Investigator-Initiated Phase II Clinical Trial of MA-5 for Mitochondrial Disease
An Exploratory, Investigator-Initiated Phase II Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MA-5 in Patients with Mitochondrial Disease and Hearing Loss
Investigator-Initiated Phase II Clinical Trial of MA-5 for Mitochondrial Disease
An Exploratory, Investigator-Initiated Phase II Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MA-5 in Patients with Mitochondrial Disease and Hearing Loss
Murayama Kei
Juntendo University Hospital
3-1-3 Hongo Bunkyo-ku Tokyo Japan
+81-3-3813-3111
k.murayama.gf@juntendo.ac.jp
Fujimura Akiho
DOT WORDL CO.,LTD.
4F NBF COMODIO Shiodome 2-14-1, Higashi-shimbashi, Minato-ku, Tokyo, Japan
+81-3-3433-6060
MA-5-02_support@crodot.jp
Recruiting
Dec. 03, 2025
15
Interventional
randomized controlled trial
double blind
placebo control
parallel assignment
treatment purpose
1.Patients with mitochondrial disease who have hearing loss
2.Patients aged 16 years or older and 65 years or younger at the time of informed consent
3.Patients who have provided written informed consent of their own free will. However, if the patient is a minor, written informed consent must be obtained from a legally authorized representative of their own free will.
1.Patients with large tympanic membrane perforation, active middle ear disease, or a history of major middle ear surgery
2.Patients with evidence of or diagnosed with traumatic brain injury or central hearing loss
3.Patients with hearing loss caused by radiation therapy to the head and neck or by administration of platinum-containing agents or aminoglycoside antibiotics
4.Patients with hearing loss due to causes other than mitochondrial disease
5.Patients using a cochlear implant
6.Patients with severe hearing impairment (average hearing level 90 dB or higher)
7.Patients who have newly started or changed the dosage of taurine, water-soluble vitamins, or coenzyme Q10 within 12 weeks prior to informed consent
8.Patients requiring mechanical ventilation
9.Patients with status epilepticus or severe coma
10.Patients with concomitant sepsis
11.Patients with renal impairment (estimated glomerular filtration rate eGFR less than 30 mL per minute per 1.73 square meters)
12.Patients with hepatic impairment (aspartate aminotransferase AST or alanine aminotransferase ALT greater than three times the institutional upper limit of normal)
13.Patients with cardiac dysfunction (left ventricular ejection fraction LVEF 35 percent or less)
14.Patients with a history of clinically significant systemic autoimmune disease such as rheumatoid arthritis, Sjogrens syndrome, multiple sclerosis, or psoriasis
15.Patients with cognitive impairment for whom cognitive testing MMSE is deemed infeasible by the investigator
16.Patients who have participated in another clinical trial or investigational study within 12 weeks prior to informed consent. Participation in non-interventional studies is acceptable if completed before consent
17.Patients who are pregnant or breastfeeding, who may be pregnant, or who intend to become pregnant, or whose partner intends to become pregnant
18.Patients unable to use effective contraception such as condoms, intrauterine devices, or oral contraceptives appropriately from the date of consent through the end of the follow-up period
19.Patients with a history of severe drug hypersensitivity
20.Any other patients deemed inappropriate by the investigator
16age old over
65age old under
Both
Mitochondrial disease with hearing loss
The blinded investigational product (capsules) will be administered orally at a dose of 2 capsules once daily before breakfast for 12 weeks.
Placebo group: 2 placebo capsules
Low-dose group: 1 active capsule + 1 placebo capsule
High-dose group: 2 active capsules
1. Hearing-related endpoints
1. Hearing threshold measured by Auditory Brainstem Response (ABR)
2. Pure-tone audiometry at frequencies 125, 250, 500, 1000, 2000, 4000, and 8000 Hz and average hearing level
3. Output level of Distortion Product Otoacoustic Emissions (DPOAE)
4. Speech audiometry under quiet and noisy conditions including best speech discrimination score and speech reception threshold
5. Degree of hearing impairment categorized as mild, moderate, severe, or profound
6. Hearing Handicap Inventory for Adults (HHIA) Japanese version questionnaire score
7. 12-item version of the Speech Spatial and Qualities of Hearing Scale (SSQ12) questionnaire score
8. Tinnitus Handicap Inventory 12 (THI-12) questionnaire score
9. Overall improvement in hearing categorized as markedly improved, improved, slightly improved, unchanged, slightly worsened, worsened, or markedly worsened
10. Patient Global Impression (PGI) categorized as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse
Note: All hearing-related endpoints will be assessed for both ears
2. Mitochondrial disease-related endpoints
1. MMSE score
2. Six-minute walk distance with secondary measures including heart rate, dyspnea, fatigue, and peripheral oxygen saturation SpO2
3. Grip strength of both upper limbs
4. Frequency of stroke occurrence
5. Renal function including eGFR and serum creatinine
6. Glucose and insulin resistance including fasting blood glucose, fasting serum insulin, HOMA-IR, HbA1c, and HOMA-beta
7. Plasma concentrations of growth differentiation factor 15 GDF15, fibroblast growth factor 21 FGF21, lactate, pyruvate, and lactate to pyruvate ratio
8. Cardiac function including LVEF by echocardiography and cardiothoracic ratio CTR by X-ray
9. Mitochondrial disease severity score JMDRS
Blood sampling schedule
1.Week 0 Day 1: pre-dose and 2, 4, 6, 8, and 24 hours post-dose plus 10 minutes
2.Week 4 Day 29: pre-dose and 2, 4, 6, 8, and 24 hours post-dose plus 10 minutes
Urine collection schedule
3.Week 0 Day 1 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours post-dose
4.Week 4 Day 29 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours post-dose
Parameters
5.Plasma pharmacokinetic parameters including Cmax, Tmax, AUC, and t1/2
6.Plasma metabolite concentrations including oxidized, reduced, sulfate conjugate, glucuronide conjugate, and decarboxylated forms
7.Urinary excretion rate
8.Urinary metabolite concentrations including oxidized, reduced, sulfate conjugate, glucuronide conjugate, and decarboxylated forms and creatinine-corrected values
9.Additional sampling at Visit 6 Week 8 and Visit 7 Week 12 four hours post-dose plus or minus one hour
Parameters include plasma MA-5 concentration, plasma metabolite concentrations, urinary MA-5 concentration and creatinine-corrected value, and urinary metabolite concentrations and creatinine-corrected values
Blood sampling schedule
1.Week 0 Day 1: pre-dose and 2, 4, 6, 8, and 24 hours post-dose plus 10 minutes
2.Week 4 Day 29: pre-dose and 2, 4, 6, 8, and 24 hours post-dose plus 10 minutes
Urine collection schedule
1.Week 0 Day 1: 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours post-dose
2.Week 4 Day 29: 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours post-dose
Parameters
1.Plasma pharmacokinetic parameters including Cmax, Tmax, AUC, and t1/2
2.Plasma metabolite concentrations including oxidized, reduced, sulfate conjugate, glucuronide conjugate, and decarboxylated forms
3.Urinary excretion rate
4.Urinary metabolite concentrations including oxidized, reduced, sulfate conjugate, glucuronide conjugate, and decarboxylated forms and creatinine-corrected values
Additional sampling at Visit 6 Week 8 and Visit 7 Week 12 four hours post-dose plus or minus one hour
Parameters include plasma MA-5 concentration, plasma metabolite concentrations, urinary MA-5 concentration and creatinine-corrected value, and urinary metabolite concentrations and creatinine-corrected values
Safety Endpoints
1.Incidence of adverse events
2.Incidence of adverse events of special interest
3.Clinical laboratory tests including blood and urine tests
4.Vital signs including blood pressure, pulse rate, and body temperature
5. 12-lead electrocardiogram
Exploratory Endpoints
1.Ankle brachial index ABI and cardio ankle vascular index CAVI
