Prospective Cohort Study of Children With GSD1b Receiving Empagliflozin

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

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

Study Overview

• Status: Recruiting
• Conditions: Glycogen Storage Disease Type IB
• Intervention / Treatment: Drug: Empagliflozin

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 11

Contacts and Locations

• Study Contact: Name: MEI KWUN KWOK, MB,BS; Phone Number: 852-57413216; Email: kwokmk@ha.org.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Hong Kong Children's Hospital
    • Contact: MEI KWUN KWOK, MB,BS; Phone Number: 852-57413216; Email: kwokmk@ha.org.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

GSD 1b patients (aged 6 months to 18 years) with diagnosis confirmed by enzymatic and/or genetic analysis, and has been on regular GCSF treatment for >= 1 month

Description

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

Study Plan

How is the study designed?

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hong Kong Children's Hospital
• Investigators: Principal Investigator: Mei Kwun Kwok, Hong Kong Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: July 27, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Actual): August 16, 2021
• Last Update Submitted That Met QC Criteria: August 8, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Disease; Glycogen Storage Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: KWOK-HKCH-GSD1-EMPA

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
• product manufactured in and exported from the U.S.: No