Active, not recruitingNCT04220021Updated Aug 20, 2026Results posted

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

A Phase 2 interventional study of Metformin in C9orf72 Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia, sponsored by University of Florida. Active, not recruiting at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-08-20.

Sponsored by University of Florida · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 41
Allocation: Not applicable
Ages: 18 Years to 80 Years
Sex: All

Study 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.

Read the 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 studied

C9orf72 Amyotrophic Lateral Sclerosis (ALS)
Frontotemporal Dementia

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Keywords

ALS
FTD
Lou Gehrigs Disease

In context

Frontotemporal Dementia

256 studies on the registry are indexed under Frontotemporal Dementia; 74 are open to participants now.

This study's enrollment of 41 is above the median of 35 across 157 interventional studies indexed under Frontotemporal Dementia.

Browse Frontotemporal Dementia studies →

Lead sponsor

University of Florida is the lead sponsor of 1,254 studies on the registry; 201 are open to participants now.

Of its 170 completed or terminated interventional studies of FDA-regulated products, 136 (80%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 80 Years
Sexes eligible: All
Accepts healthy volunteers: No

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

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 41 participants (actual)

Study arms

Experimental
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.
Drug: Metformin

Interventions

DrugMetformin
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)

What researchers measure

Primary outcomes

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
Time frame: 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.
Time frame: Baseline through week 24.

Secondary outcomes

Change in ALS Functional Rating Scale (ALSFRS-R) Score
The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to assess the capability and independence of subjects across 12 functional activities/questions. The score represents the sum of 12 functional domain items where each item is scored from 0 to 4 (Max score for each functional domain is 4 (Normal function); Minimum score for each functional domain = 0 (No ability to perform the task). The total score range is from 0 to 48, with a score of 48 meaning no functional impairment and 0 meaning complete loss of function across all domains. The mean values reported are at each study visit which occurred at baseline and at approximately 6, 12 and 24 weeks. The total number of days between study visits varied due to scheduling issues.
Time frame: Baseline through Week 24

Results

Posted Dec 2, 2025

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.

Participant flow

Recruitment period: 1/3/2020 - 8/28/2023 Recruitment location: University of Florida Neurology Clinic

Participant flow — Overall Study
Milestone	Enrolled Subjects
Started	41
Completed	23
Not completed	18
Withdrew: Withdrawal by subject	11
Withdrew: Physician decision	2
Withdrew: Non-study related illness	5

Outcome measures

PrimaryNumber 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

Time frame:: Baseline through 24 weeks
Reported as:: Count of participants · Participants

Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability]
Participants	Study Completers	All Participants
Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability]	0	0

PrimaryChange 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.

Time frame:: Baseline through week 24.
Reported as:: Median · % change (ng/ml) from study start to end

Change in Repeat Associated Non-AUG (RAN) Protein Levels
% change (ng/ml) from study start to end	Study Completers With Reliable CSF MSD Values
Change in Repeat Associated Non-AUG (RAN) Protein Levels	-27.93 (-43.98 to -1.91)

Statistical analysis

Study Completers With Reliable CSF MSD Values · Sign test · p = 0.0245 (A priori test for significance is p less than or equal to 0.05)One-tailed sign and binomial test

SecondaryChange in ALS Functional Rating Scale (ALSFRS-R) Score

The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to assess the capability and independence of subjects across 12 functional activities/questions. The score represents the sum of 12 functional domain items where each item is scored from 0 to 4 (Max score for each functional domain is 4 (Normal function); Minimum score for each functional domain = 0 (No ability to perform the task). The total score range is from 0 to 48, with a score of 48 meaning no functional impairment and 0 meaning complete loss of function across all domains. The mean values reported are at each study visit which occurred at baseline and at approximately 6, 12 and 24 weeks. The total number of days between study visits varied due to scheduling issues.

Time frame:: Baseline through Week 24
Reported as:: Mean · score on a scale

Change in ALS Functional Rating Scale (ALSFRS-R) Score
score on a scale	Study Completers	Metformin Compliant Study Completers
Baseline	38.61 ± 6.73	38.57 ± 7.06
Visit 2-approx. 6 wks	37.74 ± 6.76	37.57 ± 7.07
Visit 3-approx. 12 wks	36.30 ± 6.92	36.33 ± 7.25
Visit 4-approx.24 wks	34.13 ± 8.35	34.48 ± 8.68

Adverse events

Collected over From enrollment up to 24 weeks of treatment.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Enrolled Subjects	0/41 (0%)	2/41 (4.9%)	35/41 (85.4%)
Study Completers	0/23 (0%)	0/23 (0%)	16/23 (69.6%)

Most frequent serious events

Most frequent serious events
Event	Enrolled Subjects	Study Completers
Renal failure acuteRenal and urinary disorders	1/41	0/23
Gallbladder diseaseHepatobiliary disorders	1/41	0/23

Most frequent other events

Showing 10 of 12

Most frequent other events
Event	Enrolled Subjects	Study Completers
DiarrheaGastrointestinal disorders	16/41	9/23
FallInjury, poisoning and procedural complications	10/41	8/23
Decreased appetiteMetabolism and nutrition disorders	8/41	5/23
Unintentional Weight LossMetabolism and nutrition disorders	5/41	4/23
Post Lumbar Puncture SyndromeNervous system disorders	7/41	4/23
NauseaGastrointestinal disorders	6/41	3/23
IndigestionGastrointestinal disorders	4/41	3/23
AbrasionSkin and subcutaneous tissue disorders	4/41	3/23
GastrostomySurgical and medical procedures	4/41	2/23
Post-procedural HematomaInjury, poisoning and procedural complications	2/41	2/23

Baseline characteristics

Subjects who consented to the study.

Age, Categorical
Age, Categorical(Participants)	Enrolled Subjects
<=18 years	0
Between 18 and 65 years	22
>=65 years	19

Age, Continuous
Age, Continuous(years)	Enrolled Subjects
Mean	61.3 ± 7.6

Sex: Female, Male
Sex: Female, Male(Participants)	Enrolled Subjects
Female	17
Male	24

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Enrolled Subjects
Hispanic or Latino	2
Not Hispanic or Latino	39
Unknown or Not Reported	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Enrolled Subjects
American Indian or Alaska Native	0
Asian	1
Native Hawaiian or Other Pacific Islander	0
Black or African American	0
White	40
More than one race	0
Unknown or Not Reported	0

Region of Enrollment
Region of Enrollment(participants)	Enrolled Subjects
United States	41

ALSFRS-R
ALSFRS-R(units on a scale)	Enrolled Subjects
Mean	38.65 ± 6.51

Study locations

1 site

UF Health at the University of Florida
Gainesville, Florida 32610, United States

References and documents

Publications

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. PubMed 10540002 ↗
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. PubMed 16084801 ↗
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. PubMed 8721066 ↗
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. PubMed 25548957 ↗
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. PubMed 31578300 ↗
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. PubMed 25298304 ↗
Brown A, Armon C, Barkhaus P, Beauchamp M, Bertorini T, Bromberg M, Cadavid JM, Carter GT, Crayle J, Feldman EL, Heiman-Patterson T, Jhooty S, Linares A, Li X, Mallon E, Mcdermott C, Mushannen T, Nathaniel G, Pattee G, Pierce K, Ratner D, Slactova L, Wicks P, Bedlack R. ALSUntangled #72: Insulin. Amyotroph Lateral Scler Frontotemporal Degener. 2024 May;25(3-4):416-419. doi: 10.1080/21678421.2023.2288110. Epub 2023 Nov 28. PubMed 38018119 ↗

Study documents

Protocol and statistical analysis plan · Dec 16, 2023
Informed consent form · Apr 6, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Aug 20, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT04220021
Lead sponsor: University of Florida
Collaborators: ALS Association, United States Department of Defense
Responsible party: Sponsor
First posted: Jan 7, 2020
Start date: Jan 10, 2020
Primary completion: Aug 26, 2024
Completion: Aug 31, 2027 (estimated)
Results posted: Dec 2, 2025
Last update: Aug 20, 2026

Study contacts

Laura Ranum, PhD

principal investigator · University of Florida

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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