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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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C9orf72 Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: All participants receive medication
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C9orf72 positive ALS<br>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<br>* 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.<br>* Other names: Metformin hydrochloride sustained-release (SR);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with 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 RAN protein levels | Assess the RAN protein levels in cerebrospinal fluid (CSF) samples from participants at specific intervals. | baseline through week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ALS Functional Rating Scale (ALSFRS-R) score | 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. | Baseline through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, FTD, Lou Gehrigs Disease