Modified Ketogenic Diet in Patients With McArdle Disease Part B

Odified Ketogenic Diet in Patients With McArdle Disease Part B - a Placebo-controlled, Cross-over Study

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 a modified ketogenic diet could be a potential treatment option, by providing ketones as alternative fuel substrates for working muscle.

This blinded, placebo-controlled, cross-over study will investigate the potential effects of an optimal modified ketogenic diet found in part A (75% fat, 15%protein, 10%carbohydrates) in patients with McArdle disease compared with a healthy balanced placebo diet (>100grams of carbohydrates per day).

Study Overview

• Status: Completed
• Conditions: McArdle Disease
• Intervention / Treatment: Dietary supplement: Ketocal 4:1 liquid Nutricia (intervention); Dietary supplement: Fortini multifibre Nutrica (placebo)

Detailed Description

A blinded randomized, placebo-controlled, cross-over study to investigate the effects of a modified ketogenic diet in patients with McArdle disease.

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. Currently, there are no satisfactory treatment options for McArdle disease. Ketones are feasible fuel alternatives to muscle glycogen when muscle glycogenolysis is blocked as in McArdle disease. A key element of alleviating symptoms in McArdle disease is to provide alternative fuels for energy metabolism. Ketosis can potentially provide alternative fuel substrates by provision of endogenous ketone bodies (KBs) which are desirable fuels for skeletal muscle and brain. Ketosis can be reached by fasting and can be induced by adhering to a modified ketogenic diet, which entails a high-fat, low-carbohydrate diet, which simulates the metabolic effects of fasting.

The study design is a placebo-controlled, blind, cross over design. The study will be carried out at two sites: CNMC (Copenhagen), NHNN (London). Subjects will be randomized 1:1 to receive either a modified ketogenic diet (75% fat, 15%protein, 10% carbohydrates) or a placebo diet (>100grams of carbohydrates per day) first. Subjects will follow the diet for 4 weeks, followed by 2-4 weeks wash-out, followed by 4 weeks on the opposite diet. During the 10-12 weeks trial period, subjects will visit the trial site in London on five occasions. Effects of the diet will be evaluated by improvement in exercise capacity during submaximal exercise test on a cycle ergometer. Subjective improvements will be evaluated by questionnaires and a dietary diary.

If the diet improves exercise capacity, it will provide a safe and cheap treatment option that may lead to reduced risk of muscle injury and enhance quality of life in patients with McArdle disease.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Copenhagen Neuromuscular Center, Rigshospitalet
• United Kingdom
  • London, United Kingdom
    • National Hospital For Neurology and Neurosurgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Genetically confirmed GSDV
• Patient is willing and able to provide written informed consent prior to participation.
• Patient is ambulatory.
• Women in fertile age must be willing to practice the following medically acceptable methods of birth control

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
• Patients with porphyria or disorders of fat metabolism (primary carnitine deficiency, carnitine palmitoyltransferase I or II, β-oxidation defects etc.).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Interventional diet; A modified ketogenic diet (with the composition found in the pilot study, 75%fat, 15% protein, 10% carbohydrates)	Dietary supplement: Ketocal 4:1 liquid Nutricia (intervention); Modified ketogenic diet
PLACEBO_COMPARATOR: Placebo diet; A placebo diet (over 100 g of carbohydrates per day)	Dietary supplement: Fortini multifibre Nutrica (placebo); Placebo diet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean heart rate	Change in mean heart rate (bpm) during constant load cycling exercise (30 minute submaximal cycle test). Heart rate will be measured every minute during the cycle test at all visits.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compliance	Daily dietary diary	up 12 weeks
Change in Indirect calorimetry	Oxidation rates measured via indirect calorimetry during constant load cycling Measured at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in self-rated daily function scores	Modified SF-36 questionnaire	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in self-rated fatigue	Fatigue Severity Scale score	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in blood ketones	Ketone bodies in the blood (hydroxybutyrate+acetoacetate umol/L).	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in perceived exertion	Borg scale (scale from 6-20). During the constant load cyclinging test, subjects will be asked every minute during.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in ammonia	Blood Ammonia (umol/L). Will be measured 5 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in insulin	Blood Insulin (pmol/l). Will be measured 6 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in Adrenalin	Blood Adrenalin (pg/mL) Will be measured 6 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in glucagon	Blood Glucagon (pmol/L). Will be measured 4 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in maximal oxygen capacity	(VO2max, mL oxgen per minute) after the 30 minutes submaximal exercise test, the workload will be increased in a step vise manner to maximum.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in maximal work load	Work load (watts) after the 30 minutes submaximal exercise test, the workload will be increased in a step vise manner to maximum.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in free fatty acids	Blood Free fatty acids (umol/L). Will be measured 6 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in lactate	Blood Lactate (mM). Will be measured 6 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)
Change in glucose	Blood glucose (mM). Will be measured 6 times during the cycle test at visit 1-4.	At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks)

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: University College, London

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 3, 2019
• Primary Completion (ACTUAL): October 1, 2022
• Study Completion (ACTUAL): December 1, 2022

Study Registration Dates

• First Submitted: December 12, 2018
• First Submitted That Met QC Criteria: August 2, 2019
• First Posted (ACTUAL): August 5, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 10, 2023
• Last Verified: February 1, 2023

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-18013022-B

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