MN-166 for ALS

(COMBAT-ALS Trial)

Recruiting at 21 trial locations

Overseen By Yuichi Iwaki

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: MediciNova

Must not be taking: High-dose Vitamin B12

Disqualifiers: Hepatic insufficiency, Psychiatric disorder, Dementia, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

230 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase 2b/3 multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety and tolerability of MN-166 given to ALS participants for 12 months followed by a 6-month open-label extension phase.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are using riluzole or edaravone, you must be on a stable dose or have completed a treatment cycle before starting the study drug.

What data supports the effectiveness of the drug MN-166 (ibudilast) for ALS?

Early-phase studies suggest that MN-166 (ibudilast) may help protect nerve cells and slow down the progression of ALS by reducing inflammation in the brain. However, a trial showed no significant reduction in brain inflammation or nerve damage, and many participants experienced side effects, leading to dose reductions or stopping the drug. ^{1 2 3 4 5}

Is MN-166 (ibudilast) safe for humans?

In a study with ALS patients, 86% experienced at least one adverse event possibly related to MN-166 (ibudilast), and 31% discontinued due to these events. Some participants could not tolerate the highest dose and required a reduction, indicating that while it has been tested in humans, there are safety concerns at higher doses. ^{2 3 4 6 7}

What makes the drug MN-166 (ibudilast) unique for treating ALS?

MN-166 (ibudilast) is unique for ALS treatment because it works by reducing inflammation in the brain and spinal cord, which may help protect nerve cells. It does this by inhibiting certain enzymes and proteins that contribute to inflammation and nerve damage, which is different from the limited existing treatments that only slightly prolong survival. ^{2 4 5 8 9}

Research Team

Project Management Team

Principal Investigator

Medicinova Inc

Eligibility Criteria

This trial is for adults aged 18-80 with ALS diagnosed within the last 18 months. Participants must have a certain level of lung function and be able to swallow pills, without severe liver issues or psychiatric disorders that could interfere with assessments. They shouldn't be on high-dose Vitamin B12 injections or involved in other studies recently.

Inclusion Criteria

Last documented pulmonary function test result (i.e., slow vital capacity or forced vital capacity) must be greater than or equal to 70% predicted

I have been diagnosed with ALS according to the El Escorial criteria.

My ALS symptoms started less than 18 months ago.

Exclusion Criteria

I have been treated with high dose Vitamin B12 injections recently.

Poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator

I use a tracheostomy or need help breathing most of the day.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Double-blind Treatment

Participants receive either MN-166 or placebo for 12 months in a double-blind manner

12 months

Monthly visits (in-person)

Open-label Extension

Participants may opt into continuation of MN-166 treatment for an additional 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• MN-166
• Placebo

Trial Overview The study tests MN-166 against a placebo over 12 months to see if it's effective and safe for ALS patients, followed by everyone getting MN-166 for another six months. It's randomized (participants are put into groups by chance) and double-blind (neither participants nor researchers know who gets what treatment).

Participant Groups

Group I: MN-166 Experimental Treatment 1 Intervention

Subjects will take MN-166 10 mg capsules, up to 50 mg twice a day for 12 months.

Group II: placebo Placebo Group 1 Intervention

Subjects will take up to 5 matching placebo capsules twice a day for 12 months.

MN-166 is already approved in Japan for the following indications:

Approved in Japan as Ibudilast for:

• Anti-inflammatory

Who Is Running the Clinical Trial?

MediciNova

Lead Sponsor

Trials

21

Recruited

1,500+

Findings from Research

The MND-SMART trial aims to evaluate the efficacy of trazodone and memantine in treating motor neuron disease (MND) with up to 531 participants, using a novel adaptive trial design that allows for efficient evaluation of multiple drugs.

The primary outcomes of the trial are the ALS Functional Rating Scale and survival, with the design reducing the time, cost, and number of participants needed to assess drug effectiveness, while minimizing exposure to ineffective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease. Wong, C., Dakin, RS., Williamson, J., et al.[2023]

In a 36-week open-label trial involving 35 ALS participants, ibudilast treatment at doses up to 100 mg/day did not significantly reduce glial activation or neuroaxonal loss, as measured by PBR28-PET and serum Neurofilament light (NfL).

The treatment was associated with a high incidence of adverse events, with 86% of participants experiencing at least one possibly drug-related side effect, leading to dose reductions in 37% of participants and early discontinuation in 31%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial. Babu, S., Hightower, BG., Chan, J., et al.[2023]

Dexpramipexole was found to be safe and well tolerated in a two-part study involving subjects with ALS, with doses of 50, 150, or 300 mg assessed over 12 weeks.

The study showed promising trends indicating that dexpramipexole may slow functional decline in ALS patients, with a statistically significant difference in outcomes related to functional rating and mortality in the second part of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Cudkowicz, M., Bozik, ME., Ingersoll, EW., et al.[2022]

MN-166 (ibudilast) shows promise as a neuroprotective treatment for ALS by inhibiting inflammation and glial cell activation, with early studies indicating potential improvements in survival and disease progression.

The ongoing COMBAT-ALS study, involving a randomized, double-blind, placebo-controlled design, aims to rigorously evaluate the safety, tolerability, and efficacy of MN-166 on various outcomes in ALS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design. Oskarsson, B., Maragakis, N., Bedlack, RS., et al.[2022]

In a phase II trial involving 107 ALS patients, lithium carbonate did not slow the progression of the disease, showing a greater decline in function compared to historical controls, which raises concerns about its efficacy.

The study also noted an increase in adverse events among patients taking lithium, leading to the conclusion that it is not a recommended treatment for ALS due to safety concerns and lack of therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Miller, RG., Moore, DH., Forshew, DA., et al.[2021]

In a study of 31 ALS patients treated with edaravone, there were no significant improvements in functional measures compared to 50 historical ALS patients not treated with the drug, indicating that edaravone may not be effective for this population.

While edaravone was generally safe over the 6-month observation period, treated patients experienced a significant decrease in kidney function and a worsening quality of life, suggesting potential adverse effects despite the lack of efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of edaravone compared to historical controls in patients with amyotrophic lateral sclerosis from North-Eastern Italy. Fortuna, A., Gizzi, M., Bello, L., et al.[2020]

In the first three years of edaravone's availability for ALS treatment in the US, over 5200 patients were treated, and the drug was shown to slow the decline in physical function, although it was associated with various adverse events (AEs) including fatigue, muscular weakness, and respiratory issues.

The safety profile of edaravone remained consistent with previous clinical trials, with no new safety concerns identified, although serious adverse events included pneumonia and respiratory failure, and there were 687 reported deaths, primarily attributed to ALS progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch. Genge, A., Brooks, BR., Oskarsson, B., et al.[2022]

A review of 53 new drugs evaluated in clinical trials for ALS from 2020 to 2022 identified five promising candidates, including AMX0035, which has recently been approved by the FDA, marking it as the third drug approved for ALS treatment after riluzole and edaravone.

The review categorized these drugs into eight mechanistic groups, highlighting a diverse range of approaches being explored to combat ALS, with 13 drugs currently in phase 3 trials, indicating ongoing efforts to find more effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022. Jiang, J., Wang, Y., Deng, M.[2022]

The MND-SMART trial is a large, multi-centre, randomized controlled trial designed to evaluate the efficacy of memantine and trazodone in treating motor neuron disease, with a total of up to 531 participants expected to be randomized.

The primary outcomes of the trial include the ALS-FRS-R functional rating scale and overall survival, with a robust statistical analysis plan in place to ensure accurate comparisons between treatments and placebo, while minimizing bias and maximizing interpretability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART). Parker, RA., Weir, CJ., Pham, TM., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of edaravone compared to historical controls in patients with amyotrophic lateral sclerosis from North-Eastern Italy. [2020]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART). [2023]