Pilot Study of Metformin for Patients With Fanconi Anemia

This is a single institution, open-label, single arm pilot study of Metformin in patients with Fanconi Anemia (FA) and cytopenias with the primary endpoint of hematologic response. This study will also assess safety, tolerability, and the biologic effects of Metformin in patients with FA.

Study Overview

• Status: Completed
• Conditions: Fanconi Anemia
• Intervention / Treatment: Drug: metformin HCl

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 33 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 6 years and ≤35 years
• Lansky/Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for patients <16 years of age (see Appendix A)
• Diagnosis requirement

• Participants must have a clinical diagnosis of Fanconi Anemia.

  • Participants must have confirmed diepoxybutane-mitomycin C (DEB/MMC) stress testing to document diagnosis of Fanconi Anemia.
  • Patients must have at least one of the following cytopenias: Hemoglobin <10g/dL; Platelets <100k/uL; Absolute neutrophil count <1000/uL

• Participants must have normal organ function as defined below:

  • Hepatic Function : Total bilirubin ≤ 1.5 x upper limit of normal for age; alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 135 U/L
  • Renal Function: A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female

1. to < 2 years 0.6 0.6
2. to < 6 years 0.8 0.8

6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4

AND

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal

• Normal cardiac status as documented clinically, otherwise they will need an echocardiogram prior to enrollment
• Serum bicarbonate must be >17.
• Participants of child-bearing or child-fathering potential must agree to use adequate contraception (hormonal birth control; intrauterine device; double barrier method; or total abstinence) throughout their participation, including up until 30 days after last dose of Metformin.
• Patients must be able to swallow pills.
• Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, documented using an institutionally approved informed consent procedure

Exclusion Criteria:

• Patients must not have undergone prior bone marrow transplantation.
• Patients must not have very severe aplastic anemia at the time of enrollment which would require bone marrow transplantation (as defined by at least 2 out of the following 3: Absolute Neutrophil Count (ANC) <200k/uL, platelets <20k/uL, absolute reticulocyte count <40k/uL).
• Patients must not be taking any other concurrent medications to improve their hematopoiesis such as androgens or growth factors such as Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), or thrombopoietin (TPO) mimetics. There is a one month wash-out period for prior therapies including androgens.
• Pregnant participants will not be entered on this study given that the effects of Metformin on the developing human fetus are unknown.
• Breastfeeding mothers are not eligible because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Metformin.
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Metformin.
• Patients must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients must not have prior history of symptomatic hypoglycemia over the past year or hypoglycemia with glucose <50mg/dL on screening and baseline laboratory assessments.
• Patients must not have type 1 diabetes mellitus.
• Patients must abstain from alcohol as part of this study.
• Patients must not have a diagnosis of myelodysplastic syndrome or leukemia, or other concurrent malignancy undergoing treatment.
• Patients must not have vitamin B12 deficiency.
• Patients must not have Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; Receive metformin HCl	Drug: metformin HCl; Receive metformin HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic Response	Hematologic response is defined by specific increases in erythroid, platelet, and neutrophil counts. Erythroid response: Hemoglobin (Hgb) increase by >1.5g/dL for non-transfusion dependent patients and for patients who are transfusion dependent: Transfusion independence Only transfusions given for Hgb ≤8g/dL or for symptoms will be counted in the response evaluation Platelet response: If initially <20k/uL to start, then must increase to >20k/UL with an absolute increase of 100%. If initially ≥20k/uL to start, then must have an absolute increase of >30k/UL Neutrophil response: If initially <500/uL to start, then must increase to >500/uL with an absolute increase of > 250/uL. If initially ≥500/uL to start, then must have an absolute increase of >500/uL	6 months

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Akiko Shimamura, MD, PhD, Boston Children's Hospital

Publications and helpful links

General Publications

• Pollard JA, Furutani E, Liu S, Esrick E, Cohen LE, Bledsoe J, Liu CW, Lu K, de Haro MJR, Surralles J, Malsch M, Kuniholm A, Galvin A, Armant M, Kim AS, Ballotti K, Moreau L, Zhou Y, Babushok D, Boulad F, Carroll C, Hartung H, Hont A, Nakano T, Olson T, Sze SG, Thompson AA, Wlodarski MW, Gu X, Libermann TA, D'Andrea A, Grompe M, Weller E, Shimamura A. Metformin for treatment of cytopenias in children and young adults with Fanconi anemia. Blood Adv. 2022 Jun 28;6(12):3803-3811. doi: 10.1182/bloodadvances.2021006490.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2018
• Primary Completion (Actual): October 9, 2020
• Study Completion (Actual): October 9, 2020

Study Registration Dates

• First Submitted: December 13, 2017
• First Submitted That Met QC Criteria: January 11, 2018
• First Posted (Actual): January 16, 2018

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Metformin; Fanconi Anemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Anemia; Fanconi Syndrome; Fanconi Anemia; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: IRB-P00026540

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No