This study is designed to assess the long-term efficacy and clinical benefit of AT-007 in patients with CMT-SORD. This randomized, double-blind study will assess the effect of govorestat compared to placebo in patients with CMT-SORD for up to 36 months.
This international, multi-center, randomized, double-blinded, placebo-controlled, phase 3 study is designed to assess the efficacy and clinical benefit of long-term govorestat administration to patients with CMT-SORD utilizing functional, patient-reported, and clinical outcomes measures including the CMT-HI, 10MWRT, dorsiflexion, the CMT-FOM, and CMT-related lower extremity muscle MRI parameters along with the long-term effect of govorestat on whole blood sorbitol. Long-term safety of govorestat will also be evaluated. Patients (16 to 65 years old) with CMT-SORD will be stratified according to their sex (male vs female) and age before randomization in a 2:1 ratio to govorestat 20 mg/kg once daily (QD) or placebo. There will be a pre-planned Interim Analysis at 2 years (Month 24). If clinical benefit is determined to be met with the Interim Analysis, the study will end and not continue to 3 years. The study will be conducted at up to 16 sites worldwide. Approximately 155 subjects will be enrolled.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
155
Govorestat will be provided as a liquid suspension (200mg/mL) for weight-based administration and administered orally at 20 mg/kg QD (every 24 hours)
Placebo will also be provided as a matching liquid suspension to be taken orally QD
University of Iowa
Iowa City, Iowa, United States
Clinic for Special Children
Gordonville, Pennsylvania, United States
Sydney Childrens
Sydney, Australia
Charcot-Marie-Tooth, Health Index (CMT-HI) Total Score
The CMT-HI is a disease-specific, validated, patient-reported measure that is largely focused on functional items in addition to activities of daily living and emotional well-being. The CMT-HI was designed to assess specific impact of CMT disease and to remove redundancy.
Time frame: From enrollment to the end of treatment at 36 months
10-meter walk-run test (10MWRT)
The 10MWRT is a timed functional test used to measure walking or running speed over 10 meters by the study population
Time frame: From enrollment to the end of treatment at 36 months
Dorsiflexion
Maximum isometric dorsiflexion force measured in Newtons using a calibrated dynamometer in a standardized position; higher values indicate greater dorsiflexion strength.
Time frame: From enrollment to the end of treatment at 36 months
Charcot-Marie-Tooth, Health Index (CMT-HI) Sub-Domain Scores
The CMT-HI is a disease-specific, validated, patient-reported measure that is largely focused on functional items in addition to activities of daily living and emotional well-being. The CMT-HI was designed to assess specific impact of CMT disease and to remove redundancy. The CMT-HI has 18 sub-domains, each of which will be evaluated separately.
Time frame: From enrollment to the end of treatment at 36 months
Charcot Marie Tooth Functional Outcome Measure (CMT-FOM)
The CMT-FOM is a performance-based measure that assesses the functional ability of patients with CMT. There are 5 domains (strength, upper limb function, lower limb function, balance, and motility) that are assessed by 13 test items specifically selected to ensure functional/patient-relevance, reliability/validity, and responsiveness to change. Total and sub-domain scores of the CMT-FOM, will be evaluated to detect change over time.
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CHU La Timone
Marseille, France
Institut de Myologie
Paris, France
Uniklinik of the RWTH Aachen University
Aachen, Germany
Charité - Universitätsmedizin Berlin
Berlin, Germany
University Medicine Gottingen (UMG)
Göttingen, Germany
Carlo Besta Neurological Institute
Milan, Italy
Vall d'Hebron Institut de Recerca (VHIR)
Barcelona, Spain
...and 3 more locations
Time frame: From enrollment to the end of treatment at 36 months
Muscle Magnetic Resonance Imaging (MRI)
Patients will undergo MRI of their legs to evaluate the fat deposition and the muscle size, both CMT-related parameters of disease progression.
Time frame: From enrollment to the end of treatment at 36 months
Whole blood sorbitol levels
Patients with CMT-SORD develop extremely high sorbitol levels in cells and tissues, as aldose reductase converts glucose to sorbitol which then cannot be converted into fructose by SORD. Sorbitol is known to be toxic to many cell types. Prior studies have shown a correlation of sorbitol levels with different clinical outcomes in CMT-SORD. We will evaluate the effect of govorestat on whole blood sorbitol levels over time.
Time frame: From enrollment to the end of treatment at 36 months
Plasma drug concentration
Plasma drug concentration samples will be obtained pre-dose (within 60 minutes) and at 2, 4, 6, 8 hours after the dose.
Time frame: From enrollment through Month 3