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Physician-Initiated Phase I Study of MA-5 for the Treatment of Mitochondrial Disease
-A Phase I Study of MA-5 for the Treatment of Mitochondrial Disease in Healthy Adults

MA-5 Phase I study

58

The clinical trial involved healthy adult males, with 32 participants in Part A and 26 in Part B. The mean age (standard deviation) was 30.4 (7.44) in Part A and 33.1 (7.64) in Part B. In both Part A and B, 30 subjects (93.8%) and 25 subjects (96.2%), respectively, had no medical history.

In this study, the initial subject for Part A-1 was enrolled on January 18, 2022. Subsequent enrollments proceeded through Part A-2, A-3, A-4, and Parts B-1, B-2, B-3, culminating in a total of 58 subjects by June 13, 2023. The follow-up concluded on July 25, 2023, with the final analysis completed.

A safety evaluation was conducted on the 58 subjects who received at least one dose of the investigational drug, yielding the following conclusions: Adverse events occurred as follows: 1 event in 1 subject in Part A-2, 1 event in 1 subject in Part A-4, 1 event in 1 subject in Part B-2, 4 events in 3 subjects in Part B-3, and 1 event in 1 subject in Part B-placebo, all of which were graded as 1. No side effects were observed.

Primary Endpoints: 1. Safety Evaluation: The incidence of adverse events was 12.1% (7/58 subjects), with no side effects observed. There were no serious adverse events, nor were there any adverse events leading to discontinuation. 2. Pharmacokinetic Evaluation: Pharmacokinetic assessments were conducted on the population designated for pharmacokinetic evaluation. The plasma parameters demonstrated a dose-dependent increase. No significant changes were observed in any parameters following 7 days of repeated dosing compared to the initial dose, indicating no impact from repeated dosing. The pharmacokinetics of the investigational drug were considered to be linear, although the urinary excretion rate was not dose-dependent. Secondary Endpoints: 1. Safety Evaluation: Various markers related to tubular injury were measured, but no adverse events related to tubular injury were observed. 2. Pharmacokinetic Evaluation: Concentrations of MA-5 and its ten metabolites were measured. The primary metabolites in plasma samples were the unchanged form MA-5 and its metabolites, while the primary metabolites in urine samples were MA-5 metabolites and the unchanged form. 3. Exploratory Endpoints: An analysis was conducted on the population designated for exploratory endpoint evaluation.

The investigational drug was considered to be safe and well tolerated, and there were no events of concern in the development of the drug as a treatment for mitochondrial disease, and no new events to be noted.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210495

Sambe Takehiko

Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics

6-11-11 Kitakarasuyama Setagayaku Tokyo

t-sambe@med.showa-u.ac.jp

Yamazaki Taigi

Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics

6-11-11 Kitakarasuyama Setagayaku Tokyo

+81-3-3300-5247

t.yamazaki@cmed.showa-u.ac.jp

Complete

Dec. 17, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

other

1) Gender: Male (Japanese)
2) Age: 20 years old or older but less than 45 years old (at the time of obtaining consent)
3) BMI at the time of screening examination: 18.5 to 25.0 kg/m2 (rounded to the first decimal place)
4) Those who are judged to be healthy by the investigator or others as a result of investigations, observations, and tests (clinical examination, 12-lead electrocardiography, etc.) conducted at the time of screening and hospitalization
5) Patients who have received sufficient explanation of the contents of the clinical trial from the investigator, understand the purpose of the clinical trial, voluntarily to participate in the clinical trial, and are able to provide written consent of their own free will to participate in the clinical trial, and who are judged to be appropriate for participation in the clinical trial by the investigator.

1) Those who have used the drug within 7 days prior to the first dose of the investigational drug
2) Patients who have a primary disease that affects absorption, metabolism, or excretion of drugs in the gastrointestinal tract, liver, or kidneys, or have a history of previous disease or surgery
3) Patients with cardiovascular disease, hypotension, or suspected cardiovascular disease
4) Patients with convulsive diseases such as epilepsy or a history of such diseases
5) Those who are allergic to drugs or have a history of such allergy
6) Persons with a predisposition to allergy who are judged inappropriate by the investigator
7) Patients who have a QTc of 450 msec or more or a QTc interval that cannot be measured on a resting 12-lead ECG at screening or prior to Day 1 administration
8) Patients with risk factors for torsades de pointes. 8) Patients with uncontrolled hypokalemia or hypomagnesemia, history of heart failure, history of clinically significant bradycardia/symptomatic bradycardia, or QT prolongation syndrome, or family history of sudden unexpected death or congenital QT prolongation syndrome.
9) Patients with alcohol or drug dependence or a history of such dependence
10) Patients who participated in a clinical trial and received medication within 16 weeks prior to the administration of the investigational drug (except for patch test within 4 weeks prior to the administration of the investigational drug)
11) Subjects who have had more than 400 mL of whole blood drawn within 12 weeks prior to the administration of the investigational drug, or more than 200 mL of whole blood drawn within 4 weeks prior to the administration of the investigational drug, or who have donated blood components within 2 weeks prior to the administration of the investigational drug.
12) Patients who have tested positive for HBs antigen, HCV antibody, HIV antigen or antibody, or syphilis qualitative test (TP antibody method, RPR method) in the clinical examination conducted at the time of screening.
13) Those who are not willing to use appropriate contraception during the clinical trial.
14) Those who are judged inappropriate to participate in the clinical trial by the investigator, etc., based on the results of investigations, observations, tests, etc. at the time of screening and hospitalization.

Male

None (for healthy volunteers)

The dosage and administration period for each step.

-Part A-
Cohort 1: A single fasting dose of 5 mg MA-5 or 1 placebo capsule.
Cohort 2: MA-5 10 mg or placebo, 1 capsule, given as a single dose on an empty stomach.
Cohort 3: 10 mg MA-5 or 2 capsules of placebo given as a single dose on an empty stomach.
Cohort 4: 10 mg of MA-5 or 4 capsules of placebo given as a single dose on an empty stomach.

-Part B-
Cohort 1: MA-5 10 mg or placebo 1 capsule given repeatedly for 7 days on an empty stomach.
Cohort 2: MA-5 10 mg or placebo 2 capsules in a fasting state for 7 days.
Cohort 3: MA-5 10 mg or placebo 4 capsules given fasting for 7 days.

Healthy volunteers

1) Evaluation of safety
The safety and tolerability of single or repeated doses of MA-5 should be evaluated by subjective symptoms, other findings, physiological tests, and clinical examinations.
2) Evaluation of pharmacokinetics
The pharmacokinetics of single or repeated administration of MA-5 should be investigated based on MA-5 concentrations in plasma and urine, pharmacokinetic parameters in plasma, and urinary excretion rate.

1) Safety evaluation
Measure and evaluate markers for tubular disorders (NAG, b2-microglobulin, L-FABP, NGAL).
2) Evaluation of pharmacokinetics
The concentration of MA-5 enantiomer and metabolites (oxidized form, sulfate conjugate, glucuronide conjugate) in plasma and urine will be measured and evaluated.
3) Exploratory endpoints
The following exploratory endpoints of single or repeated administration of MA-5 will be evaluated for the Phase II study.
- GDF-15 concentration in blood
- Blood lactate/pyruvate concentration
- Muscle strength (6-minute walk, grip strength of both upper limbs)

+81-3-3300-5247

Aug. 23, 2021

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