Update on MND clinical Trials from the MND Symposium
Below is a brief run-down on some common terms used when describing clinical trials. Clinical trials are run in phases, with each phase dependent on the success of the previous phase. Usually trials are run as Phase I, Phase II and Phase III but additional phases can be added (e.g. Phase 2b, Phase 2c) if different doses or methods of delivery need to be investigated.

Clinical Trial Terminology
Phase I Safety trial to test the safety and tolerability of a new treatment. This can be done in healthy controls or MND patients.
Phase II Trial with a small number of patients to usually test safety and/or different doses of the treatment. Usually some efficacy data may be collected, collectively called primary endpoints.
Phase III A bigger trial with a much larger number of patients recruited. Usually multiple types of efficacy data on the treatment are collected.
Multi-site When a trial is being run at more than one clinic/hospital location. Single site trials may lead to site-specific reporting bias.
Placebo controlled This is a study where a MND patient will receive either the new treatment group or a placebo, which is an inactive version of the treatment. MND patients receiving placebo are referred to as placebo controls. Placebo controls are as closely matched to a treatment patients as possible (matched for age/sex/site of symptom onset) and are vital in determining the efficacy of new treatments.
Historical control placebo or untreated MND patients from previous studies where disease-related data has been collected and is used for comparison in new trials.
Randomized This is when patients are randomly allocated to the treatment group or placebo group randomly. Randomization is often performed via a computer program that assigns patients to a group. Randomization is important to remove the bias of neurologist’s allocation of certain types of patients into the treatment group and to remove any decision making about which patients will receive treatment and which one’s wont.
Blind/Double blind A “blind” study means that the patient is blinded to/unaware which treatment group they have been allocated to (placebo versus treatment). A “double-blind” study is when both the patient and the clinician are blinded to which treatment group the patient is in.  This is an important step in removing any patient and clinician bias when reporting the efficacy of the therapy.

The most thorough and scientific robust clinical trials are Phase III randomized, double-blind, placebo-control, multi-centre studies.

Clinical Trial outcomes presented at the 27th International Symposium on ALS/MND

Phase II CANALS study

Dr Nilo Riva from Italy reported on the results of the Phase II CANALS study where they investigated the effect of Cannabis Sativa extract on spasticity and muscle pain/cramps in patients. This trial was a randomized, double-blind placebo controlled trial. 55% of patients reported small improvements in their treatment arm and a reduction in pain with some minor side effects (low on energy and/or nausea). This study will be expanded to a Phase III trial for further investigation.

Edavarone

Edavarone (MCI-186), which has anti-oxidant effects, has previously been tested as a treatment for stroke. More recently Edavarone has been tested in MND patients in Japan. Dr Palumbo from the USA reported on a Phase III randomized trial which showed a slowing in decline of function but only in a subset of early diagnosed and slow progressing MND patients.

Ibudilast

Dr Brooks presented data on an ongoing Phase 1b/2a single-centre trial of the drug Ibudilast (PDE-4) which acts on immune cells. Ibudilast appeared to slow the decline of bulbar but not limb symptoms. Interestingly Dr Brooks also reported that 2 weeks after stopping treatment patients had a decline in muscle strength and flexion which warrants further investigation.

Rasagiline

Rasagiline, currently used in Parkinson’s disease patients, targets mitochondria, the energy centre of the cell. Dr Barohn reported on an ongoing Phase II trial where they tracked mitochondrial markers in patient’s blood. Rasagiline improved patient’s mitochondrial function, but interim results indicate no effect on disease progression.

Tirasemtiv

The VITALITY-ALS trial is an extension of a previous trial of Tirasemtiv, a drug that acts on muscle and has been shown to improve muscle strength in MND mice.  This trial focused on improving the tolerability of the drug for patients and showed much improved tolerability and a reduction in the number of patients reporting adverse events including dizziness, fatigue and nausea. The study is due to be completed in August 2017, when efficacy results will be released.

Pyrimethamine

Pyrimethamine is a treatment specific for MND patients with a SOD1 mutation. It targets and takes down SOD1 accumulation in the cerebral spinal fluid (CSF). Dr Lange from USA reported that while some patients struggled with the higher dose of pyrimethamine, 79% of those on the highest dose had a reduction in SOD1 in the CSF. This study is ongoing.

Nurown

Dr Berry from the USA presented results from the NurOwn® trial, a Phase 2a, randomized double-blind placebo trial of intrathecal autologous mesenchymal stromal cells (MSCs) secreting neurotrophic factors. Autologous, means cells/tissue obtained from the same individual and autologous MSCs are cells that are taken from a patient’s fat or bone marrow and chemically converted into MSCs. These cells are primed in a laboratory to release factors that are known to support neuronal survival. In this studies, patients received an injection of MSCs (primed from their own cells) into their CSF (much like a lumbar puncture). The results showed a slowing in disease progression, however this was only short term (4 weeks). A Phase III trial investigating multiple doses and repeated injections has been proposed.

Arimoclomol

This trial was specific for MND patients with a SOD1 A4V mutation. Dr Benatar presented results from an ongoing study with arimoclomol, a drug shown to reduce protein aggregates in neurons. He showed that there was a trend towards a slowing in disease progression and an increase in survival, however, these results were not significantly different to placebo treated patients.