Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS
Brief summary
This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks. The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and an Off-Treatment Follow-up Phase (4 Weeks). Number of Subjects (Planned): Approximately 45 subjects are planned to be screened with the goal of enrolling 35 subjects.
Detailed description
This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks. The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and a Off-Treatment Follow-up Phase (4 Weeks). During the Screening Phase, eligible ALS subjects will sign an informed consent form and the following screening assessments will be performed: review of inclusion/exclusion criteria: El Escorial ALS Diagnostic criteria, medical history and demographics, ALS diagnosis history, physical and neurological examination, U. Penn upper motor Neuron Burden (UMNB), pulmonary function tests, vital signs including height and weight, blood for safety labs including TSPO affinity test, ECG and review and documentation of concomitant medications and therapies. Screening Phase (up to 6 weeks) The Treatment Phase will consist of a Baseline visit and 3 subsequent clinic visits at Weeks 4, 12, 24, and 36. Telephone follow-ups will occur at Weeks 1, 2, 8, 16, 20, 28, and 32. Open-Label Treatment Phase (36 weeks) At the Baseline visit, subjects will return to the clinic and the following assessments will be performed/administered: review of inclusion and exclusion criteria for continued eligibility, vital signs, blood for safety labs and biomarkers, ECG, ALSFRS-R questionnaire, slow vital capacity (SVC), baseline strength as measured by hand held dynamometry (HHD), and Columbia Suicide Severity Rating Scale (C-SSRS). At this visit, study drug will be dispensed, and adverse events, concomitant medications and therapies will be assessed and documented. At subsequent visits during the Treatment Phase, similar assessments will be performed. In addition, a \[11C\]PBR28-PET scan will be performed once between the Screening and Baseline visit, and once between the Week 12 and Week 28 phone calls. The ALSFRS-R, SVC and U Penn Upper Motor Neuron Burden will be repeated on the same day as the PET scans. The follow-up visit will consist of a telephone call to document adverse events and concomitant therapies
Interventions
DRUGibudilast
Ibudilast is a small molecule that crosses the blood-brain barrier after oral administration. Its potential as a neuroprotective agent is based on in vitro and in vivo evidence of its ability to reduce microglial activation, inhibit microglia-monocyte recruitment to the central nervous system (CNS), and trigger the release of neurotrophic factors.
DRUGIbudilast
Ibudilast is a small molecule that crosses the blood-brain barrier after oral administration. Its potential as a neuroprotective agent is based on in vitro and in vivo evidence of its ability to reduce microglial activation, inhibit microglia-monocyte recruitment to the central nervous system (CNS), and trigger the release of neurotrophic factors.
Sponsors
Massachusetts General Hospital
South Shore Neurologic Associates
MediciNova
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Participants were assigned to one of 2 groups at the discretion of the Principal Investigator.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must be diagnosed as having possible, probable, probable-laboratory supported, or definite ALS, either sporadic or familial according to modified El Escorial criteria. 2. Age 18 or above, able to provide informed consent, and safely comply with study procedures. 3. Vital capacity (VC) of at least 50% predicted value for gender, height and age at screening visit, or in the opinion of the study physician, able to safely tolerate study procedures. (Not applicable to flexible arm) 4. Subject must be able to swallow oral medication at the Baseline Visit and expected to be able to swallow the capsules throughout the course of the study. 5. Subject 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 screening (riluzole-naïve participants are permitted in the study). (Not applicable to flexible arm) 6. Women must not be able to become pregnant (e.g. post-menopausal, surgically sterile, or using adequate birth control) for the duration of the study and 3 months after study completion. 7. Males should practice contraception for the duration of the study and 3 months after completion. 8. Ability to safely lie flat for 90 min for PET procedures in the opinion of the study physician. (Not applicable to flexible arm) 9. High or mixed affinity to bind TSPO protein (Ala/Ala or Ala/Thr) (not applicable to flexible arm). 10. Upper motor Neuron Burden (UMNB) Score ≥25 (out of 45) at screening visit. (Not applicable to flexible arm)
Exclusion criteria
1. Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of the normal. 2. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal. 3. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the participant to provide informed consent, according to PI judgment. 4. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the participant if they were to participate in the study. 5. History of HIV, clinically significant chronic hepatitis, or other active infection. 6. Active inflammatory condition of autoimmune disorder (Not applicable to flexible arm) 7. Females must not be lactating or pregnant. 8. Active participation in another ALS clinical trial or exposure to an off-label ALS experimental treatment within 30 days of the Baseline Visit (Not applicable to flexible arm) 9. Exposure to immunomodulatory medications within 30 days of the Baseline Visit. (Not applicable to flexible arm) 10. Any contraindication to undergo MRI studies such as * History of a cardiac pacemaker or pacemaker wires * Metallic particles in the body * Vascular clips in the head * Prosthetic heart valves * Claustrophobia (Not applicable to flexible arm) 11. Radiation exposure that exceeds the site's current guidelines (Not applicable to flexible arm) 12. EKG finding of QTc prolongation \> 450 msec for males and \> 470 msec for females at screening or baseline. 13. Not on any prohibitive medication or known QT prolonging medication:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Impact of MN-166 on [11C]-PBR28 Uptake in the Motor Cortices and Brain Stem Measured by Positron Emission Tomography (PET) Imaging at 12 - 24 Weeks | 12- 24 weeks (post treatment [11C]-PBR28-PET scan will be performed between the Week 12 and Week 24 visits. | Glial activation will be estimated in eligible participants in the Regular arm by combined magnetic resonance positron emission tomography (MR-PET) using the \[11C\]-PBR28 radioligand. \[11C\]-PBR28 uptake is quantified as the ratio of the standardized uptake value (SUVR). An independent neuroimaging rater blinded to the clinical data will assess for quality control of the PBR28-PET images and SUVR. The primary analysis will be performed on the modified Intent-to-Treat (mITT) population. The median (90% confidence interval \[CI\]) changes from baseline in SUVR from pre- to post-treatment visit will be presented. |
| Impact of MN-166 on Several Markers of Neuro-inflammation Measured by Blood Biomarkers at Week 36 | 36 weeks | Mean change from baseline (pre-dose) to Week 36 in blood biomarkers for neuroinflammation, including macrophage migration inhibitory factor (MIF), tumor necrosis factor (TNF)-alpha, and neurofilament light (NfL). All blood biomarkers are measured in picograms/milliliter (pg/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of MN-166 Over 36 Weeks | 36 weeks | Clinical and laboratory treatment-emergent adverse events (TEAEs) will be collected and stratified by severity, persistence over time, and relationship to study drug. |
| Evaluate the Effect of MN-166 on ALS Clinical Outcomes (ALS Functional Rating Scale-revised [ALSFRS-R]) Over 36 Weeks. | 36 weeks | Mean change from baseline to Week 36 on ALSFRS-R score. ALSFRS-R rating scale is a tool to assess patient's capability and independence in 12 functional activities. The ALSFRS-R total score is a composite of sub-scores measuring speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. Each subscale ranges from 0 (no ability) to 4 (normal ability). The ALSFRS-R score is the sum total ranging from 0 (zero) to 48, with higher scores meaning better outcome. |
| Mean Change From Baseline in Slow Vital Capacity (Percent Predicted) Normal Volume at Week 36 | 36 weeks | Slow vital capacity (SVC) is the maximum volume of air that can be slowly exhaled after slow, maximal inhalation, measured in liters. The maximum volume expired is converted to percent of predicted (% pred.) normal volume. Higher SVC (% pred.) normal volume indicates better pulmonary function. The results below reflect the mean change in SVC (% pred.) from baseline to week 36. |
| Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | 36 weeks | HHD assesses isometric strength using a MicroFET2 hand-held dynamometer in kilograms (kg). To calculate megascores, the mean and standard deviation of each muscle group, without regard to laterality, is calculated from the baseline assessment. Nine upper and lower extremity muscles or muscle groups were examined: shoulder flexion, elbow flexion, wrist extension, first dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each group was measured at least twice bilaterally and the average of the 2 highest measurements were analyzed. To calculate megascores, the mean and standard deviation of each group were calculated from baseline. |
Countries
United States
Participant flow
Pre-assignment details
Analysis Sets: Safety (n=35, n=30 Regular arm, n=5 Flexible arm) = All participants initiated at least the first MN-166 dose. Intent-to-Treat (ITT) (n=30) = All participants initiated at least the first MN-166 dose, excluding Flexible arm. Modified ITT (n=22) = Subset of ITT who completed pre- and post-treatment PET scans. Per Protocol (PP) (n=16) Subset of ITT who successfully titrated up to and maintained the full dose of 50 mg bid.
Participants by arm
| Arm | Count |
|---|---|
| Regular Participants will receive up to 100 mg /day MN-166 for 36 weeks. MN-166 dosing may vary based on individual tolerability. | 30 |
| Flexible Participants will receive up to 100 mg /day MN-166 for 36 weeks. MN-166 dosing may vary based on individual tolerability. Participants will have all assessments except PET scans. | 5 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Flexible | Total | Regular |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 14.3 | 56.6 years STANDARD_DEVIATION 10.7 | 57.1 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 35 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mean delay between symptom onset and ALS diagnosis | 0.74 Mean years | 1.06 Mean years | 1.12 Mean years |
| Mean years since ALS onset | 1.93 mean years since ALS onset | 2.04 mean years since ALS onset | 2.06 mean years since ALS onset |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 5 Participants | 34 Participants | 29 Participants |
| Region of Enrollment United States | 5 participants | 35 participants | 30 participants |
| Sex: Female, Male Female | 1 Participants | 15 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 20 Participants | 16 Participants |
| Site of ALS onset Bulbar onset | 2 Participants | 12 Participants | 10 Participants |
| Site of ALS onset Lower Limb | 2 Participants | 11 Participants | 9 Participants |
| Site of ALS onset Upper Limb | 1 Participants | 12 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 30 | 0 / 5 |
| other Total, other adverse events | 30 / 30 | 5 / 5 |
| serious Total, serious adverse events | 6 / 30 | 0 / 5 |
Outcome results
Primary
Impact of MN-166 on [11C]-PBR28 Uptake in the Motor Cortices and Brain Stem Measured by Positron Emission Tomography (PET) Imaging at 12 - 24 Weeks
Glial activation will be estimated in eligible participants in the Regular arm by combined magnetic resonance positron emission tomography (MR-PET) using the \[11C\]-PBR28 radioligand. \[11C\]-PBR28 uptake is quantified as the ratio of the standardized uptake value (SUVR). An independent neuroimaging rater blinded to the clinical data will assess for quality control of the PBR28-PET images and SUVR. The primary analysis will be performed on the modified Intent-to-Treat (mITT) population. The median (90% confidence interval \[CI\]) changes from baseline in SUVR from pre- to post-treatment visit will be presented.
Time frame: 12- 24 weeks (post treatment [11C]-PBR28-PET scan will be performed between the Week 12 and Week 24 visits.
Population: modified Intent-to-Treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regular | Impact of MN-166 on [11C]-PBR28 Uptake in the Motor Cortices and Brain Stem Measured by Positron Emission Tomography (PET) Imaging at 12 - 24 Weeks | 0.0015 SUV ratio |
Primary
Impact of MN-166 on Several Markers of Neuro-inflammation Measured by Blood Biomarkers at Week 36
Mean change from baseline (pre-dose) to Week 36 in blood biomarkers for neuroinflammation, including macrophage migration inhibitory factor (MIF), tumor necrosis factor (TNF)-alpha, and neurofilament light (NfL). All blood biomarkers are measured in picograms/milliliter (pg/mL).
Time frame: 36 weeks
Population: Intent-to-Treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regular | Impact of MN-166 on Several Markers of Neuro-inflammation Measured by Blood Biomarkers at Week 36 | macrophage migration inhibitory factor | -673387.22 picograms/milliliters | Standard Deviation 943313.53 |
| Regular | Impact of MN-166 on Several Markers of Neuro-inflammation Measured by Blood Biomarkers at Week 36 | tumor necrosis factor-alpha | -0.31 picograms/milliliters | Standard Deviation 0.57 |
| Regular | Impact of MN-166 on Several Markers of Neuro-inflammation Measured by Blood Biomarkers at Week 36 | neurofilament light | 21.43 picograms/milliliters | Standard Deviation 47.71 |
Secondary
Evaluate the Effect of MN-166 on ALS Clinical Outcomes (ALS Functional Rating Scale-revised [ALSFRS-R]) Over 36 Weeks.
Mean change from baseline to Week 36 on ALSFRS-R score. ALSFRS-R rating scale is a tool to assess patient's capability and independence in 12 functional activities. The ALSFRS-R total score is a composite of sub-scores measuring speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. Each subscale ranges from 0 (no ability) to 4 (normal ability). The ALSFRS-R score is the sum total ranging from 0 (zero) to 48, with higher scores meaning better outcome.
Time frame: 36 weeks
Population: Intent-to-Treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Regular | Evaluate the Effect of MN-166 on ALS Clinical Outcomes (ALS Functional Rating Scale-revised [ALSFRS-R]) Over 36 Weeks. | -4.5 Total ALSFRS-R score | Standard Deviation 4.5 |
Secondary
Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36.
HHD assesses isometric strength using a MicroFET2 hand-held dynamometer in kilograms (kg). To calculate megascores, the mean and standard deviation of each muscle group, without regard to laterality, is calculated from the baseline assessment. Nine upper and lower extremity muscles or muscle groups were examined: shoulder flexion, elbow flexion, wrist extension, first dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each group was measured at least twice bilaterally and the average of the 2 highest measurements were analyzed. To calculate megascores, the mean and standard deviation of each group were calculated from baseline.
Time frame: 36 weeks
Population: Intent-to-Treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | upper limbs, proximal | -0.5803 kilograms | Standard Deviation 0.8108 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | upper limbs, distal | -0.5004 kilograms | Standard Deviation 0.4823 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | upper limbs, cumulated | -0.5324 kilograms | Standard Deviation 0.5738 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | lower limbs, proximal | -0.2778 kilograms | Standard Deviation 0.7749 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | lower limbs, distal | -0.3525 kilograms | Standard Deviation 0.6492 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | lower limbs, cumulated | -0.3151 kilograms | Standard Deviation 0.6824 |
| Regular | Mean Change From Baseline in Isometric Strength as Measured by Hand-held Dynamometry (HHD) at Week 36. | cumulated | -0.4358 kilograms | Standard Deviation 0.5863 |
Secondary
Mean Change From Baseline in Slow Vital Capacity (Percent Predicted) Normal Volume at Week 36
Slow vital capacity (SVC) is the maximum volume of air that can be slowly exhaled after slow, maximal inhalation, measured in liters. The maximum volume expired is converted to percent of predicted (% pred.) normal volume. Higher SVC (% pred.) normal volume indicates better pulmonary function. The results below reflect the mean change in SVC (% pred.) from baseline to week 36.
Time frame: 36 weeks
Population: Intent-to-Treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Regular | Mean Change From Baseline in Slow Vital Capacity (Percent Predicted) Normal Volume at Week 36 | -9.27 percent predicted normal volume | Standard Deviation 11.23 |
Secondary
Safety and Tolerability of MN-166 Over 36 Weeks
Clinical and laboratory treatment-emergent adverse events (TEAEs) will be collected and stratified by severity, persistence over time, and relationship to study drug.
Time frame: 36 weeks
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regular | Safety and Tolerability of MN-166 Over 36 Weeks | 30 Participants |
| Flexible | Safety and Tolerability of MN-166 Over 36 Weeks | 5 Participants |