Low Protein Diet in Patients With Collagen VI Related Myopathies

NCT ID: NCT01438788

Last Updated: 2016-10-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2013-09-30

Brief Summary

• 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.

Conditions

Bethlem Myopathy; Ullrich Congenital Muscular Dystrophy

Keywords

Bethlem myopathy; Ullrich congenital muscular dystrophy; Low protein diet; Autophagy; Pilot clinical trial

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

All patients on a low protein diet

Group Type: EXPERIMENTAL

Low protein diet

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Istituto Ortopedico Rizzoli

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Luciano Merlini, MD

Role: PRINCIPAL_INVESTIGATOR

Istituto Ortopedico Rizzoli, Bologna, Italy

Locations

Istituto Ortopedico Rizzoli

Bologna, , Italy

Countries

Italy

References

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.

Reference Type: BACKGROUND

PMID: 21037586 (View on PubMed)

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.

Reference Type: RESULT

PMID: 27656840 (View on PubMed)

Other Identifiers

IOR-0018156

Identifier Type: -

Identifier Source: org_study_id