax 98692 0
Email 98692 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.