Oral Ketone Body Supplementation in Patients With McArdle Disease (GSDV)

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.

Study Overview

• Status: Completed
• Conditions: McArdle Disease
• Intervention / Treatment: Dietary supplement: β-hydroxybuturate esters; Dietary supplement: 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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Copenhagen Neuromuscular Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Intervention sequence 1; Ketone drink first - Placebo drink secondly	Dietary supplement: β-hydroxybuturate esters; Oral dietary supplement product containing β-hydroxybuturate esters; Dietary supplement: Placebo drink; Oral placebo drink
PLACEBO_COMPARATOR: Intervention sequence 2; Placebo drink first - Ketone drink secondly	Dietary supplement: β-hydroxybuturate esters; Oral dietary supplement product containing β-hydroxybuturate esters; Dietary supplement: Placebo drink; Oral placebo drink

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate	Change between visit 1 and 2 in mean heart rate during constant load cycling exercise (40 minute submaximal cycle test)	30 minuts x 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ketone metabolism	Change between visit 1 and 2, measured with stable isotope technique during the constant load cycling test	150 minuts x 2
Carbohydrate metabolism	Change between visit 1 and 2, measured with stable isotope technique during the constant load cycling test	150 minuts x 2
Fat metabolism	Change between visit 1 and 2, measured with stable isotope technique during the constant load cycling test	150 minuts x 2
Indirect calorimetry	Changes in oxidation rates at visit 1 and visit 2, measured via indirect calorimetry before and during exercise	30 minuts x 2
Perceived exertion	Changes in perceived exertion beween visit 1 and 2 during the cycle test	30 minuts x 2
Blood ketone	Changes in ketone bodies in the blood between visit 1 and 2, measured at both before, during and at end exercise.	150 minuts x 2
Insulin	Insulin changes between visit 1 and 2 measured before, during and at end exercise.	30 minuts x 2
Metabolites	changes between visit 1 and 2	30 minuts x 2

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 6, 2019
• Primary Completion (ACTUAL): October 1, 2020
• Study Completion (ACTUAL): October 1, 2020

Study Registration Dates

• First Submitted: February 18, 2019
• First Submitted That Met QC Criteria: May 9, 2019
• First Posted (ACTUAL): May 10, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 6, 2020
• Last Update Submitted That Met QC Criteria: October 5, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type V
• Other Study ID Numbers: H-18033230.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No