Pharmacological Treatment of a Rare Genetic Disease: N-acetylcysteine in Myopathy Associated Selenoprotein N-related Myopathy (SEPN1-RM)

Study Overview
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Brief Summary
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The objective of this study is to determine whether the administration of N-acetylcysteine (NAC) improves oxidative stress. To determine this, the study will assess the impact of oral treatment on the balance between reduced and oxidized form of glutathione in erythrocytes of peripheral blood.

Detailed Description
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A prospective, monocentric, crossover, double-blind, placebo-controlled study. For each patient the study will be divided in two treatment periods of 6 months separated by a 2 month washout period. 24 patients will be randomized in two groups, one group treated first with placebo during 6 months, followed by 6 months; the second group treated in the reverse sequence, then placebo. 24 healthy volunteers will also be enrolled in the study in order to collect reference values for biochemical biomarkers. D-1: run-up visit, patients will be hospitalized in intensive care unit to collect information about diet, physical activity and smoking. During follow-up visits: we will analyze the impact of treatment with N-acetylcysteine (NAC) on: Biomarkers of redox homeostasis, Measures of locomotor functional capacity, Body mass composition, Respiratory functional abilities. Biomarkers that reflect the status of antioxidant defense mechanisms, parameters that reflect the cell damage to oxidative stress, the markers of inflammation and metabolic alterations induced by oxidative stress, body composition in terms of lean mass and fat mass, the motor functional abilities, respiratory function capabilities, will be compare before and after treatment. These measures could complement the information on the status of oxidative stress and clarify the effects of N-acetylcysteine (NAC) on the evolution of the disease in these patients. The correlation of biomarker measurements in muscle and systemic tissues will be checked. Furthermore we will collect information about the lifestyle through standardized questionnaires that include diet, smoking, and habitual physical activity. Environmental factors and lifestyle can influence the balance oxidant / antioxidant patients and contribute to the variability of the clinical severity of the disease.

Official Title
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Pharmacological Treatment of a Rare Genetic Disease: Pilot Trial Phase II-III With N-acetylcysteine in Myopathy Associated SEPN1-RM (Selenoprotein N-related Myopathy)

Conditions
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Selenoprotein N-related Myopathy

Intervention / Treatment
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* Drug: N-Acetylcysteine followed by Placebo
* Drug: Placebo followed by N-Acetylcysteine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For patients: Patient >18 and <60 years old Patients with Selenoprotein N-related myopathy with homozygous or compound heterozygous mutations in the gene SEPN1-RM Informed written consent Patients capable of being followed up throughout the duration of the study Patient trained in the use of cough assist Patients having an health insurance Patient accepting to commit not to introduce major changes in diet and lifestyle during the study period For healthy volunteers: volunteers >18 and <60 years old Informed written consent Health insurance Exclusion Criteria: For patients: Pregnancy Intolerance to N-acetylcysteine (NAC), galactose or fructose; malabsorption glucose or galactose; lactase deficiency Consumption of synthetic vitamins, NAC and other antioxidants within 3 months prior to inclusion Treatment with corticosteroids or non-steroidal anti-inflammatory from time to time in the 4 weeks preceding the inclusion or for more than 3 days between 12 and 4 weeks before inclusion Planned surgery within 3 months before inclusion or during the inclusion period Intercurrent or existing illnesses such as chronic infectious diseases (HIV, hepatitis, etc.), asthma, malignant tumor pathology, Hematological Pathology Expected survival less than 14 months Inability to understand the instructions or the implications of the Protocol For healthy volunteers: Pregnancy Consumption of synthetic vitamins, NAC and other antioxidants within 3 months prior to inclusion Treatment with corticosteroids or non-steroidal anti-inflammatory from time to time in the 4 weeks preceding the inclusion or for more than 3 days between 12 and 4 weeks before inclusion Planned surgery within 3 months before inclusion or during the inclusion period Intercurrent or existing illnesses such as chronic infectious diseases (HIV, hepatitis, etc.), asthma, malignant tumor pathology, Hematological Pathology Inability to understand the instructions or the implications of the Protocol Bleeding disorders or other bleeding risks or risk of infection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo followed by N-Acetylcysteine<br>Arm receiving placebo for 6 months, then N-Acetylcysteine (NAC) for 6 months. | Drug: Placebo followed by N-Acetylcysteine<br>* Arm receiving placebo for 6 months then N-acetylcysteine (NAC) for 6 months. Treatment periods are separated by a 2 month washout.<br>|
| Experimental: N-Acetylcysteine followed by Placebo<br>Arm receiving N-Acetylcysteine (NAC) for 6 months and then placebo for 6 months. | Drug: N-Acetylcysteine followed by Placebo<br>* Arm receiving N-Acetylcysteine (NAC) for 6 months and then placebo for 6 months. Treatment periods are separated by a 2 month washout.<br>|
| No Intervention: Healthy volunteers<br>The purpose of this group is to collect reference values for biochemical markers. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of reduced glutathione and oxidized glutathione in blood erythrocytes. |  | 6 months in each period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| measure of health status according The 36-Item Short Form Health Survey (SF36) |  | 6 months in each crossover period | 
| Evaluate the impact of fatigue according the Fatigue Severity Scale (FSS) |  | 6 months in each crossover period | 
| Measurement of biomarkers in blood samples, muscle and fibroblasts |  | 6 months in each crossover period | 
| Measure of Activity Limitation (Activlim test) |  | 6 months in each crossover period | 
| Running speed measured by the test of 10 m |  | 6 months in each crossover period | 
| Measures of motor function according a Motor Function Measure scale (MFM ) |  | 6 months in each crossover period | 
| Muscular endurance is measured by the test of 2 minutes walk |  | 6 months in each crossover period | 
| Measurement of the maximum voluntary contraction of the quadriceps |  | 6 months in each crossover period | 
| The measurement of the endurance of the quadriceps |  | 6 months in each crossover period | 
| Assessment of dyspnea according Borg scale |  | 6 months in each crossover period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-ACETYLCYSTEINE, Selenoprotein N-related myopathy, biomarkers, washout