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

NCT04220021 | Active Not Recruiting Phase 2 Results FDA Drug

• 5 other identifiers: IRB201800620UF2019-001OCR20620CDMRP AL220089AGR DTD 12-20-2022
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

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.

Conditions

C9orf72 Amyotrophic Lateral Sclerosis (ALS); Frontotemporal Dementia

Keywords

ALS; FTD; Lou Gehrigs Disease

Outcome Measures

Primary Outcomes (2)

• Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability]

  The safety and tolerability of Metformin in participants with C9orf72 ALS currently treated with Metformin will be evaluated by the number of subjects with treatment-emergent adverse events

  Baseline through 24 weeks

• Change in Repeat Associated Non-AUG (RAN) Protein Levels

  Assessment of RAN protein levels in cerebrospinal fluid (CSF) samples from participants calculated as the percentage change in polyglycine-proline (GP) levels in ng/ml at study start \& end of the study as measured by Meso Scale Discovery (MSD) assays.

  Baseline through week 24.

Secondary Outcomes (1)

• Change in ALS Functional Rating Scale (ALSFRS-R) Score

  Baseline through Week 24

Study Arms (1)

C9orf72 positive ALS

EXPERIMENTAL

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.

Drug: Metformin

Interventions

Metformin 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.

Also known as: Metformin hydrochloride sustained-release (SR)

C9orf72 positive ALS

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• University of Florida: lead
• ALS Association: collaborator
• United States Department of Defense: collaborator

Study Sites (1)

UF Health at the University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (6)

• 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.

  PMID: 10540002 BACKGROUND

• 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.

  PMID: 16084801 BACKGROUND

• 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.

  PMID: 8721066 BACKGROUND

• 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.

  PMID: 25548957 BACKGROUND

• 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.

  PMID: 31578300 BACKGROUND

• 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.

  PMID: 25298304 BACKGROUND

MeSH Terms

Conditions

Frontotemporal Dementia; Amyotrophic Lateral Sclerosis

Interventions

Metformin

Condition Hierarchy (Ancestors)

Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders; Spinal Cord Diseases; Motor Neuron Disease; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

Our C9orf72 ALS metformin clinical trial was not placebo-controlled but ALSFRS-R scores were compared to previously published C9orf72 ALS (PMID: 31578300) and all ALS patient (PMID: 25298304) natural history studies.

Results Point of Contact

• Title: Laura P.W. Ranum, PhD
• Organization: University of Florida

ranum@ufl.edu

(352) 294-5209

Study Officials

• Laura Ranum, PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants receive medication

Study Record Dates

• First Submitted: January 3, 2020
• First Posted: January 7, 2020
• Study Start: January 10, 2020
• Primary Completion: August 26, 2024
• Study Completion (Estimated): June 30, 2026
• Last Updated: December 2, 2025
• Results First Posted: December 2, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)