Energy Supplements to Improve Exercise Tolerance in Metabolic Myopathies

Patients suffering from the metabolic myopathy Glycogen Storage Disease type IIIa (GSDIIIa) have a problem releasing sugar stored in cells that is needed for energy production. This causes several systemic impairments, but only recently have the exercise-related symptoms in the muscles been examined. A previous study showed signs that intravenous infusion of glucose relieves some of these symptoms. The purpose of this study is to investigate in a randomized and placebo-controlled fashion whether oral ingestion of sugar can alleviate muscular symptoms in patients with GSDIIIa.

Study Overview

• Status: Completed
• Conditions: Glycogen Storage Disease Type III
• Intervention / Treatment: Dietary supplement: FAXE Kondi; Dietary supplement: Faxe Kondi Free

Detailed Description

It has recently been documented how patients with GSDIIIa have a moderate to severely reduced exercise capacity, and that exercise induces muscle pain and cramps. These symptoms are caused by the inability to mobilize skeletal muscle glycogen and are most likely the consequence of a severe energy deficiency within muscles. The study changed the phenotype of GSDIIIa, to include exercise-induced symptoms, which is a typical presentation in other metabolic myopathies. It also documented that exercise capacity was significantly improved while exercise-induced muscular symptoms were relieved by an intravenous glucose infusion. Based on these findings, this study wishes to investigate if oral ingestion of sucrose has the same effects on work capacity on a larger number of patients, in a randomized, placebo-controlled, cross-over setup. Ingestion of sucrose has the potential to be an effective, cheap and easily accessible dietary treatment of muscular symptoms in GSDIIIa.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Astrid E Buch, BSc Medicine; Phone Number: +45 35 45 61 35; Email: astrid.emilie.buch.02@regionh.dk
• Study Contact Backup: Name: Nicolai Preisler, MD; Phone Number: +45 35 45 61 26; Email: nicolai.preisler@regionh.dk

Study Locations

• Denmark
  • Region Hovedstaden
    • Copenhagen, Region Hovedstaden, Denmark, 2100
      • Copenhagen Neuromuscular Center, department 3342, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Genetically and/or biochemically verified GSDIIIa.
• 18 years or older.

Exclusion Criteria:

• Clinically significant cardiac or pulmonary disease.
• Pregnancy or lactation.
• Severe mental disorders or participants that are in other ways unable to understand the purpose of the trials.
• Subjects where the investigator assess that it is not possible or very difficult to place an intravenous catheters.
• Other conditions of the joints or skeletal muscle such as arthritis or sprains. If the condition is expected to resolve before the study inclusion period is stopped, the subject may be included at a later time.
• Moderate to severe muscle weakness, where the participants are not expected to complete 10 minutes of cycle-ergometry exercise at 70 % of VO2peak.
• Verified diabetes.
• Participation in other clinical trials that may interfere with the results.
• Medications that may interfere with the results or increase the risk of bleeding.
• Blood-clotting or bleeding disorders.
• Blood donation one month or less prior to inclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FAXE Kondi - a sugary soft-drink; 100 ml FAXE Kondi (10 grams of carbohydrates per 100 ml) is ingested every ten minutes during exercise plus 400 ml before exercise start.	Dietary supplement: FAXE Kondi; Sucrose and glucose containing softdrink
Placebo Comparator: FAXE Kondi Free - a sugarfree soft-drink; 100 ml FAXE Kondi Free (0 grams of carbohydrates per 100 ml) is ingested every ten minutes during exercise plus 400 ml before exercise start.	Dietary supplement: Faxe Kondi Free; Diet softdrink with artificial sweeteners aspartame and acesulfame potassium. Both sweeteners are approved for use as food additives in the European Union and by the FDA. Aspartame metabolism is well understood and normal doses does not affect plasma concentrations of lipids, amino acids, glucose levels, key regulatory hormones or skeletal muscle metabolism. Acesulfame Potassium is not metabolized in humans and is excreted as the parent compound in urine. Since the two artificial sweeteners does not affect skeletal muscle metabolism or blood glucose levels, and both compounds have a well documented safety profiles, FAXE Kondi Free is considered to be an ideal placebo soft drink in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximal work capacity	Area Under the Curve (AUC) = resistance times duration of workout	After up to 1 hour of bicycling on the 2nd and 4th day.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak oxygen consumption	(VO2peak)	After up to 1 hour of cycling on the 2nd and 4th day.
Peak workload	(Wpeak)	After up to 1 hour of cycling on the 2nd and 4th day.
Peak respiratory exchange ratio	(RER)	After up to 1 hour of cycling on the 2nd and 4th day.
p-lactate	Analysis of blood sample	measured at rest and max on day 1, and before first dose of soft drink, before exercise and every 10 minutes during exercise at day 2 and 4.
Heart rate	pulsemonitoring	Continously during the cycle test (max. 1 hour) on the 2nd and 4th day
Borg score	Rate of percieved exertion	Measured periodically during the cycle test (max. 1 hour) on the 2nd and 4th day

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue	Fatigue Severity Score (FSS)	Assessed on days 3 and 5 of the trial
p-Creatine kinase	To asses muscle damage	measured on day 1, 3 and 5.
p-myoglobin	To asses muscle damage	measured on day 1, 3 and 5.
Respiratory exchange ratio, RER	VO2/VCO2	measured continously during the exercise test day 2 and 4.
p-glucose	Analysis of blood sample	measured at rest and max on day 1, and before first dose of soft drink, before exercise and every 10 minutes during exercise at day 2 and 4.
Pain	Pain assessed on a visual analog scale (VAS) with a scale of 0 to 10 cm	Assessed on days 3 and 5 of the trial
p-ammonia	Analysis of blood sample	measured at rest and max on day 1, and before exercise, at 10 minutes, 20 min of exercise and at max on day 2 and 4.
p-insulin	analysis of blood sample	measured at rest and max on day 1 and before exercise and every 10 minutes during exercise at day 2 and 4.
p-glucagon	analysis of blood sample	measured at rest and max on day 1, and before exercise, at 10 minutes, 20 min of exercise and at max on day 2 and 4.
p-catecholamines	analysis of blood sample	measured at rest and max on day 1, and before exercise, at 10 minutes, 20 min of exercise and at max on day 2 and 4.
Hypoglycemic episodes	Clinical observation as well as blood glucose levels monitored during exercise tests	2 hour observation after each of the two exercise test.

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Astrid E Buch, BSc Medicine, Copenhagen Neuromuscular Center

Publications and helpful links

General Publications

• Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med. 1970;2(2):92-8. No abstract available.
• Dupont WD, Plummer WD Jr. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990 Apr;11(2):116-28. doi: 10.1016/0197-2456(90)90005-m.
• Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS; ACMG. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. 2010 Jul;12(7):446-63. doi: 10.1097/GIM.0b013e3181e655b6. Erratum In: Genet Med. 2010 Sep;12(9):566.
• Van Hoof F, Hers HG. The subgroups of type 3 glycogenosis. Eur J Biochem. 1967 Oct;2(3):265-70. doi: 10.1111/j.1432-1033.1967.tb00134.x. No abstract available.
• Coleman RA, Winter HS, Wolf B, Gilchrist JM, Chen YT. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med. 1992 Jun 1;116(11):896-900. doi: 10.7326/0003-4819-116-11-896.
• Preisler N, Pradel A, Husu E, Madsen KL, Becquemin MH, Mollet A, Labrune P, Petit F, Hogrel JY, Jardel C, Maillot F, Vissing J, Laforet P. Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency? Mol Genet Metab. 2013 May;109(1):14-20. doi: 10.1016/j.ymgme.2013.02.008. Epub 2013 Feb 19.
• Haller RG, Vissing J. Spontaneous "second wind" and glucose-induced second "second wind" in McArdle disease: oxidative mechanisms. Arch Neurol. 2002 Sep;59(9):1395-402. doi: 10.1001/archneur.59.9.1395.
• Preisler N, Laforet P, Madsen KL, Hansen RS, Lukacs Z, Orngreen MC, Lacour A, Vissing J. Fat and carbohydrate metabolism during exercise in late-onset Pompe disease. Mol Genet Metab. 2012 Nov;107(3):462-8. doi: 10.1016/j.ymgme.2012.08.019. Epub 2012 Aug 31.
• Coyle EF. Carbohydrate supplementation during exercise. J Nutr. 1992 Mar;122(3 Suppl):788-95. doi: 10.1093/jn/122.suppl_3.788.
• Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc. 2006 Sep;81(9):1159-71. doi: 10.4065/81.9.1159.
• Chattopadhyay S, Raychaudhuri U, Chakraborty R. Artificial sweeteners - a review. J Food Sci Technol. 2014 Apr;51(4):611-21. doi: 10.1007/s13197-011-0571-1. Epub 2011 Oct 21.
• Marinovich M, Galli CL, Bosetti C, Gallus S, La Vecchia C. Aspartame, low-calorie sweeteners and disease: regulatory safety and epidemiological issues. Food Chem Toxicol. 2013 Oct;60:109-15. doi: 10.1016/j.fct.2013.07.040. Epub 2013 Jul 23.
• Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, Spencer PS, Waddell WJ, Walker R, Williams GM. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol. 2007;37(8):629-727. doi: 10.1080/10408440701516184.
• EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to food), 2013. Scientific Opinion on the re-evaluation of aspartame (E 951) as a food additive. EFSA Journal 2013;11(12):3496, 263 pp. doi:10.2903/j.efsa.2013.3496
• Harris RA. Carbohydrate metabolism I: Major metabolic pathways and their control. In: Devlin TM, ed. Textbook of biochemistry with clinical correlations, 6th ed Wiley-Liss, 2006:581-635
• DiMauro S, Hays AP, Tsujino S. Metabolic Disorders Affecting Muscle. In: Engel AG, Franzini-Armstrong C, eds. Myology, 3rd ed McGraw-Hill, 2004:1535-1558

Helpful Links

• Scientific Committee on Food. Re-evaluation of acesulfame K with reference to the previous SCF opinion of 1991.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): April 17, 2017
• Study Completion (Actual): May 25, 2021

Study Registration Dates

• First Submitted: May 15, 2015
• First Submitted That Met QC Criteria: May 15, 2015
• First Posted (Estimated): May 19, 2015

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

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 III
• Other Study ID Numbers: H-4-2014-014

Plan for Individual participant data (IPD)

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