A Biomarker Study to Evaluate MN-166 in Subjects With Amyotrophic Literal Sclerosis (ALS)
NCT ID: NCT02714036
Last Updated: 2024-09-24
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE1/PHASE2
Total Enrollment
35 participants
Study Classification
INTERVENTIONAL
Study Start Date
2016-05-06
Study Completion Date
2020-06-30
Brief Summary
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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.
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.
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Detailed Description
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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
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
Conditions
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Amyotrophic Lateral Sclerosis
Study Design
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Allocation Method
NON_RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Participants were assigned to one of 2 groups at the discretion of the Principal Investigator.
Study Groups
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Regular
Participants will receive up to 100 mg /day MN-166 for 36 weeks. MN-166 dosing may vary based on individual tolerability.
Group Type
EXPERIMENTAL
ibudilast
Intervention Type
DRUG
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.
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.
Group Type
EXPERIMENTAL
Ibudilast
Intervention Type
DRUG
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.
Interventions
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ibudilast
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.
Intervention Type
DRUG
Ibudilast
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.
Intervention Type
DRUG
Other Intervention Names
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MN-166
MN-166
Eligibility Criteria
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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)
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:
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:
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Massachusetts General Hospital
OTHER
Sponsor Role
collaborator
South Shore Neurologic Associates
INDUSTRY
Sponsor Role
collaborator
MediciNova
INDUSTRY
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Suma Babu, MBBS, MPH
Role: PRINCIPAL_INVESTIGATOR
Massachusetts General Hospital
Locations
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Massachusetts General Hospital
Boston, Massachusetts, United States
Site Status
South Shore Neurologic Associates, P.C.
Patchogue, New York, United States
Site Status
Countries
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United States
References
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Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004 Feb;55(2):221-35. doi: 10.1002/ana.10805.
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BACKGROUND
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Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11313-8. doi: 10.1073/pnas.1002716107. Epub 2010 Jun 8.
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BACKGROUND
Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res. 1999 Aug 7;837(1-2):203-12. doi: 10.1016/s0006-8993(99)01666-2.
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Kiebala M, Maggirwar SB. Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells. PLoS One. 2011 Apr 8;6(4):e18633. doi: 10.1371/journal.pone.0018633.
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Kagitani-Shimono K, Mohri I, Fujitani Y, Suzuki K, Ozono K, Urade Y, Taniike M. Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model. J Neuroinflammation. 2005 Apr 6;2(1):10. doi: 10.1186/1742-2094-2-10.
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Fujimoto T, Sakoda S, Fujimura H, Yanagihara T. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol. 1999 Mar 1;95(1-2):35-42. doi: 10.1016/s0165-5728(98)00251-3.
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Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R; MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010 Mar 30;74(13):1033-40. doi: 10.1212/WNL.0b013e3181d7d651. Epub 2010 Mar 3.
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Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur J Pharmacol. 2006 May 24;538(1-3):39-42. doi: 10.1016/j.ejphar.2006.02.053. Epub 2006 Mar 13.
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BACKGROUND
Tominaga Y, Nakamura Y, Tsuji K, Shibata T, Kataoka K. Ibudilast protects against neuronal damage induced by glutamate in cultured hippocampal neurons. Clin Exp Pharmacol Physiol. 1996 Jun-Jul;23(6-7):519-23. doi: 10.1111/j.1440-1681.1996.tb02772.x.
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BACKGROUND
Takuma K, Lee E, Enomoto R, Mori K, Baba A, Matsuda T. Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. Br J Pharmacol. 2001 Jul;133(6):841-8. doi: 10.1038/sj.bjp.0704146.
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BACKGROUND
Yoshioka A, Shimizu Y, Hirose G, Kitasato H, Pleasure D. Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity. J Neurochem. 1998 Jun;70(6):2416-23. doi: 10.1046/j.1471-4159.1998.70062416.x.
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BACKGROUND
Fox RJ. Primary neuroprotection: the Holy Grail of multiple sclerosis therapy. Neurology. 2010 Mar 30;74(13):1018-9. doi: 10.1212/WNL.0b013e3181d6b165. Epub 2010 Mar 3. No abstract available.
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Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. doi: 10.1038/jcbfm.2011.147. Epub 2011 Oct 19.
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BACKGROUND
Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB; Biomarkers Consortium PET Radioligand Project Team. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab. 2013 Jan;33(1):53-8. doi: 10.1038/jcbfm.2012.131. Epub 2012 Sep 12.
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BACKGROUND
Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, Lawson RJ, Frosch MP, Pochet N, Fatimy RE, Krichevsky AM, Gygi SP, Lassmann H, Berry J, Cudkowicz ME, Weiner HL. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol. 2015 Jan;77(1):75-99. doi: 10.1002/ana.24304. Epub 2014 Nov 27.
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BACKGROUND
Babu S, Hightower BG, Chan J, Zurcher NR, Kivisakk P, Tseng CJ, Sanders DL, Robichaud A, Banno H, Evora A, Ashokkumar A, Pothier L, Paganoni S, Chew S, Dojillo J, Matsuda K, Gudesblatt M, Berry JD, Cudkowicz ME, Hooker JM, Atassi N. Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial. Neuroimage Clin. 2021;30:102672. doi: 10.1016/j.nicl.2021.102672. Epub 2021 Apr 15.
Reference Type
DERIVED
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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MN-166-ALS-1202
Identifier Type: -
Identifier Source: org_study_id
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NCT02525471
COMPLETED
PHASE1
Muscular Biomarkers in Amyotrophic Lateral Sclerosis
NCT02670226
COMPLETED
NA
Safety, Tolerability, and Exploratory Efficacy Study of Intrathecally Administered Gene Therapy AMT-162 in Adult Participants With SOD1 Amyotrophic Lateral Sclerosis (SOD1-ALS)
NCT06100276
ACTIVE_NOT_RECRUITING
PHASE1/PHASE2
iPSC-based Drug Repurposing for ALS Medicine (iDReAM) Study
NCT04744532
UNKNOWN
PHASE1/PHASE2
Methodology Study of Novel Outcome Measures to Assess Progression of ALS
NCT02611674
COMPLETED
A Study to Evaluate the Safety, Tolerability and Efficacy of ILB in Patients With Amyotrophic Lateral Sclerosis
NCT03613571
TERMINATED
PHASE2
Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04165824
COMPLETED
PHASE3
Dose-Escalation, Safety and Pharmacokinetic Study of IC14 in Motor Neurone Disease
NCT03487263
COMPLETED
PHASE1
A Study of STRO4 in Patients Amyotrophic Lateral Sclerosis (ALS)
NCT06910384
TERMINATED
PHASE2
Neuromuscular Magnetic Stimulation in ALS Patients
NCT03618966
COMPLETED
PHASE2
Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT00677768
COMPLETED
A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy
NCT04641962
TERMINATED
PHASE2
Study of Safety and Proof of the Mechanism of BLZ945 in ALS Patients
NCT04066244
TERMINATED
PHASE2
A follow-on Study to Assess Long-term Safety and Tolerability of i.c.v Administration of sNN0029 in Patients With ALS
NCT02269436
TERMINATED
PHASE1