Low Protein Diet in Patients With Collagen VI Related Myopathies

Bethlem Myopathy Clinical Trial

— LPD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01438788
• Other study ID #: IOR-0018156
• Status: Completed
• Phase: Phase 2
• First received: September 21, 2011
• Last updated: October 28, 2016
• Start date: October 2011
• Est. completion date: September 2013

Study information

• Verified date: October 2016
• Source: Istituto Ortopedico Rizzoli
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Institute of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: September 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bethlem Myopathy
• Muscular Diseases
• Muscular Dystrophies
• Sclerosis
• Ullrich Congenital Muscular Dystrophy

Intervention

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.

Locations

Country	Name	City	State
Italy	Istituto Ortopedico Rizzoli	Bologna

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Ortopedico Rizzoli

Country where clinical trial is conducted

Italy, 

References & Publications (2)

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 p — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Assess the safety of a LPD in patients with BM/UCMD . Nutritional parameters . Muscle mass . Muscle strength		one year	Yes