Modified Ketogenic Diet in Patients With McArdle Disease Part B

• ClinicalTrials.gov Identifier: NCT04044508
• Recruitment Status: Completed
• First Posted: August 5, 2019
• Last Update Posted: February 13, 2023
• Sponsor: Rigshospitalet, Denmark
• Collaborator: University College, London
• Information provided by (Responsible Party): Nicoline Løkken, Rigshospitalet, Denmark

Study Description

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 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).

Condition or disease	Intervention/treatment	Phase
McArdle Disease	Dietary Supplement: Ketocal 4:1 liquid Nutricia (intervention); Dietary Supplement: Fortini multifibre Nutrica (placebo)	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Randomized, blind, placebo-controlled, cross over study
• Masking: Double (Participant, Investigator)
• Masking Description: Disguise products (Oral supplements: Nutricia 'ketocal' (intervention) or Nutricia 'fortini' (placebo)
• Primary Purpose: Treatment
• Official Title: Odified Ketogenic Diet in Patients With McArdle Disease Part B - a Placebo-controlled, Cross-over Study
• Actual Study Start Date: August 3, 2019
• Actual Primary Completion Date: October 1, 2022
• Actual Study Completion Date: December 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in mean heart rate [ Time Frame: At Visit 1 (baseline), Visit 2 (4 weeks), Visit 3 (8 weeks), and Visit 4 (12 weeks) ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.).

Contacts and Locations

Locations

Denmark

Copenhagen Neuromuscular Center, Rigshospitalet

Copenhagen, Denmark

United Kingdom

National Hospital for Neurology and neurosurgery

London, United Kingdom

Sponsors and Collaborators

Rigshospitalet, Denmark

University College, London

More Information

• Responsible Party: Nicoline Løkken, MD, Research fellow, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT04044508
• Other Study ID Numbers: H-18013022-B
• First Posted: August 5, 2019
• Last Update Posted: February 13, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Glycogen Storage Disease Type V; Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases