Table 3.

Phase 3 clinical trials in ALS with a medical product targeting (neuro)inflammation

Intervention, Sponsor or Collaborators, Phase	Target or Mechanism of Action and Protocol	Outcome Measures	Pharmacodynamic Biomarker	Study results	Reference Clinical Trial ID
Drug: minocyclineSponsor: National Institute of Neurological Disorders and Stroke (NINDS) Phase: 3	- anti-inflammatory - daily dose for 9 months	- change in function as detected by the ALSFRS-R - changes in manual muscle testing (MMT), forced vital capacity (FVC, percent predicted), quality of life (QOL) and survival	none listed or described	- ALSFRS-R score deterioration was faster - (non-significant tendencies towards faster decline in FVC and MMT score, and greater mortality during the 9-month treatment phase - Quality-of-life scores did not differ between the treatment groups. - Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score.	Gordon et al., 2007 [3]NCT00047723
Drug: Granulocyte Colony Stimulating FactorSponsor: Tehran University of Medical Sciences Phase: 2/3	- G-CSF administered per subcutaneous injection - 5 days treatment with 3 month follow-up	- patient’s function - mobilizing bone marrow stem cells- amplitude of compound muscle action potential in ulnar and peroneal nerve- quality of life- muscle power	mobilizing bone marrow stem cells: - cluster of differentiation 34 (CD34) - white blood cell (WBC) counting	- no significant effect	Amirzagar et al., 2015 [4] NCT01825551
Drug: MediCabilis CBD Oil Sponsor: Gold Coast Hospital and Health Service, BOD Australia Phase: 3	- anti-inflammatory - treatment for 6 months	- difference in mean ALSFRS-R - difference in mean Forced Vital Capacity (FVC) - nature and number of adverse events - difference in mean Numeric Rating Scale for spasticity - difference in mean Numeric Rating Scale for pain total score - difference in mean Percentage of Total Weight Loss score - difference in mean ALS Specific Quality of Life- Revised	none listed	- not available yet (recruiting)	Urbi et al., 2019 [5] NCT03690791
Drug: Masitinib (4.5/3.0)Sponsor: AB Science Phase: 2/3	- microglia & mast cells through c-kit - 48 weeks	- change in ALSFRS-R - change of Forced Vital Capacity (FVC) - progression Free Survival - overall Survival	none listed or described	- “Normal progressor” subpopulation received a benefit from the drug on the ΔALSFRS-R and on the ALSAQ-40, FVC, and time-to-event analysis. - No differences were detected in the full sample (“Normal and Fast Progressor”).	Mora et al., 2020 [6] NCT02588677
Drug: Masitinib (6.0/4.5) Sponsor: AB Science Phase: 3	- microglia & mast cells through c-kit - 48 weeks	- ALSFRS-R - ALSAQ-40 - progression free survival - FVC - HHD	none listed	- not available yet (recruiting)	NCT03127267
Drug: ZilucoplanSponsor: Ra Pharmaceuticals Phase: 2/3	- complement C5 inhibitor - 24 weeks	- disease progression - respiratory function - muscle strength - survival	none listed	- not available yet (recruiting)	NCT04436497
Drug: VerdiperstatSponsor: Biohaven Pharmaceuticals, Inc. Phase: 2/3	- myeloperoxidase (MPO) enzyme inhibitor - 24 weeks	- disease progression - respiratory function - muscle strength - survival	none listed	- not available yet (recruiting)	NCT04436510
Drug: MN-166 (Ibudilast)Sponsor: MediciNova Phase: 2/3	- phosphodiesterase inhibitor (PDE4) - 52 weeks of treatment	- change from baseline in ALSFRS-R score at Month 12 - survival time - mean change of muscle strength measured by hand-held dynamometry - mean change from baseline on quality of life by ALSAQ-5 - mean change from baseline of functional activity by ALSFRS-R - responders, measured in percent of subjects overall, whose ALSFRS-R total score was stable or improved - time to survival - number of Participants with Treatment-Related Adverse Events - changes from Baseline in Laboratory Values	not specified (laboratory values)	- not available yet (recruiting)	NCT04057898
Biological: LenzumestrocelSponsor: Corestem, Inc. Phase: 3	- intrathecal autologous bone marrow-derived mesenchymal stem cells injections to minimize pro-inflammatory cytokines - Study drug injections twice in a 26-day interval followed by repeated three times study drug injections every three months.	- joint rank scores (CAFS, Combined Assessment of Functional and Survival) - ALSFRS-R score - time to event - Slow Vital Capacity (SVC)	Exploratory investigation of biological markers in plasma, blood and CSF. Comparison of change before and after treatment. Measurement cytokines: TGF-β1, IL-10, IL-6, TNF, MCP-1, IL-8, IL-1RA, MIP-1β, RANTES and IP-10 etc.	- not available yet (recruiting)	NCT04745299
Biological: RavulizumabSponsor: Alexion Pharmaceuticals Phase: 3	- complement inhibitor - 50 weeks	- change From Baseline ALSFRS-R Total Score - time To Ventilator Assistance-free Survival - change From Baseline In Slow Vital Capacity - incidence Of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, And TEAEs Leading To Study Drug Discontinuation - change From Baseline In Muscle Strength As Assessed By Handheld Dynamometry - change From Baseline In Serum Neurofilament Light Chain	none listed	- not available yet (recruiting)	NCT04248465

ALSAQ-5 five item ALS assessment questionnaire, ALSAQ-40 forty item ALS assessment questionnaire, ALSFRS-R ALS functional rating scale revised, CAFS Combined Assessment of Functional and Survival, CD34 cluster of differentiation 34, c-kit tyrosine-protein kinase Kit, CSF cerebral spinal fluid, FVC forced vital capacity, HHD hand-held dynamometry, IL interleukin, IL-1RA interleukin 1 receptor agonist, IP-10 Interferon gamma-induced protein 10, MCP-1 Monocyte Chemoattractant Protein 1, MIP-1β Macrophage inflammatory protein 1 beta, MMT manual muscle testing, MPO myeloperoxidase, NINDS National Institute of Neurological Disorders and Stroke, PDE4 phosphodiesterase inhibitor 4, QOL quality of life, RANTES Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted, SVC Slow Vital Capacity, TEAEs Treatment-emergent Adverse Events, TGF-β1 tumor growth factor beta 1, TNF tumor necrosis factor, WBC white blood cell