A phase 1 study in patients with Fukuyama-type congenital muscular dystrophy

JRCT ID: jRCT2031210252

Registered date:18/08/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Fukuyama-type congenital muscular dystrophy
• Date of first enrollment: 06/09/2021
• Target sample size: 12
• Study type: Interventional
• Intervention(s): This study consists of the following 4 cohorts. The study will start with cohort 1 and only D-mannitol will be administered once during the premedication phase, followed by 12 simultaneous doses of NS-035 and D-mannitol once weekly during the treatment phase. The dose of D-mannitol was fixed at 500 mg / kg in all cohorts, and NS-035 was gradually increased from cohort 1 to cohort 4 (1.6 mg/kg, 6.0 mg/kg, 20 mg/kg and 40 mg/kg, respectively).

Outcome(s)

Primary Outcome

Safety-related endpoints
Adverse events and side effects
Physical examination
Vital signs
Clinical examination
Immunological test
Electrocardiogram
Echocardiography
Ultrasonography (kidney, ureter, bladder)
Percutaneous arterial oxygen saturation (SpO2)
Balance of fluid intake and output

Secondary Outcome

Efficacy and pharmacokinetic related endpoints
Glycosylation rate of alpha-DG
Expression of glycosilated alpha-DG
Exon-trapping inhibition efficiency
Evaluation of gross motor function
Changes in blood CK value
Plasma concentration
Urinary concentration

Key inclusion & exclusion criteria

• Age minimum: >= 5age old
• Age maximum: <= 10age old
• Gender: Both

Include criteria

1) Patients with homozygous or complex heterozygous mutations in the fukutin gene and a definitive diagnosis of FCMD
2) Patients who do not have DNA polymorphism that may compromise double helix formation with NS-035, as judged by DNA sequencing of retrotransposon insertion mutations in the 3'untranslated region of the fukutin gene
3) Patients aged 5 to 10 at the time of consent
4) Patients whose legal guardian capable of providing informed consent has provided written informed consent upon thorough understanding of the study procedure. Efforts should be made so that the subjects themselves give voluntary assent after having been provided with an explanation according to their ability to understand.
5) Patients who are expected to survive until the end of this trial
6) Patients who have intact muscles allowing appropriate evaluation of the effect of the study drug (neither loss nor severe atrophy of the deltoid or the biceps brachii muscle)
7) Patients who can maintain a sitting position without assistance (FCMD motor function level (Ueda classification) is >=2)
8) Patients with QTc (based on Fridericia's correction) <450 msec on 12-lead ECG performed during the pre-observation period (patients with QTc <480 msec if bundle branch block is observed)

Exclude criteria

1) Patients with percutaneous arterial oxygen saturation (SpO2) <95%
2) Patients with Left ventricular ejection fraction (LVEF) <50% or fractional shortening (FS) <25% based on echocardiogram performed during the pre-observation period
3) Patients with a history of epilepsy who have had status epilepticus within the past year since the consent was obtained.
4) Patients who are continuously using a ventilator (NPPV can be used while sleeping)
5) Patients whose serum cystatin C exceeds the upper limit of the institutional reference value in the tests performed during the pre-observation period and is judged to be clinically variable
6) Patients undergoing gastric tube feeding
7) Patients who used systemic corticosteroids within 3 months before the start of study drug administration
8) Patients who underwent surgery within 3 months before the start of administration of the investigational drug and patients who are scheduled to undergo surgery after provisional registration until the end of the post-observation period
9) Patients with active or uncontrollable infections, cardiomyopathy, liver disease and kidney disease
10) Patients with acute intracranial hematoma on MRI examination performed during the pre-observation period
11) Patients with dehydration or electrolyte imbalance in the pre-observation period
12) Patients with renal dysfunction such as urinary retention or diabetic nephropathy
13) Patients with dysphagia
14) Patients who are positive for HBsAg, HCV antibody, HIV antibody or syphilis test
15) Patients with immunodeficiency or autoimmune disease
16) Patients who received other investigational drugs or study drugs in clinical studies within 3 months before the start of administration of the study drug
17) Patients with a history of severe drug hypersensitivity
18) Pregnant patients or potentially pregnant patients who do not agree to contraception during the trial period (including menarche during the trial period)
19) Patients who are judged by the investigator (or subinvestigator) to be inappropriate for this clinical trial for any reason

Related Information

• Primary Sponsor: Toda Tatsushi
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development