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

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ClinicalTrials.gov Identifier: NCT04220021
Recruitment Status : Recruiting
First Posted : January 7, 2020
Last Update Posted : September 16, 2022
Information provided by (Responsible Party):
University of Florida

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.

Condition or disease Intervention/treatment Phase
C9orf72 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia Drug: Metformin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Center, Open Label Study to Assess the Safety and Tolerability of Metformin in Subjects With C9orf72 Amyotrophic Lateral Sclerosis Over 24 Weeks of Treatment
Actual Study Start Date : January 10, 2020
Estimated Primary Completion Date : April 6, 2023
Estimated Study Completion Date : April 6, 2023

Arm Intervention/treatment
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
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.
Other Name: Metformin hydrochloride sustained-release (SR)

Primary Outcome Measures :
  1. Number of subjects with treatment-emergent adverse events [Safety and Tolerability] [ Time Frame: Baseline through 24 weeks ]
    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

  2. Change in RAN protein levels [ Time Frame: baseline through week 24 ]
    Assess the RAN protein levels in cerebrospinal fluid (CSF) samples from participants at specific intervals.

Secondary Outcome Measures :
  1. Change in ALS Functional Rating Scale (ALSFRS-R) score [ Time Frame: Baseline through Week 52 ]
    The ALSFRS-R is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities/questions. Scores of 4 equaling 'normal' and scores of 0 equaling total lack of ability.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04220021

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Contact: Deborah Morrison, MA 352-273-5189 dgmorrison@ufl.edu

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United States, Florida
UF Health at the University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Deborah Morrison, MA    352-273-5189    dgmorrison@ufl.edu   
Principal Investigator: Laura Ranum, PHD         
Sub-Investigator: James Wymer, MD, PHD         
Sub-Investigator: Emily Plowman, PHD, CCC-SLP         
Sponsors and Collaborators
University of Florida
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Principal Investigator: Laura Ranum, PhD University of Florida
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT04220021    
Other Study ID Numbers: IRB201800620
UF2019-001 ( Other Identifier: University of Florida )
OCR20620 ( Other Identifier: UF OnCore )
UF2019-001 ( Other Identifier: UF Protocol ID )
First Posted: January 7, 2020    Key Record Dates
Last Update Posted: September 16, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Neuromuscular Diseases
Spinal Cord Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Frontotemporal Lobar Degeneration
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Hypoglycemic Agents
Physiological Effects of Drugs