Safety, Efficacy Evaluation of Empagliflozin Administration for Neutropenia in Glycogenosis Type 1b and G6PC3 Deficiency

Study Overview
=================
Brief Summary
-----------------
Treatment of neutropenia of G6PC3 and Glycogenosis type 1b patients with empagliflozin

Detailed Description
-----------------
Ubiquitous glucose-6-phosphatase deficiency (G6PC3) and glucose-6-phosphate transporter deficiency (G6PT/SLC37A4) both cause neutropenia. Studies on a G6PC3 deficient mouse model by Dr Veiga-da-Cunha and Prof. Van Schaftingen and colleagues have shown that these two proteins collaborate to hydrolyze a metabolite that exerts toxic effects on neutrophils. This metabolite is 1,5-anhydroglucitol-6-phosphate. It is formed by phosphorylation of a glucose analogue, 1,5-anhydroglucitol, which is present in the blood of all humans, mice and other mammals. This discovery of the function of G6PC3 and G6PT opens up therapeutic prospects, in that lowering the concentration of 1,5-anhydroglucitol in the blood should reduce the concentration of 1,5-anhydroglucitol-6-phosphate in the cells and thus reduce its toxic effects. Veiga-da-Cunha, Van Schaftingen and colleagues have already shown that this is the case for a model of mice deficient in G6PC3 treated with empagliflozin . Following these discoveries, the aim of the investigator's experiment is to test the effect of the efficacy of empagliflozin on urinary excretion and elimination of blood 1,5-anhydroglucitol in patients with glucose-6-phosphate transporter deficiency (type Ib glycogenosis) and patients with G6PC3 deficiency. This should allow patients to significantly lower the level of 1,5-anhydroglucitol-6-phosphate found in their neutrophils and thus cure their neutropenia. Empagliflozin (marketed in Belgium under the name of Jardiance®) belongs to the class of drugs called oral hypoglycemic agents. It works on the kidney by inhibiting the glucose transporter in the proximal tubules, SGLT2, which leads to glucosuria that results in the elimination of 1,5-anhydroglucitol in the urine. At present, Empagliflozin alone or in combination with other drugs is commonly used in people with type 2 diabetes to control their blood sugar levels.

Official Title
-----------------
Evaluation of the Safety and Efficacy of Empagliflozin Administration as a Treatment for Neutropenia in Patients With Glycogenosis Type 1b and G6PC3 Deficiency

Conditions
-----------------
Glycogen Storage Disease Type I, Glucose 6 Phosphatase Deficiency

Intervention / Treatment
-----------------
* Drug: Empagliflozin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Glycogenosis type 1b confirmed by biochemical analyzes and / or genetic analysis. These patients with Glycogenosis must have had a liver transplant Alternatively, G6PC3 deficiency confirmed by genetic analysis Age 1 to 18 years old female or male Informed consent signed by the recipient and / or parents / assigns. Information and agreement of the referring medical team. A Negative Blood Pregnancy Test at the time of screening and a negative urinary pregnancy test at Day 1 of the protocol are required for female with child bearing potential. Sexually active patients should use an effective method of contraception throughout the duration of the study and up to 7 days after the last dose of Empaglifozine. (The combination of a hormonal method and a barrier method; Two barrier methods, the male condom being one of these two methods;Use intrauterine device or tubal ligation;-A total sex abstinence.) Exclusion Criteria: Presence of advanced fibrosis (Metavir F4) or cirrhosis. Impossibility of long-term and / or non-compliance monitoring. Other medical problems which, in the opinion of the physicians in charge of the patient, would constitute a contraindication to the procedure. Sexually active patients who do not consent to use effective contraception during the study.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Oral empaglifozin 5 mg 1x/day, increase up to 10 mg 1x/day if no 25% decrease of blood1,5-anhydroglucitol level | Drug: Empagliflozin<br>* oral administration of Empagliflozin<br>* Other names: Jardiance;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Empaglifozin safety (blood test-glycemia): measured by absence of hypoglycaemia due to gliflozin treatment | Empaglifozin safety is measured by absence of hypoglycaemia due to gliflozin treatment (continuous monitoring during the first 2 days of treatment and glycemia punctual monitoring every 7 days for 2 months) (mg/dl) | from start of treatment to 2 months post treatment | 
| Empaglifozin Efficacy (blood test-hemogram) | Efficacy of drug is measured by an Increased neutrophil count as compared to pre-treatment (10exp3/µl) | from start of treatment to 2 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Empaglifozin Clinical efficacy (questionnaire) | Empaglifozin Clinical efficacy is measured as a Decrease in the number of infections -Decrease in the number of episodes of oral aphtosis (stomatitis) We will use numerical scale: higher scores mean worse outcome | from start of treatment to 2 months post treatment | 
| Empaglifozin Biological efficacy on blood 1,5-anhydroglucitol level (blood test-LCMS) | Empaglifozin Biological efficacy is measured as a Decrease of blood 1,5-anhydroglucitol (µM) | from start of treatment to 2 months post treatment | 
| Empaglifozin Biological efficacy on 1,5-anhydroglucitol-6-phosphate levels in neutrophils (blood test-LCMS) | Empaglifozin Biological efficacy is measured as decrease in the level of 1,5-anhydroglucitol-6-phosphate in neutrophils (µM) | from start of treatment to 2 months post treatment | 
| Empaglifozin Clinical efficacy on urinary 1,5-anhydroglucitol excretion increase (urine test-LCMS) | Empaglifozin Biological efficacy is measured as increased excretion of urinary 1,5-anhydroglucitol (µM) | from start of treatment to 2 months post treatment | 
| Empaglifozin Clinical efficacy on neutrophil function (blood test) | Empaglifozin Biological efficacy is measured as improved neutrophilic function (glycosylation analysis, Western Blot) | from start of treatment to 2 months post treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Empaglifozin