Oral Ketone Body Supplementation in Patients With McArdle Disease

NCT ID: NCT03945370

Last Updated: 2020-10-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-06
• Study Completion Date: 2020-10-01

Brief Summary

McArdle disease, glycogen storage disease type V, is a rare metabolic disease. Affected individuals are unable to utilize sugar stored as glycogen in muscle.

Investigators hypothesize that ketones can be an alternative fuel substrate for skeletal muscle when muscle glycogenolysis is blocked as in McArdle disease.

In this study investigators will investigate the immediate effects of an oral supplementation of exogenous ketone bodies (poly-hydroxybuturate) on exercise capacity in patients with metabolic myopathies, compared with a placebo drink.

Detailed Description

McArdle disease, glycogen storage disease type V, is a rare metabolic disease caused by mutations in the PYGM gene resulting in absence of the enzyme muscle phosphorylase. Affected individuals are unable to utilize sugar stored as glycogen in muscle, leading to exercise intolerance, exercise-induced muscle pain, contractures and rhabdomyolysis, which may cause renal failure. Currently, there are no satisfactory treatment options for McArdle disease.

A key element of alleviating symptoms in McArdle disease is to provide alternative fuels for energy metabolism. Investigators hypothesize that ketones can be an alternative fuel substrate for skeletal muscle when muscle glycogenolysis is blocked as in McArdle disease.

Aim: To investigate the immediate effects of an oral supplementation of exogenous ketone bodies (poly-hydroxybuturate) on exercise capacity in patients with metabolic myopathies.

Supplement description: food supplement containing β-hydroxybuturate esters

Methods:

Study design: Placebo-controlled, single-blind, cross-over study. Inclusion: 5-8 patients with McArdle disease and 3-5 healthy controls.

Time table:

Subjects will meet to 2 test days. Subjects will be randomized using a 1:1 assignment ratio to receive either the keto-drink or placebo drink first. The oral supplement received will be blinded for the participants and the investigators. On each test day, subjects spend approximately 4 hours at the laboratory:

• Insertion of peripheral brachial venous catheters for extracting blood samples and stable isotope infusion and hydroxybutyrate infusion.
• Baseline blood sampling, medical examination, vital sign measurements, weight and height.
• Stable isotope infusion 2 hours before the cycling exercise test. Three stable isotope tracers [2,4-13C2]-D- β-hydroxybutyrate, [1,1,2,3,3-2H5]-glycerol and [6,6-2H2]-glucose solutions, are infused via a venous catheter until a steady-state is reached. The tracer infusions will continue during the cycling test. The tracers (all from Cambridge Isotope Laboratories, Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl) through a bacterial filter.
• One Ketone or placebo drink administration 30 minutes before the exercise test
• Subjects will perform a 40 minutes cycle exercise test at a constant load corresponding to 60-70% of their VO2max (found in a screening study). During the test, subjects wear a mask for continuous gas-exchange measurements and ECG electrodes to determine VO2 and heart rate during constant load cycling (VO2const and HRconst). Blood samples will be drawn 4 times before, every 10 minutes during exercise and after exercise. During the test participants will be asked to rate perceived exertion (RPE) on a Borg scale.

Conditions

McArdle Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Intervention sequence 1

Ketone drink first - Placebo drink secondly

Group Type: ACTIVE_COMPARATOR

β-hydroxybuturate esters

Intervention Type: DIETARY_SUPPLEMENT

Oral dietary supplement product containing β-hydroxybuturate esters

Placebo drink

Intervention Type: DIETARY_SUPPLEMENT

Oral placebo drink

Intervention sequence 2

Placebo drink first - Ketone drink secondly

Group Type: PLACEBO_COMPARATOR

β-hydroxybuturate esters

Intervention Type: DIETARY_SUPPLEMENT

Oral dietary supplement product containing β-hydroxybuturate esters

Placebo drink

Intervention Type: DIETARY_SUPPLEMENT

Oral placebo drink

Interventions

β-hydroxybuturate esters

Oral dietary supplement product containing β-hydroxybuturate esters

Intervention Type: DIETARY_SUPPLEMENT

Placebo drink

Oral placebo drink

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• Genetically confirmed McArdle disease or healthy control.
• Patient is willing and able to provide written informed consent prior to participation.
• Patient is ambulatory.

Exclusion Criteria

• Patient has any prior or current medical conditions that, in the judgment of the Investigator, would prevent the patient from safely participating in and/or completing all study requirements.
• Pregnancy or breastfeeding
• Patient does not have the cognitive capacity to understand/comprehend and complete all study assessments.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Nicoline Løkken

Principle investigator, MD, research fellow

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Copenhagen Neuromuscular Center

Copenhagen, , Denmark

Countries

Denmark

Other Identifiers

H-18033230.1

Identifier Type: -

Identifier Source: org_study_id