Trial Outcomes & Findings for Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD (NCT NCT04220021)

NCT ID: NCT04220021

Last Updated: 2025-12-02

Results Overview

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

• Recruitment status: ACTIVE_NOT_RECRUITING
• Study phase: PHASE2
• Target enrollment: 41 participants
• Primary outcome timeframe: Baseline through 24 weeks
• Results posted on: 2025-12-02

Participant Flow

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

Participant milestones

Measure	Enrolled Subjects Subjects who consented to participate in the study.
Overall Study STARTED	41
Overall Study COMPLETED	23
Overall Study NOT COMPLETED	18

Reasons for withdrawal

Measure	Enrolled Subjects Subjects who consented to participate in the study.
Overall Study Withdrawal by Subject	11
Overall Study Physician Decision	2
Overall Study Non-study related illness	5

Baseline Characteristics

23 subjects who started the study medication and who completed the ALSFRS-R evaluations at baseline and 24 weeks.

Baseline characteristics by cohort

Measure	Enrolled Subjects n=41 Participants Subjects who consented to participate in the study
Age, Categorical <=18 years	0 Participants n=41 Participants
Age, Categorical Between 18 and 65 years	22 Participants n=41 Participants
Age, Categorical >=65 years	19 Participants n=41 Participants
Age, Continuous	61.3 years STANDARD_DEVIATION 7.6 • n=41 Participants
Sex: Female, Male Female	17 Participants n=41 Participants
Sex: Female, Male Male	24 Participants n=41 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=41 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	39 Participants n=41 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=41 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=41 Participants
Race (NIH/OMB) Asian	1 Participants n=41 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=41 Participants
Race (NIH/OMB) Black or African American	0 Participants n=41 Participants
Race (NIH/OMB) White	40 Participants n=41 Participants
Race (NIH/OMB) More than one race	0 Participants n=41 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=41 Participants
Region of Enrollment United States	41 participants n=41 Participants
ALSFRS-R	38.65 units on a scale STANDARD_DEVIATION 6.51 • n=23 Participants • 23 subjects who started the study medication and who completed the ALSFRS-R evaluations at baseline and 24 weeks.

PRIMARY outcome

Timeframe: Baseline through 24 weeks

Population: Forty-one subjects agreed to participate in the study. Twenty-three participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 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

Outcome measures

Measure	Study Completers n=23 Participants Participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 24 weeks.	All Participants n=41 Participants Subjects who consented to participate in the study.
Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability]	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline through week 24.

Population: Data from 17 of the 23 subjects were analyzed: 2 samples were excluded because the subjects were not drug compliant; data from 3 subjects were excluded because GP levels were not reliably detected; 1 sample was excluded because CSF was not able to be collected at the 24 week visit.

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.

Outcome measures

Measure	Study Completers n=17 Participants Participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 24 weeks.	All Participants Subjects who consented to participate in the study.
Change in Repeat Associated Non-AUG (RAN) Protein Levels	-27.93 % change (ng/ml) from study start to end Interval -43.98 to -1.91	—

SECONDARY outcome

Timeframe: Baseline through Week 24

Population: Twenty three subjects were analyzed as per protocol at baseline, week 6 and week 24. Twenty-two subjects were analyzed at week 12 because the ALSFRS-R was not completed due to coronavirus disease 2019 (COVID-19) travel difficulties at the 12 week time point. Two subjects who were not compliant with the medication throughout the study were excluded in "Metformin compliant study completers" study arm.

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.

Outcome measures

Measure	Study Completers n=23 Participants Participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 24 weeks.	All Participants n=21 Participants Subjects who consented to participate in the study.
Change in ALS Functional Rating Scale (ALSFRS-R) Score Visit 3-approx. 12 wks	36.30 score on a scale Standard Deviation 6.92	36.33 score on a scale Standard Deviation 7.25
Change in ALS Functional Rating Scale (ALSFRS-R) Score Visit 4-approx.24 wks	34.13 score on a scale Standard Deviation 8.35	34.48 score on a scale Standard Deviation 8.68
Change in ALS Functional Rating Scale (ALSFRS-R) Score Baseline	38.61 score on a scale Standard Deviation 6.73	38.57 score on a scale Standard Deviation 7.06
Change in ALS Functional Rating Scale (ALSFRS-R) Score Visit 2-approx. 6 wks	37.74 score on a scale Standard Deviation 6.76	37.57 score on a scale Standard Deviation 7.07

Adverse Events

Enrolled Subjects

Serious events: 2 serious events

Other events: 35 other events

Deaths: 0 deaths

Study Completers

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Measure	Enrolled Subjects n=41 participants at risk Subjects consented to participate in the study	Study Completers n=23 participants at risk Study participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 24 weeks.
Renal and urinary disorders Renal failure acute	2.4% 1/41 • Number of events 1 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	0.00% 0/23 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Hepatobiliary disorders Gallbladder disease	2.4% 1/41 • Number of events 1 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	0.00% 0/23 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.

Other adverse events

Measure	Enrolled Subjects n=41 participants at risk Subjects consented to participate in the study	Study Completers n=23 participants at risk Study participants were defined as having "Completed" the study if they started the study medication and completed the ALSFRS-R evaluation at baseline and 24 weeks.
Injury, poisoning and procedural complications Post-procedural Hematoma	4.9% 2/41 • Number of events 2 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	8.7% 2/23 • Number of events 2 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Musculoskeletal and connective tissue disorders Backache	4.9% 2/41 • Number of events 3 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	8.7% 2/23 • Number of events 3 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Nervous system disorders Headache	7.3% 3/41 • Number of events 4 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	4.3% 1/23 • Number of events 1 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Gastrointestinal disorders Diarrhea	39.0% 16/41 • Number of events 21 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	39.1% 9/23 • Number of events 14 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Gastrointestinal disorders Nausea	14.6% 6/41 • Number of events 6 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	13.0% 3/23 • Number of events 3 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Gastrointestinal disorders Indigestion	9.8% 4/41 • Number of events 6 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	13.0% 3/23 • Number of events 4 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Injury, poisoning and procedural complications Fall	24.4% 10/41 • Number of events 20 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	34.8% 8/23 • Number of events 17 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Skin and subcutaneous tissue disorders Abrasion	9.8% 4/41 • Number of events 8 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	13.0% 3/23 • Number of events 7 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Metabolism and nutrition disorders Decreased appetite	19.5% 8/41 • Number of events 8 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	21.7% 5/23 • Number of events 5 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Metabolism and nutrition disorders Unintentional Weight Loss	12.2% 5/41 • Number of events 6 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	17.4% 4/23 • Number of events 5 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Surgical and medical procedures Gastrostomy	9.8% 4/41 • Number of events 4 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	8.7% 2/23 • Number of events 2 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.
Nervous system disorders Post Lumbar Puncture Syndrome	17.1% 7/41 • Number of events 8 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.	17.4% 4/23 • Number of events 5 • From enrollment up to 24 weeks of treatment. Adverse Events are reported as defined by ClinicalTrials.gov definition.

Additional Information

Laura P.W. Ranum, PhD

University of Florida

Phone: (352) 294-5209

Email: ranum@ufl.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place