Nutritional Therapy in Late-onset Pompe Disease (PDT-MIS)

Multi-ingredient Supplementation as an Adjunctive Therapy in Late-onset Pompe Disease

RATIONALE: Pompe disease (PD) is a recessive genetic disorder wherein the body cannot break down glycogen due to a mutation in the acid alpha glucosidase (GAA) gene, which encodes for acid alpha-glucosidase. The adult/late onset form (LOPD) leads to glycogen accumulation and autophagic buildup, causing progressive muscle weakness that leads to wheelchair dependence, reduced quality of life and premature death due to cardiorespiratory insufficiency. While nutritional strategies, such as the low carbohydrate/high protein and ketogenic diets, have been used clinically, they are difficult to maintain and have limited benefits. Multi-ingredient supplementation (MIS) allows for targeting of several underlying pathogenic pathways and may be more convenient than traditional dietary strategies, thereby improving both adherence and LOPD pathology.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Lysosomal Storage Diseases; Muscle Loss; Glycogen Storage Disease Type II; Pompe Disease; Nutrition Poor; Glycogen Storage Disease Type II, Adult; Glycogen Storage Disease Type II Late Onset
• Intervention / Treatment: Dietary supplement: Multi-ingredient supplement (PDT-MIS); Dietary supplement: Placebo (PLA)

Detailed Description

DESIGN AND INTERVENTION: The present study is a 4-month randomized, double-blind, placebo-controlled clinical trial (RCT) with sampling pre and post intervention in late onset Pompe disease patients undergoing enzyme replacement therapy (ERT) (21-90 years of age). Each patient will be randomized into either a Pompe-Targeted Multi-Ingredient Supplement (PDT-MIS; high-quality proteins, antioxidants, plant extracts, vitamins, and omega-3 fatty acids,) or placebo (PLA; collagen, safflower, and cellulose) group and then undergo four months of daily supplementation with concurrent rehabilitative exercise training (mixed cardio and strength four days/week) and respiratory muscle training (four days/week).

GENERAL RESEARCH AIMS AND HYPOTHESIS: The purpose of this study is to investigate the benefits of PDT-MIS on muscle and blood pathology, muscle function, respiratory capacity, and health-related quality of life (HRQOL) in LOPD patients on enzyme replacement therapy (ERT). It is generally hypothesized that PTD-MIS will mitigate mitochondrial dysfunction, oxidative damage, inflammation and alleviate 'autophagic block' in skeletal muscle of LOPD patients. PDT-MIS may therefore improve muscle pathology by affecting several cell pathways simultaneously, and thereby enhance muscle function, respiratory capacity, and HRQOL of LOPD patients.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mark A Tarnopolsky, MD/PhD; Phone Number: 76593 9055212100; Email: tarnopol@mcmaster.ca
• Study Contact Backup: Name: Mats I Nilsson, PhD; Phone Number: 76680 9055252100; Email: nilsson@mcmaster.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genetically confirmed LOPD
• Have undergone enzyme replacement therapy for at least three months.
• Physically capable of doing rehabilitative exercise, respiratory muscle training, and the clinical tests described herein.

Exclusion Criteria:

• Dairy protein allergy
• Renal disease (creatinine > 140)
• Attempting pregnancy or currently pregnant
• Current supplementation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multi-ingredient supplement (PDT-MIS); Multi-ingredient supplementation (PDT-MIS) consists of daily intake of high-quality proteins, creatine, vitamin D, calcium, plant extracts (green coffee bean, green tea, beet root, and forskolin), and Omega-3 fatty acids. Concurrent with supplementation, patients will do mixed rehabilitative exercise (cardio and strength) and respiratory muscle training four days a week.	Dietary supplement: Multi-ingredient supplement (PDT-MIS); Supplementation with active PDT-MIS daily
Placebo Comparator: Placebo (PLA); Placebo (PLA) consists of daily intake of collagen, safflower, and microcrystalline cellulose. Concurrent with supplementation, patients will do mixed rehabilitative exercise (cardio and strength) and respiratory muscle training four days a week.	Dietary supplement: Placebo (PLA); Supplementation with inactive placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in the body composition index by DEXA analyses	Body composition index (lean mass/fat mass ratio)	Baseline to 4 months
Percent change in seated pulmonary function by spirometry	Seated forced expiratory volume/forced vital capacity ratio (FEV1/FVC)	Baseline to 4 months
Percent change in supine pulmonary function by spirometry	Supine forced expiratory volume/forced vital capacity ratio (FEV1/FVC)	Baseline to 4 months
Percent change in 6-minute walking test distance	6-minute walking test distance (meters)	Baseline to 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in health-related quality of life by SF-36 Survey	36-item short form survey (ranging from low 0 to high 100)	Baseline to 4 months
Percent change in health-related quality of life by Rotterdam Handicap Score	Rotterdam Handicap Score (ranging from low 9 to high 36)	Baseline to 4 months
Percent change in health-related quality of life by the R-Pact Questionnaire	Rasch-built Pompe-specific Activity (ranging from low 0 to high 100 points)	Baseline to 4 months
Percent change in maximal grip strength by dynamometry	Maximal grip strength (kilogram)	Baseline to 4 months
Percent change in isometric leg strength by Biodex	Isometric leg strength (newton meters)	Baseline to 4 months
Percent change in leg strength by 4-step stair climb test	4-step stair climb time (seconds)	Baseline to 4 months
Percent change in lower extremity functioning by short physical performance battery (SPPB)	Short physical performance battery (ranging from low 0 to high 12)	Baseline to 4 months
Percent change in lower extremity functioning by timed get up and go test (TUG)	Timed get up and go test (seconds)	Baseline to 4 months
Percent change in total muscle glycogen by ELISA	Total muscle glycogen (ug per mg of tissue)	Baseline to 4 months
Percent change in lysosomal glycogen in muscle by high-resolution light microscopy	Lysosomal glycogen (% total muscle area)	Baseline to 4 months
Percent change in autophagic area in muscle by electron microscopy	Autopgahic area (% total muscle area)	Baseline to 4 months
Percent change in p62 expression in muscle by Western blotting	p62 expression (optical density)	Baseline to 4 months
Percent change in complex I-V expression in muscle by Western blotting	Complex I-V expression (optical density)	Baseline to 4 months
Percent change in 4-hydroxynonenal levels in muscle by Western blotting	4-hydroxynonenal levels (optical density)	Baseline to 4 months
Percent change in galactin-3 expression in muscle by Western blotting	Galactin-3 expression (optical density)	Baseline to 4 months
Percent change in superoxide dismutase 1 expression in muscle by Western blotting	Superoxide dismutase 1 expression (optical density)	Baseline to 4 months
Percent change in superoxide dismutase 2 expression in muscle by Western blotting	Superoxide dismutase 2 expression (optical density)	Baseline to 4 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in malondialdehyde levels in blood	Malondialdehyde levels (ng/mL)	Baseline to 4 months
Percent change in Oxygen Radical Absorbance Capacity in blood	Oxygen Radical Absorbance Capacity (relative fluorescence units)	Baseline to 4 months
Percent change in interleukin 6 levels in blood	interleukin 6 levels (pg/dL)	Baseline to 4 months
Percent change in interleukin 1 levels in blood	interleukin 1 levels (pg/dL)	Baseline to 4 months
Percent change in interleukin 10 levels in blood	interleukin 10 levels (pg/dL)	Baseline to 4 months
Percent change in tumor necrosis factor alpha levels in blood	tumor necrosis factor alpha (pg/dL)	Baseline to 4 months
Percent change in c-reactive protein levels in blood	c-reactive protein levels (mg/dL)	Baseline to 4 months

Collaborators and Investigators

• Sponsor: McMaster University
• Investigators: Principal Investigator: Mark Tarnopololsky, MD/PhD, McMaster University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: November 8, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Actual): November 14, 2023

Study Record Updates

• Last Update Posted (Actual): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Antioxidants; Oxidative stress; Obesity; Vitamin D; Vitamin E; Weight loss; Performance; Casein; CoQ10; Mitochondria; Omega-3; Muscle strength; Calcium; Creatine; Muscle; Autophagy; Supplements; Pompe disease; Green tea; Whey; Alpha-lipoic acid; Forskolin; Glycogen; Beet root; Green coffee bean; 6-meter walk test
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Lysosomal Storage Diseases, Nervous System; Disease; Malnutrition; Metabolic Diseases; Lysosomal Storage Diseases; Glycogen Storage Disease Type II; Glycogen Storage Disease
• Other Study ID Numbers: 17004

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