Amyotrophic Lateral Sclerosis (ALS)
Conditions
Brief summary
ALS is a disorder that weakens motor strength and lung function. Rapid loss of motor neurons in the brain and spinal cord of ALS patients causes the symptoms of increasing weakness and loss of muscle function. Motor neurons are responsible for sending signals to muscles in our bodies to trigger movement. While there are drugs to help relieve symptoms of ALS, there is no cure for ALS. Rasagiline is a drug with possible neuroprotective characteristics. Neuroprotective means that the nervous system may be protected against weakening. It is known that rasagiline has possible neuroprotective characteristics, but the effectiveness of rasagiline for patients with ALS has not been tested. Rasagiline is approved for the treatment of Parkinson's disease. Rasagiline for treatment of ALS is not approved by the U.S. Food and Drug Administration (FDA) and is investigational. Investigational drugs are studied to find out if they are safe and effective in the treatment of diseases or conditions. By doing this study, researchers hope to learn if rasagiline is safe and slows disease progression in patients with ALS. Funding Source - FDA OOPD (FDA Orphan Products Division).
Detailed description
The study is a phase II, double-blind, placebo-controlled, multicenter study of rasagiline 2mg/day. Subjects will be assigned to either active agent or placebo (3:1) for twelve months. Subjects will undergo outpatient evaluations at screening, baseline, and months 1, 2, 4, 6, 8, 10 and 12 and telephone assessments at months 3, 5, 7 and 9. There will be a close-out phone call 30 days post month 12.
Interventions
DRUGRasagiline
Rasagiline 2mg once a day for 12 months.
DRUGPlacebo
Placebo (looks like study drug but has no active ingredients) once a day for 12 months.
Sponsors
Richard Barohn, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. A clinical diagnosis of laboratory-supported probable, probable, or definite ALS, according to a modified El Escorial criteria, by the study investigator (Appendix IV). 2. 21 to 80 years of age inclusive. 3. VC greater or equal to 75% of predicted at screening and baseline. 4. Onset of weakness within 2 years prior to enrollment. 5. If patients are taking riluzole for ALS, they must be on a stable dose for at least thirty days prior to the baseline visit. 6. Women of childbearing age must be non-lactating and surgically sterile or using an effective method of birth control and have a negative pregnancy test. 7. Willing and able to give signed informed consent that has been approved by the Institutional Review Board (IRB).
Exclusion criteria
1. Requirement for tracheotomy ventilation or non-invasive ventilation for \> 23 hours per day. 2. Patients on sympathomimetic agents. This includes pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine. 3. Patients on analgesics with serotoninergic properties such as meperidine, tramadol, methadone and propoxyphene, flexeril. 4. Patients on fluoxetine or fluvoxamine. 5. Patients taking amitriptyline \> 50 mg/d, trazodone and sertraline \> 100 mg/d, citalopram \> 20 mg/d or paroxetine \> 30 mg/d. 6. Diagnosis of other neurodegenerative diseases (Parkinson disease, Alzheimer disease, etc). 7. Clinically significant history of unstable medical illness (unstable angina, advanced cancer, etc) over the last 30 days. 8. Has a diaphragm pacing device or plan on obtaining a diaphragm pacing device during the course of the study. 9. History of renal disease. 10. History of liver disease. 11. Current pregnancy or lactation. 12. Limited mental capacity such that the patient cannot provide written informed consent or comply with evaluation procedures. 13. History of recent alcohol or drug abuse or noncompliance with treatment or other experimental protocols. 14. Vital Capacity (VC) \< 75% of predicted. 15. Receipt of any investigational drug within the past 30 days. 16. Women with the potential to become pregnant who are not practicing effective birth control. 17. Poorly controlled hypertensive subjects or resting systolic blood pressure (SBP) \> 160 mmHg and/or diastolic (DBP) \> 95 mmHg. 18. Use of BiPAP at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ALS Functional Rating Scale-Revised (ALSFRS-R) | ALS Functional Rating Scale-Revised (ALSFRS-R) Difference from Baseline to Month 12 | Difference in ALS Functional Rating Scale - Revised (ALSFRS-R) score. The ALSFRS-R is an ordinal rating scale that assesses 12 functional activities. Each activity is scored between 0-4, with a total score ranging from 48 (normal function) to 0 (no function). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quality of Life | Quality of Life Change from Baseline to Month 12 | Participants completed the single-item ALSQOL (ALS Quality of Life) which asks participants to rank their global quality of life, considering all parts of their lives - physical, emotional, social, spiritual and financial - in the last 7 days and rate on a scale of 0 (very bad) to 10 (excellent). |
| Number of Participants With Adverse Events | Adverse Events from Baseline to Month 12 | Determine if participants on rasagiline 2 mg had a different safety profile than patients not on rasagiline. Adverse event information to be collected from date of enrollment until end of study participation. |
| Change in Vital Capacity (VC) | Vital Capacity Change from Baseline to Month 12 | Determine if decline in vital capacity is slower in participants taking 2 mg rasagiline than controls. |
| Effect of Study Drug on Apoptosis Markers | Apoptosis Marker change from Baseline to Month 12 | Effect of rasagiline on the apoptosis markers (Annexin V stain) in participants with ALS. Assessed at baseline, month 6, and month 12; change from baseline to month 12 reported. Extra time point was not a pre-specified Primary or Secondary Outcome Measure. |
| Effect of Study Drug on Oxidative Stress | Oxidative Stress change from Baseline to Month 12 | Determine if oxygen radical antioxidant capacity is targeted by rasagiline in participants with ALS. Assessed at baseline, month 6, and month 12; change from baseline to month 12 reported. Extra time point was not a pre-specified Primary or Secondary Outcome Measure. |
| Difference in Survival Status Between Study Groups | Survival status at Month 12 | Determine if there is a difference in survival between participants on rasagiline than patients not on rasagiline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rasagiline Rasagiline 1mg administered orally as a 2mg single dose once daily for 12 months.
Rasagiline: Rasagiline 2mg once a day for 12 months. | 60 |
| Placebo Inactive ingredient equal to 1mg rasagiline 2mg administered as a single dose once daily for 12 months.
Placebo: Placebo (looks like study drug but has no active ingredients) once a day for 12 months. | 20 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death | 5 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Physician decision to withdraw | 6 | 7 |
Baseline characteristics
| Characteristic | Rasagiline | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 10.2 | 57.5 years STANDARD_DEVIATION 8.5 | 57.95 years STANDARD_DEVIATION 9.35 |
| Sex: Female, Male Female | 20 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 40 Participants | 13 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 60 | 1 / 20 |
| other Total, other adverse events | 28 / 60 | 15 / 20 |
| serious Total, serious adverse events | 0 / 60 | 0 / 20 |
Outcome results
Primary
ALS Functional Rating Scale-Revised (ALSFRS-R)
Difference in ALS Functional Rating Scale - Revised (ALSFRS-R) score. The ALSFRS-R is an ordinal rating scale that assesses 12 functional activities. Each activity is scored between 0-4, with a total score ranging from 48 (normal function) to 0 (no function).
Time frame: ALS Functional Rating Scale-Revised (ALSFRS-R) Difference from Baseline to Month 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rasagiline | ALS Functional Rating Scale-Revised (ALSFRS-R) | -1.00 score on a scale |
| Placebo | ALS Functional Rating Scale-Revised (ALSFRS-R) | -1.26 score on a scale |
Secondary
Change in Quality of Life
Participants completed the single-item ALSQOL (ALS Quality of Life) which asks participants to rank their global quality of life, considering all parts of their lives - physical, emotional, social, spiritual and financial - in the last 7 days and rate on a scale of 0 (very bad) to 10 (excellent).
Time frame: Quality of Life Change from Baseline to Month 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rasagiline | Change in Quality of Life | -0.09 Score on a scale |
| Placebo | Change in Quality of Life | -0.12 Score on a scale |
Secondary
Change in Vital Capacity (VC)
Determine if decline in vital capacity is slower in participants taking 2 mg rasagiline than controls.
Time frame: Vital Capacity Change from Baseline to Month 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rasagiline | Change in Vital Capacity (VC) | -2.24 Liters |
| Placebo | Change in Vital Capacity (VC) | -2.48 Liters |
Secondary
Difference in Survival Status Between Study Groups
Determine if there is a difference in survival between participants on rasagiline than patients not on rasagiline
Time frame: Survival status at Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rasagiline | Difference in Survival Status Between Study Groups | 55 Participants |
| Placebo | Difference in Survival Status Between Study Groups | 19 Participants |
Secondary
Effect of Study Drug on Apoptosis Markers
Effect of rasagiline on the apoptosis markers (Annexin V stain) in participants with ALS. Assessed at baseline, month 6, and month 12; change from baseline to month 12 reported. Extra time point was not a pre-specified Primary or Secondary Outcome Measure.
Time frame: Apoptosis Marker change from Baseline to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Effect of Study Drug on Apoptosis Markers | 0.019 percentage of change | Standard Deviation 0.023 |
| Placebo | Effect of Study Drug on Apoptosis Markers | 0.02 percentage of change | Standard Deviation 0.019 |
Secondary
Effect of Study Drug on Oxidative Stress
Determine if oxygen radical antioxidant capacity is targeted by rasagiline in participants with ALS. Assessed at baseline, month 6, and month 12; change from baseline to month 12 reported. Extra time point was not a pre-specified Primary or Secondary Outcome Measure.
Time frame: Oxidative Stress change from Baseline to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Effect of Study Drug on Oxidative Stress | 0.14 pmole/ml | Standard Deviation 0.73 |
| Placebo | Effect of Study Drug on Oxidative Stress | 1.21 pmole/ml | Standard Deviation 2.34 |
Secondary
Number of Participants With Adverse Events
Determine if participants on rasagiline 2 mg had a different safety profile than patients not on rasagiline. Adverse event information to be collected from date of enrollment until end of study participation.
Time frame: Adverse Events from Baseline to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rasagiline | Number of Participants With Adverse Events | 28 Participants |
| Placebo | Number of Participants With Adverse Events | 15 Participants |