Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Gilenya, Fingolimod
Brief summary
The purpose of this study is to determine whether Gilenya, also known as fingolimod, is safe and tolerable in patients with Amyotrophic Lateral Sclerosis (ALS).
Detailed description
The primary objective of the study is to determine the acute safety and tolerability of oral administration of Gilenya (fingolimod) 0.5mg daily vs. matched oral placebo administered daily. The primary outcome measure will be safety and tolerability; safety will be assessed by the occurrence of adverse events and clinically meaningful changes in vital signs, ophthalmologic examination, physical examination, electrocardiogram and standard clinical laboratory blood tests, and tolerability will be defined as the ability of subjects to complete the entire 4-week study. The secondary outcome measure will be the measured effect of the treatment on circulating lymphocyte populations in patients with ALS. Exploratory outcome measures will include the rate of decline of the ALS Functional Rating Scale (Revised) (ALSFRS-R) and Slow Vital Capacity (VC) during the course of treatment. This study will be conducted in subjects who meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At screening, eligible subjects must be at least 18 years old, must have an SVC ≥ 65% of predicted capacity for age, height and gender, and must provide written informed consent prior to screening. Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at screening are eligible for inclusion as long as they meet specific protocol requirements. Subjects will remain on randomized, placebo-controlled, double-blind treatment until the Week 4 visit. Each randomized subject will also have a Week 8 Follow-up Telephone Interview to assess for adverse events (AEs), changes in concomitant medications and to administer the ALSFRS-R.
Interventions
DRUGGilenya
0.5mg Gilenya orally by mouth once daily for approximately 28 days
OTHERPlacebo
0.5mg placebo (sugar pill) orally by mouth once daily for approximately 28 days
Sponsors
ALS Therapy Development Institute
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years or older. 2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1). 3. Onset of weakness or spasticity due to ALS ≤ 2 years (24 months) prior to Baseline Visit. 4. Slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at the screening visit. 5. Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to randomization (riluzole-naïve subjects are permitted in the study). 6. Subjects must be able to swallow oral medication at the Screening Visit and expected to be able to swallow the capsule throughout the course of the study. 7. Capable of providing informed consent and following trial procedures. 8. Geographically accessible to the site. 9. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal (patch or contraceptive ring, for example) contraception), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method. 10. Subjects must agree not to take live attenuated vaccines (including seasonal flu vaccine) 30 days before randomization, throughout the duration of the trial and for 60 days following the trial.
Exclusion criteria
1. Prior use of fingolimod (Gilenya®). 2. History or presence of cardiac conditions including: 1. Cardiovascular or cerebrovascular disease in the previous 6 months (eg. myocardial infarction, unstable angina, or stroke) 2. Congestive heart failure 3. First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances 4. Any history of Torsades de Pointes 3. Treatment with a prohibited medication within 30 days of the Baseline Visit: a. Class Ia or III antiarrhythmic medications: i.e., Quinidine, Sotalol Includes Nuedexta b. QT interval prolonging medications c. Ketoconazole d. Beta-blockers e. Calcium channel blockers f. Immunosuppressant medication g. Chemotherapeutic (anti-neoplastic) medications 4. Evidence on examination or ECG of bradycardia (\<55 bpm), QTc \>450ms for women or \>430 msec for men, or 1st degree or higher conduction block. 5. History of unexplained syncope or cardiac syncope. 6. Serum AST and ALT value \>2.0 times the upper normal limit. 7. Active infection (acute or chronic). 8. History of diabetes. 9. History of macular edema or uveitis. 10. History of lymphopenia. 11. History of acquired or inherited immune deficiency syndrome, including leukopenia. 12. History of severe untreated chronic obstructive sleep apnea. 13. Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Baseline Visit. 14. Presence of tracheostomy. 15. Use of non-invasive ventilation for hypoventilation due to ALS (such as BiPAP). 16. Presence of feeding tube. 17. Presence of diaphragmatic pacing system. 18. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to PI judgment, or a history of active substance abuse within the prior year. 19. Clinically significant history of unstable or severe cardiac, oncologic, hepatic, or renal disease, or other medically significant illness. 20. Pregnant women or women currently breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 0, Week 2, Week 4 and Week 8 | The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival. |
| Change in Slow Vital Capacity Score (SVC) | Week 0, Week 2, Week 4 and Week 8 | The vital capacity (VC) (percent of predicted normal) was determined using the slow VC method. Vital Capacity is the maximum amount of air a person can expel from the lungs after a maximum inhalation. A subject's VC depends on their age, sex and height. The value is recorded as a percent of predicted normal. |
| Forced Expiratory Volume in 1 Second (FEV1) | Screening, Week 0, Week 2, and Week 4 | Forced Expiratory Volume (FEV1): Forced Expiratory Volume (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lymphocyte (T-Cell) Subset Trajectories | Week 0, Week 2, and Week 4 | Gilenya (fingolimod) has been shown to successfully reduce circulating lymphocytes (a type of white blood cell) by blocking their egress (exit) from the lymph nodes. A secondary objective of the study is to quantify the effect of the treatment on circulating lymphocyte populations in patients with ALS. |
| Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Screening, Week 0, Week 2, and Week 4 | Forced Expiratory Volume (FEV1): Forced Expiratory Volume (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Slow Vital Capacity (SVC): Vital Capacity is the maximum amount of air a person can expel from the lungs after a maximum inhalation. A subject's VC depends on their age, sex and height. The value is recorded as a percent of predicted normal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gilenya (Fingolimod) 0.5mg Gilenya (fingolimod) orally once daily for 28 days +/- 3 days
Gilenya: 0.5mg Gilenya orally by mouth once daily for approximately 28 days | 18 |
| Placebo 0.5mg placebo (sugar pill) orally once daily for 28 days +/- 3 days
Placebo: 0.5mg placebo (sugar pill) orally by mouth once daily for approximately 28 days | 10 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued Study Drug | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Gilenya (Fingolimod) | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 11.3 | 56.4 years STANDARD_DEVIATION 8 | 55.9 years STANDARD_DEVIATION 9.1 |
| ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | 37.9 Score on a Scale STANDARD_DEVIATION 5.8 | 38.8 Score on a Scale STANDARD_DEVIATION 4.1 | 38.5 Score on a Scale STANDARD_DEVIATION 4.7 |
| Body Mass Index (BMI) | 26.3 kilograms/meter^2 (kg/m^2) STANDARD_DEVIATION 4.9 | 26.1 kilograms/meter^2 (kg/m^2) STANDARD_DEVIATION 3 | 26.2 kilograms/meter^2 (kg/m^2) STANDARD_DEVIATION 3.7 |
| Bulbar Onset Bulbar Onset | 4 participants | 2 participants | 6 participants |
| Bulbar Onset Other | 6 participants | 16 participants | 22 participants |
| El Escorial Criteria (EEC) Definite | 4 participants | 11 participants | 15 participants |
| El Escorial Criteria (EEC) Probable | 3 participants | 6 participants | 9 participants |
| El Escorial Criteria (EEC) Probable Laboratory Supported | 3 participants | 1 participants | 4 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Forced Expiratory Volume (FEV1) (max %-predicted) | 81.4 % of Predicted Max Value STANDARD_DEVIATION 27.9 | 83.5 % of Predicted Max Value STANDARD_DEVIATION 16.1 | 82.8 % of Predicted Max Value STANDARD_DEVIATION 20.6 |
| Months Since Diagnosis | 6.0 Months STANDARD_DEVIATION 4 | 5.5 Months STANDARD_DEVIATION 3.9 | 5.7 Months STANDARD_DEVIATION 3.9 |
| Months Since Symptom Onset | 15.0 Months STANDARD_DEVIATION 6.2 | 12.6 Months STANDARD_DEVIATION 4.8 | 13.5 Months STANDARD_DEVIATION 5.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 18 Participants | 26 Participants |
| Region of Enrollment United States | 10 participants | 18 participants | 28 participants |
| Riluzole Usage at Screening Not on riluzole at screening | 4 participants | 7 participants | 11 participants |
| Riluzole Usage at Screening On riluzole at screening | 6 participants | 11 participants | 17 participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 15 Participants |
| Slow Vital Capacity (max %-predicted) | 82.8 % of Predicted Max Value STANDARD_DEVIATION 21.9 | 92.8 % of Predicted Max Value STANDARD_DEVIATION 18.5 | 89.2 % of Predicted Max Value STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 18 | 8 / 10 |
| serious Total, serious adverse events | 0 / 18 | 0 / 10 |
Outcome results
Primary
ALSFRS-R Total Score at Weeks 0, 2, 4 and 8
The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.
Time frame: Week 0, Week 2, Week 4 and Week 8
Population: The reported results are model estimates from a model that estimates a single baseline value across all randomized participants, i.e., reflecting the true state of the population prior to randomization.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gilenya (Fingolimod) | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 2 | 38.15 scores on a scale |
| Gilenya (Fingolimod) | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 0 | 38.60 scores on a scale |
| Gilenya (Fingolimod) | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 8 | 36.74 scores on a scale |
| Gilenya (Fingolimod) | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 4 | 38.03 scores on a scale |
| Placebo | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 8 | 37.10 scores on a scale |
| Placebo | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 0 | 38.60 scores on a scale |
| Placebo | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 4 | 37.88 scores on a scale |
| Placebo | ALSFRS-R Total Score at Weeks 0, 2, 4 and 8 | Week 2 | 38.29 scores on a scale |
Comparison: Fingolimod vs. Placebo Weeks 0-4p-value: 0.7895% CI: [-1.53, 2.03]Random slopes model
Primary
Change in Slow Vital Capacity Score (SVC)
The vital capacity (VC) (percent of predicted normal) was determined using the slow VC method. Vital Capacity is the maximum amount of air a person can expel from the lungs after a maximum inhalation. A subject's VC depends on their age, sex and height. The value is recorded as a percent of predicted normal.
Time frame: Week 0, Week 2, Week 4 and Week 8
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gilenya (Fingolimod) | Change in Slow Vital Capacity Score (SVC) | Week 4 | 86.51 Percentage of predicted max value |
| Gilenya (Fingolimod) | Change in Slow Vital Capacity Score (SVC) | Week 2 | 88.54 Percentage of predicted max value |
| Gilenya (Fingolimod) | Change in Slow Vital Capacity Score (SVC) | Week 8 | 86.02 Percentage of predicted max value |
| Gilenya (Fingolimod) | Change in Slow Vital Capacity Score (SVC) | Week 0 | 88.28 Percentage of predicted max value |
| Placebo | Change in Slow Vital Capacity Score (SVC) | Week 8 | 87.59 Percentage of predicted max value |
| Placebo | Change in Slow Vital Capacity Score (SVC) | Week 2 | 88.54 Percentage of predicted max value |
| Placebo | Change in Slow Vital Capacity Score (SVC) | Week 4 | 86.70 Percentage of predicted max value |
| Placebo | Change in Slow Vital Capacity Score (SVC) | Week 0 | 88.28 Percentage of predicted max value |
Comparison: Fingolimod vs. Placebo Weeks 0-4p-value: 0.82395% CI: [-5, 3.99]Random slopes model
Primary
Forced Expiratory Volume in 1 Second (FEV1)
Forced Expiratory Volume (FEV1): Forced Expiratory Volume (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Time frame: Screening, Week 0, Week 2, and Week 4
Population: The reported results are model estimates from a model that estimates a single baseline value across all randomized participants, i.e., reflecting the true state of the population prior to randomization.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) | Screening | 84.70 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) | Week 0 | 81.93 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) | Week 2 | 81.19 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) | Week 4 | 80.38 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) | Week 4 | 78.16 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) | Screening | 84.70 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) | Week 2 | 80.30 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) | Week 0 | 81.93 Percentage of predicted max value |
Secondary
Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio
Forced Expiratory Volume (FEV1): Forced Expiratory Volume (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Slow Vital Capacity (SVC): Vital Capacity is the maximum amount of air a person can expel from the lungs after a maximum inhalation. A subject's VC depends on their age, sex and height. The value is recorded as a percent of predicted normal.
Time frame: Screening, Week 0, Week 2, and Week 4
Population: The reported results are model estimates from a model that estimates a single baseline value across all randomized participants, i.e., reflecting the true state of the population prior to randomization.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Screening | 77.39 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 0 | 74.36 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 2 | 75.46 Percentage of predicted max value |
| Gilenya (Fingolimod) | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 4 | 76.34 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 4 | 71.49 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Screening | 77.39 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 2 | 73.14 Percentage of predicted max value |
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) / Slow Vital Capacity (SVC) Ratio | Week 0 | 74.36 Percentage of predicted max value |
Comparison: Fingolimod vs. Placebo Weeks 0-4p-value: 0.29495% CI: [-3.78, 12.33]Random slopes model
Secondary
Lymphocyte (T-Cell) Subset Trajectories
Gilenya (fingolimod) has been shown to successfully reduce circulating lymphocytes (a type of white blood cell) by blocking their egress (exit) from the lymph nodes. A secondary objective of the study is to quantify the effect of the treatment on circulating lymphocyte populations in patients with ALS.
Time frame: Week 0, Week 2, and Week 4
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gilenya (Fingolimod) | Lymphocyte (T-Cell) Subset Trajectories | Week 0 | 1.751 10^3/uL |
| Gilenya (Fingolimod) | Lymphocyte (T-Cell) Subset Trajectories | Week 2 | 0.580 10^3/uL |
| Gilenya (Fingolimod) | Lymphocyte (T-Cell) Subset Trajectories | Week 4 | 0.499 10^3/uL |
| Placebo | Lymphocyte (T-Cell) Subset Trajectories | Week 0 | 1.751 10^3/uL |
| Placebo | Lymphocyte (T-Cell) Subset Trajectories | Week 2 | 1.732 10^3/uL |
| Placebo | Lymphocyte (T-Cell) Subset Trajectories | Week 4 | 1.822 10^3/uL |
Comparison: Fingolimod vs. Placebo Weeks 0-4p-value: 0.74695% CI: [-7.17, 9.96]Random slopes model