Nutritional Therapy in Late-onset Pompe Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Nutrition Poor, Pompe Disease, Muscle Loss, Obesity, Lysosomal Storage Diseases, Glycogen Storage Disease Type II, Glycogen Storage Disease Type II Late Onset, Glycogen Storage Disease Type II, Adult

Intervention / Treatment
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* Dietary Supplement: Multi-ingredient supplement (PDT-MIS)
* Dietary Supplement: Placebo (PLA)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The present study is a 4-month randomized double-blind, placebo controlled, clinical trial with two treatments arms and groups (PDT-MIS and PLA).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multi-ingredient supplement (PDT-MIS)<br>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)<br>* Supplementation with active PDT-MIS daily<br>|
| Placebo Comparator: Placebo (PLA)<br>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)<br>* Supplementation with inactive placebo<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oxidative stress, Mitochondria, Autophagy, Glycogen, Forskolin, Beet root, Performance, Muscle, Supplements, Antioxidants, Whey, Casein, Vitamin D, Creatine, Calcium, Omega-3, Green coffee bean, Green tea, CoQ10, Alpha-lipoic acid, Vitamin E, Weight loss, Obesity, Muscle strength, 6-meter walk test, Pompe disease