Low Protein Diet in Patients With Collagen VI Related Myopathies

Study Overview
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Brief Summary
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This is a 2 stage exploratory study with a 3-month observational phase on the natural course, followed by a 12-month, open-label, non-comparative, single-arm, phase II pilot study on the efficacy, safety and tolerability of a low-protein diet (LPD) in 8 adult patients with Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). Objective of this trial is to test the effect of a normocaloric LPD to reactivate autophagy in BM/UCMD patients. The primary end point of the study will be the change in muscle biopsy of Beclin 1, a marker of autophagy, at 1 year of LPD treatment when compared to baseline. The rationale rests on our discoveries that (i) mitochondrial dysfunction mediated by inappropriate opening of the PTP plays a key role in collagen VI myopathies; (ii) defective autophagy with impaired removal of defective mitochondria amplifies the defect; and (iii) reactivation of autophagy with a low-protein diet or treatment with cyclosporine A, the mitochondrial PTP inhibitor, cured Co6a1-/- mice, hinting at a common target among all beneficial treatments - namely autophagy. Specific aims of this project are to (i) study the modifications of clinical, nutritional and laboratory parameters in a cohort of patients with BM/UCMD during a 3-month observational period before starting the LPD treatment; (ii) assess the effect of a normocaloric LPD in correcting defective autophagy in muscle of patients; (iii) test if new non-invasive biomarkers of activation of autophagy examined in the blood are mirroring the effect of LPD in the muscle biopsy; (iv) assess the clinical efficacy and safety of the LPD with an innovative combination of complementary measures of the nutritional status in patients. The anticipated output is defining and validating a therapeutic nutritional approach in autophagy upregulation for BM/UCMD.

Official Title
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Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies

Conditions
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Bethlem Myopathy, Ullrich Congenital Muscular Dystrophy

Intervention / Treatment
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* Other: Low protein diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged ≥18 years. Women of childbearing age must have a negative pregnancy test and must use adequate contraception during the study. Clinical and molecular diagnosis of Bethlem myopathy or Ullrich congenital muscular dystrophy. No previous treatment with CsA within 6 months prior to the start of the study. Willing and able to adhere to the study visit schedule and other protocol requirements. Written informed consent signed. Exclusion Criteria: Current or history of liver or renal disease. Pregnant or breast-feeding women. Any serious internal medicine condition interfering with the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All patients on a low protein diet<br> | Other: Low protein diet<br>* Patients will receive a diet with 0.6-0.8 grams of protein/kilogram body weight/day for one year. Bread, biscuits and pasta will be in part substituted with aproteic food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reactivation of autophagy measured as a change in Beclin 1 as a marker of autophagy in muscle biopsy from baseline (Day 1) to Day 365 |  | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety of a LPD in patients with BM/UCMD . Nutritional parameters . Muscle mass . Muscle strength |  | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bethlem myopathy, Ullrich congenital muscular dystrophy, Low protein diet, Autophagy, Pilot clinical trial