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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Multi-ingredient supplement (PDT-MIS) | Experimental | 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. |
|
| Placebo (PLA) | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Multi-ingredient supplement (PDT-MIS) | Dietary Supplement | Supplementation with active PDT-MIS daily |
|
| 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 |
| 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 |
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Mark A Tarnopolsky, MD/PhD | Contact | 9055212100 | 76593 | tarnopol@mcmaster.ca |
| Mats I Nilsson, PhD | Contact | 9055252100 | 76680 | nilsson@mcmaster.ca |
| Name | Affiliation | Role |
|---|---|---|
| Mark Tarnopololsky, MD/PhD | McMaster University | Principal Investigator |
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| ID | Term |
|---|---|
| D006009 | Glycogen Storage Disease Type II |
| D009133 | Muscular Atrophy |
| D009765 | Obesity |
| D044342 | Malnutrition |
| D016464 | Lysosomal Storage Diseases |
| D015431 | Weight Loss |
| ID | Term |
|---|---|
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
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The present study is a 4-month randomized double-blind, placebo controlled, clinical trial with two treatments arms and groups (PDT-MIS and PLA).
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Following medical screening and consent, all patients accepted into the study will be assigned a unique identifier number (1-28), which will be provided to an outside party not associated with Dr. Tarnopolsky or co-investigators that will randomize each subject to one of two experimental conditions. Dr. Tarnopolsky, co-investigators, and the subjects will be blinded to the treatment allocations for the duration of the 4-month trial.
| Placebo (PLA) | Dietary Supplement | Supplementation with inactive placebo |
|
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 |
| 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 |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006008 | Glycogen Storage Disease |
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D001284 | Atrophy |
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D001836 | Body Weight Changes |