Low Protein Diet in Patients With Collagen VI Related Myopathies (LPD)

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

• 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.

Study Overview

• Status: Completed
• Conditions: Bethlem Myopathy; Ullrich Congenital Muscular Dystrophy
• Intervention / Treatment: Other: Low protein diet

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40136
    • Istituto Ortopedico Rizzoli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All patients on a low protein diet	Other: Low protein diet; 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.

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Istituto Ortopedico Rizzoli
• Investigators: Principal Investigator: Luciano Merlini, MD, Istituto Ortopedico Rizzoli, Bologna, Italy

Publications and helpful links

General Publications

• Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med. 2010 Nov;16(11):1313-20. doi: 10.1038/nm.2247. Epub 2010 Oct 31.
• Castagnaro S, Pellegrini C, Pellegrini M, Chrisam M, Sabatelli P, Toni S, Grumati P, Ripamonti C, Pratelli L, Maraldi NM, Cocchi D, Righi V, Faldini C, Sandri M, Bonaldo P, Merlini L. Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial. Autophagy. 2016 Dec;12(12):2484-2495. doi: 10.1080/15548627.2016.1231279. Epub 2016 Sep 22.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: September 21, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (Estimate): September 22, 2011

Study Record Updates

• Last Update Posted (Estimate): October 31, 2016
• Last Update Submitted That Met QC Criteria: October 28, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Autophagy; Low protein diet; Bethlem myopathy; Ullrich congenital muscular dystrophy; Pilot clinical trial
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Sclerosis; Muscular Dystrophies; Muscular Diseases
• Other Study ID Numbers: IOR-0018156