C9orf72 Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia
Conditions
Keywords
ALS, FTD, Lou Gehrigs Disease
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.
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.
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.
Sponsors
University of Florida
ALS Association
United States Department of Defense
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants receive medication
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability] | 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 |
| Change in Repeat Associated Non-AUG (RAN) Protein Levels | Baseline through week 24. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ALS Functional Rating Scale (ALSFRS-R) Score | Baseline through Week 24 | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORLaura Ranum, PhD
University of Florida
Participant flow
Recruitment details
Recruitment period: 1/3/2020 - 8/28/2023 Recruitment location: University of Florida Neurology Clinic
Participants by arm
| Arm | Count |
|---|---|
| Enrolled Subjects Subjects who consented to participate in the study | 41 |
| Total | 41 |
Baseline characteristics
| Characteristic | Enrolled Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 19 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 61.3 years STANDARD_DEVIATION 7.6 |
| ALSFRS-R | 38.65 units on a scale STANDARD_DEVIATION 6.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 41 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 23 |
| other Total, other adverse events | 35 / 41 | 16 / 23 |
| serious Total, serious adverse events | 2 / 41 | 0 / 23 |
Outcome results
Primary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Study Completers | Change in Repeat Associated Non-AUG (RAN) Protein Levels | -27.93 % change (ng/ml) from study start to end |
Comparison: Sign and binomial test with one-tail analysis where the null hypothesis predicts a 50/50 split (p=0.5) for two outcomes.p-value: 0.0245Sign test
Primary
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
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Completers | Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability] | 0 Participants |
| All Participants | Number of Subjects With Unexpected Treatment-emergent Adverse Events [Safety and Tolerability] | 0 Participants |
Secondary
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
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Completers | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Baseline | 38.61 score on a scale | Standard Deviation 6.73 |
| Study Completers | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 2-approx. 6 wks | 37.74 score on a scale | Standard Deviation 6.76 |
| Study Completers | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 3-approx. 12 wks | 36.30 score on a scale | Standard Deviation 6.92 |
| Study Completers | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 4-approx.24 wks | 34.13 score on a scale | Standard Deviation 8.35 |
| All Participants | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 4-approx.24 wks | 34.48 score on a scale | Standard Deviation 8.68 |
| All Participants | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Baseline | 38.57 score on a scale | Standard Deviation 7.06 |
| All Participants | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 3-approx. 12 wks | 36.33 score on a scale | Standard Deviation 7.25 |
| All Participants | Change in ALS Functional Rating Scale (ALSFRS-R) Score | Visit 2-approx. 6 wks | 37.57 score on a scale | Standard Deviation 7.07 |