Prospective Cohort Study of Children With GSD1b Receiving Empagliflozin

Study Overview
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Brief Summary
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This is a prospective cohort study of children with GSD1b to evaluate their outcome after using empagliflozin for neutrophil defects.

Detailed Description
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Glycogen Storage Disease Type 1b (GSD1b) is an ultra-rare inborn error of carbohydrate metabolism, characterized by low neutrophil count, neutrophil dysfunction, and the associated recurrent infections and inflammatory bowel conditions. The current standard treatment with granulocyte colony-stimulating factor (GCSF) only increases neutrophil count but does not improve neutrophil function. It achieves only partial clinical response. Fever, recurrent infections, and gastrointestinal upset remain significant problems. Long-term regular GCSF injection is needed to sustain the clinical effect, but is also associated with development of serious complications including massive spleen enlargement, acute myeloid leukemia and myelodysplastic syndrome. Accumulation of a toxic metabolite called 1,5-anhydroglucitol-6-phosphate (1,5AG6P) is recently discovered as the cause of neutrophil problems in GSD1b. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor widely used as anti-diabetic drug, is known to promote excretion of 1,5-anhydroglucitol (1,5AG) in kidney. Since 1,5AG is the precursor of 1,5AG6P, empagliflozin also reduces the accumulation of 1,5AG6P. This is confirmed by animal studies that empagliflozin is shown to improve neutrophil count and function in GSD1b mouse model. Similar benefits are also recently reported in human cases (3 adults and 2 children with GSD1b), that GCSF dose could be significantly reduced or even stopped. This is a prospective cohort study of children with GSD1b to examine their outcome after receiving empagliflozin treatment. The objective is to evaluate the short to medium term safety and efficacy of empagliflozin. The ultimate goal is to assess if SGLT2 inhibitor could be an effective alternative of GCSF with less side effects and risks, and to improve the clinical outcomes and quality of life for patients and families with GSD1b.

Official Title
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Evaluation of Safety and Efficacy of Empagliflozin for Neutropenia and Neutrophil Dysfunction in Children With Glycogen Storage Disease Type 1b (GSD1b)

Conditions
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Glycogen Storage Disease Type IB

Intervention / Treatment
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* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Subject (aged 6 months to 18 years) is enzymatically/genetically confirmed to have GSD 1b and has been on regular GCSF treatment for >= 1 month Exclusion Criteria: Subject fails to provide relevant background medical information, or comply with all requirements of the clinical trial, or sign the informed consent Subject has any co-morbidity or condition that could increase the risk of empagliflozin treatment (e.g. renal failure with eGFR <30 mL/min/1.73m2 or requiring dialysis, diabetes requiring insulin &/or oral hypoglycemic agents, dyslipidemia requiring pharmacological intervention) Subject is pregnant, or a sexually active female who does not consent to use effective contraception during the study History of liver transplantation is NOT an exclusion criterium

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Empagliflozin|All subjects will have a baseline assessment and be prospectively followed up for 52 weeks to examine their outcome after receiving empagliflozin for neutropenia and neutrophil dysfunction.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of empagliflozin - usage of granulocyte colony stimulating factor (GCSF) | Dosage and frequency of administration of GCSF | from the start to the 52nd week of empagliflozin treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of empagliflozin - neutrophil number and function | Average neutrophil count and neutrophil oxidative burst | from the start to the 52nd week of empagliflozin treatment | 
| Efficacy of empagliflozin - bowel manifestations | Severity of bowel inflammation, diarrhea, and aphthous ulcers | from the start to the 52nd week of empagliflozin treatment | 
| Efficacy of empagliflozin - frequency of infections | Number of infections requiring hospitalization and antibiotics/surgical intervention | from the start to the 52nd week of empagliflozin treatment | 
| Efficacy of empagliflozin - biochemical improvement | Blood 1,5-anhydroglucitol level and urine glucose excretion | from the start to the 52nd week of empagliflozin treatment | 
| General metabolic control - GSD1b metabolic & imaging profile, concomitant interventions | Metabolic profile and concomitant interventions that reflects metabolic control of GSD1b | from the start to the 52nd week of empagliflozin treatment | 
| General well being - Quality of life | Pediatric Quality of Life Inventory™ (PedsQL™) - English or Cantonese/Chinese versions | from the start to the 52nd week of empagliflozin treatment | 
| Safety of empagliflozin - presence or absence of hypoglycemia | Frequency of symptomatic or severe hypoglycemia, average glucose levels | from the start to the 52nd week of empagliflozin treatment | 
| Safety of empagliflozin - prescence of absence of empagliflozin-related side effects | number of empagliflozin-related adverse events | from the start to the 52nd week of empagliflozin treatment |