Empagliflozin for Severe Congenital Neutropenia

Overseen By David H McDermott, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: Renal failure, Type 1 diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether empagliflozin, a medication, can help people with Severe Congenital Neutropenia (SCN) by boosting their neutrophil levels. Neutrophils, a type of white blood cell, help fight infections, and people with SCN have low levels, making them prone to illness. The trial seeks adults with SCN caused by G6PC3 deficiency who typically have low neutrophil counts. Participants will take the study drug as a daily pill for 12 months and will have regular check-ups to monitor health and side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that empagliflozin is likely to be safe for humans?

In a previous study, patients with low levels of neutrophils, a type of white blood cell, experienced an increase after using empagliflozin. After three months, the average neutrophil count rose to 1.95 × 10³ cells per microliter and increased further to 2.24 × 10³ cells per microliter over time.

The FDA has already approved empagliflozin for other conditions, indicating its general safety. However, since this trial is in an early stage, it primarily focuses on assessing how well people with severe congenital neutropenia (SCN) can tolerate the treatment and its safety for them. While evidence from other uses of empagliflozin suggests safety, this trial will provide more specific information about its safety for people with SCN. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for severe congenital neutropenia, which often include granulocyte colony-stimulating factors (G-CSF) to boost white blood cell production, Empagliflozin offers a novel approach. Empagliflozin is primarily known as a diabetes medication that works by affecting sugar levels, but researchers are excited because it might also impact neutrophil function through its unique mechanism. This could provide an alternative treatment path with potentially fewer side effects, making it an attractive option for patients who don't respond well to traditional therapies.

What evidence suggests that empagliflozin might be an effective treatment for severe congenital neutropenia?

Research shows that empagliflozin, the treatment under study in this trial, may help increase white blood cell counts in people with severe congenital neutropenia (SCN). Studies have found that during treatment, the average number of these cells in patients rose significantly, reaching 1.95 × 10³ cells per microliter after three months and 2.24 × 10³ cells per microliter after a longer period. These increases suggest that empagliflozin might help the body fight infections better by boosting white blood cell levels. Additionally, researchers have observed that empagliflozin improves the function of these cells, further helping to reduce infection rates. Originally used for diabetes, this drug is now being explored for its potential benefits in treating neutropenia. ^{1 2 3 5 6}

Who Is on the Research Team?

David H McDermott, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Adults over 18 with severe congenital neutropenia (SCN) due to G6PC3 deficiency, who have low white blood cell counts and agree to use two forms of birth control can join. Those with kidney failure, type 1 diabetes, fasting hypoglycemia, pregnancy or known allergy to empagliflozin cannot participate.

Inclusion Criteria

I agree to use two forms of birth control, including a condom, during the study.

Able to provide informed consent

My severe congenital neutropenia is due to a G6PC3 deficiency.

Exclusion Criteria

Fasting hypoglycemia (<60 mg/dL)

Any condition that, in the opinion of the investigator, contraindicates participation in this study

Pregnant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase A

Participants receive 10 mg of oral empagliflozin daily for 2 months. Blood draws every two weeks for clinical lab evaluations and remote AE assessments.

8 weeks

4 visits (local lab), 4 remote assessments

Treatment Phase B

Participants may increase to 25 mg daily if needed. Blood draws and remote AE assessments monthly for the first 4 months, and bimonthly for the last 6 months. Outpatient visits at NIH at months 6 and 12.

10 months

6 visits (local lab), 6 remote assessments, 2 visits (in-person at NIH)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin

Trial Overview The trial is testing if the drug empagliflozin can increase white blood cells in SCN patients. Participants will take the drug daily for a year and monitor their health at home and through visits including heart tests, liver ultrasounds, possibly colonoscopies or bone marrow biopsies.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 1 Intervention

Patients with GCPC3 will receive daily Empagliflozin for 12 months.

Empagliflozin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

Approved in United States as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease
• Cardiovascular risk reduction

Approved in Canada as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

Approved in Japan as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Empagliflozin (EMPA) significantly improved clinical outcomes in patients with Glycogen Storage Disease type 1b (GSD 1b), including reduced infection frequency and improved bowel function, while also enhancing postoperative wound healing.

EMPA effectively treated neutropenia in GSD 1b patients, allowing for a reduction or complete withdrawal of the standard therapy granulocyte colony-stimulating factor (G-CSF), without significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose cotransporter type 2 channel inhibitor: Breakthrough in the treatment of neutropenia in patients with glycogen storage disease type 1b? Kaczor, M., Greczan, M., Kierus, K., et al.[2022]

Empagliflozin effectively lowers blood sugar levels in patients with type 2 diabetes by inhibiting glucose reabsorption in the kidneys, resulting in an average reduction of HbA1c by approximately 0.8% without causing hypoglycemia, except in those already on insulin or sulphonylureas.

In addition to improving glycemic control, empagliflozin promotes weight loss (about 2 kg) and lowers blood pressure (systolic by approximately 4 mm Hg), while also providing cardiovascular protection, as demonstrated in the EMPA-REG OUTCOME trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. Scheen, AJ.[2022]

Empagliflozin (Jardiance) is now approved for reducing the risk of cardiovascular death and hospitalization in adults with heart failure, even in those without diabetes, highlighting its expanded therapeutic use.

Healthcare providers, including nurses and nurse practitioners, should closely monitor patients for potential adverse effects, particularly fluid deficits, to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. Aschenbrenner, DS.[2023]

SGLT2 inhibitors, like empagliflozin, effectively reduce levels of 1,5-anhydroglucitol and its phosphate form, leading to improved neutrophil counts and function in children with G6PC3 deficiency, allowing for the cessation of granulocyte colony-stimulating factor (GCSF) treatment.

In a study involving two G6PC3-deficient children, treatment with empagliflozin resulted in both children remaining infection-free for over a year, with no reported side effects, highlighting the safety and efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5. Boulanger, C., Stephenne, X., Diederich, J., et al.[2022]

Congenital neutropenia syndromes are linked to various genetic defects, including known entities like ELANE and novel ones like VPS45 deficiency, which enhance our understanding of neutrophil biology and function.

Recent advancements in genetic and biochemical techniques allow for more tailored treatment approaches, potentially leading to personalized medicine for patients with congenital neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Hauck, F., Klein, C.[2019]

Severe congenital neutropenia encompasses a diverse range of disorders with different inheritance patterns, which can be better understood through molecular classification.

Treatment options include G-CSF (filgrastim) to boost neutrophil counts and reduce infection risks, while hematopoietic stem cell transplantation is the only curative approach available for some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A molecular classification of congenital neutropenia syndromes. Boxer, LA., Newburger, PE.[2009]

Empagliflozin, a drug typically used for type 2 diabetes, was successfully repurposed to treat neutropenia and neutrophil dysfunction in four patients with glycogen storage disease type Ib (GSD-Ib), leading to a decrease in harmful intracellular levels of 1,5-anhydroglucitol-6-phosphate (1,5AG6P).

The treatment resulted in significant clinical improvements, including resolution of frequent infections and inflammatory bowel disease symptoms, stabilization of neutrophil counts, and enhanced neutrophil function, all without causing symptomatic hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. Wortmann, SB., Van Hove, JLK., Derks, TGJ., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9540799/

Successful use of empagliflozin to treat neutropenia in two ... Our results indicate that it might be more efficient in treating the neutropenia in G6PC3‐deficient compared to the one in GSDIb patients: (1) ...

2. metabolismjournal.com metabolismjournal.com/article/S0026-0495(24)00305-6/fulltext

Successful repurposing of empagliflozin to treat ... This action results in improvement of neutropenia and neutrophil dysfunction in G6PC3-deficient patients [4]. The effect of SGLT-2 inhibitors has also been ...

3. ashpublications.org ashpublications.org/bloodadvances/article/8/11/2790/515503/Neutrophil-functions-in-patients-with-neutropenia

Neutrophil functions in patients with neutropenia due to ... During empagliflozin treatment, the median neutrophil count of 7 patients increased to 1.95 × 103 cells per μL after 3 months, and 2.24 × 103 cells per μL after ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05078879/empagliflozin-as-a-treatment-for-severe-congenital-neutropenia-due-to-g6pc3-deficiency

Empagliflozin as a Treatment for Severe Congenital ... In this phase 1 open-label study, we will evaluate the safety, tolerability, and efficacy of the sodium glucose co transporter 2 inhibitor ...

5. jaci-inpractice.org jaci-inpractice.org/article/S2213-2198(22)01062-5/pdf

Empagliflozin restores neutropenia and neutrophil ... Empagliflozin, a potential therapeutic option, restores neutrophil counts and function, reduces the incidence of infection, and allows the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04930627

Safety and Efficacy of Empagliflozin in GSD1b Patients ... The aim of our study is to evaluate the efficacy and safety of neutropenia in patients with GSD Ib with empagliflozin (Jardiance®).