Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD

NCT ID: NCT04220021

Last Updated: 2025-12-02

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-10
• Study Completion Date: 2026-06-30

Brief Summary

The primary objective is to assess the safety and tolerability of Metformin in subjects with C9orf72 amyotrophic lateral sclerosis administered for 24 weeks. The overall objective is to determine if Metformin is safe in C9orf72 ALS patients and is a potentially viable therapeutic treatment for C9-ALS that reduces repeat-associated non-canonical start codon - in DNA (non-ATG) (RAN) proteins that are produced by the C9orf72 repeat expansion mutation.

Detailed Description

The C9orf72 repeat expansion is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Metformin, a well-tolerated diabetes drug, blocks a key pathway for expression of toxic proteins produced from the C9orf72 repeat expansion via repeat associated non-canonical start codon - in RNA (non-AUG) (RAN) translation. In mouse model of C9-ALS/FTD, metformin treatment decreases RAN protein levels and improves disease features. This current study is a small-scale clinical trial to assess the safety and potential efficacy of metformin for the treatment of C9-ALS/FTD.

Conditions

C9orf72 Amyotrophic Lateral Sclerosis (ALS); Frontotemporal Dementia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

C9orf72 positive ALS

Subjects with C9orf72 positive ALS will be instructed in the use of Metformin and receive the first dose of Metformin under supervision of the investigator during Visit 1, Day 2.

Subjects will then continue on Metformin per the dose escalation schedule twice daily for 24 weeks.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin is a widely used, well-tolerated drug that has been used for decades as a first-line defense for treating type 2 diabetes. Its safety has been well established. Subjects will begin treatment with Metformin at a dosage of 500mg with an escalation of dosage by 500mg every week to a maximal dosage of 2000mg. Dosing will be twice daily.

Interventions

Metformin

Metformin is a widely used, well-tolerated drug that has been used for decades as a first-line defense for treating type 2 diabetes. Its safety has been well established. Subjects will begin treatment with Metformin at a dosage of 500mg with an escalation of dosage by 500mg every week to a maximal dosage of 2000mg. Dosing will be twice daily.

Intervention Type: DRUG

Other Intervention Names

Metformin hydrochloride sustained-release (SR)

Eligibility Criteria

Inclusion Criteria

• Subjects have a diagnosis of probable or definite ALS in accordance with the Revisited El-Escorial Criteria.
• Subjects have a likely diagnosis of chromosome 9 open reading frame 72 (C9orf72) positive ALS/FTD.
• Subjects must be currently on an oral diet and able to take foods, pills and liquids by mouth equivalent to a score of 4 or above on the Functional Oral Intake Scale
• Subjects must have no known allergy to barium sulfate or Metformin.
• Subjects or subject's legally authorized representative must be willing and able to complete informed consent/assent and HIPAA authorization.
• Ability to comprehend and be informed of the nature of the study, as assessed by the PI or Co-Investigators.
• Subjects prescribed to take Metformin at or before the time of first dosing. (The study is open to subjects currently taking Metformin or subjects who have taken Metformin in the past).
• Availability to participate for the entire study duration.
• Female subjects of childbearing potential must have a negative urine pregnancy test prior to Videofluoroscopic Swallow Study (VFSS) exam during Visit 1, 3, and 4.

Exclusion Criteria

• Subjects who score 3 or below on the Functional Oral Intake Scale
• Subjects who do not carry the C9ORF72 hexanucleotide repeat expansion as determined by laboratory analysis.
• Subjects with a history of clinically significant liver disease, renal disease, or any other medical condition judged to be exclusionary by the investigator.
• Subjects who are unwilling to sign informed consent or subjects who for any other reason in the judgment of investigator are unable to complete the study.
• Female subjects who have a positive urine pregnancy test (βhCG) at screening or visit 1, are trying to become pregnant or are breastfeeding.
• Subjects with active cancer within the previous 2 years, except treated basal cell carcinoma of the skin.
• Subjects who have taken any experimental drug within 30 days prior to enrollment or within 5 half-lives of the investigational drug -whichever is the longer period.
• Subjects with known history or presence of moderate or severe renal impairment as defined by an estimated glomerular filtration rate (eGFR) value below 30 mL/min/1.73 m2.
• Subjects with hepatic impairment as defined by baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin).
• Use of potentially hepatotoxic drugs: (e.g., allopurinol, methyldopa, sulfasalazine).
• Subjects with clinically significant abnormal laboratory values in the judgment of the investigator.
• Subject with implanted electrical device (i.e. cardiac pacemaker or a neurostimulator), metal or metallic clip(s) in their body (i.e. an aneurysm clip in the brain) that will be damaged by participation in the MRI portion of the study.
• Anything else that, in the opinion of the investigator, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ALS Association

OTHER

Sponsor Role: collaborator

United States Department of Defense

FED

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Laura Ranum, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Health at the University of Florida

Gainesville, Florida, United States

Countries

United States

References

Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21. doi: 10.1016/s0022-510x(99)00210-5.

Reference Type: BACKGROUND

PMID: 10540002 (View on PubMed)

Crary MA, Mann GD, Groher ME. Initial psychometric assessment of a functional oral intake scale for dysphagia in stroke patients. Arch Phys Med Rehabil. 2005 Aug;86(8):1516-20. doi: 10.1016/j.apmr.2004.11.049.

Reference Type: BACKGROUND

PMID: 16084801 (View on PubMed)

Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia. 1996 Spring;11(2):93-8. doi: 10.1007/BF00417897.

Reference Type: BACKGROUND

PMID: 8721066 (View on PubMed)

Watanabe H, Atsuta N, Nakamura R, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, Izumi Y, Morita M, Tomiyama H, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Aoki M, Tsuji S, Nakano I, Kaji R, Sobue G. Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2015 Jun;16(3-4):230-6. doi: 10.3109/21678421.2014.990036. Epub 2014 Dec 30.

Reference Type: BACKGROUND

PMID: 25548957 (View on PubMed)

Cammack AJ, Atassi N, Hyman T, van den Berg LH, Harms M, Baloh RH, Brown RH, van Es MA, Veldink JH, de Vries BS, Rothstein JD, Drain C, Jockel-Balsarotti J, Malcolm A, Boodram S, Salter A, Wightman N, Yu H, Sherman AV, Esparza TJ, McKenna-Yasek D, Owegi MA, Douthwright C; Alzheimer's Disease Neuroimaging Initiative; McCampbell A, Ferguson T, Cruchaga C, Cudkowicz M, Miller TM. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. Neurology. 2019 Oct 22;93(17):e1605-e1617. doi: 10.1212/WNL.0000000000008359. Epub 2019 Oct 2.

Reference Type: BACKGROUND

PMID: 31578300 (View on PubMed)

Atassi N, Berry J, Shui A, Zach N, Sherman A, Sinani E, Walker J, Katsovskiy I, Schoenfeld D, Cudkowicz M, Leitner M. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014 Nov 4;83(19):1719-25. doi: 10.1212/WNL.0000000000000951. Epub 2014 Oct 8.

Reference Type: BACKGROUND

PMID: 25298304 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

UF2019-001

Identifier Type: OTHER

Identifier Source: secondary_id

OCR20620

Identifier Type: OTHER

Identifier Source: secondary_id

UF2019-001

Identifier Type: OTHER

Identifier Source: secondary_id

CDMRP AL220089

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AGR DTD 12-20-2022

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IRB201800620

Identifier Type: -

Identifier Source: org_study_id