31p-mrs imaging to assess the effects of cnm-au8 on impaired neuronal redox state in amyotrophic lateral sclerosis (repair-als)

Conditions: Amyotrophic Lateral Sclerosis

Summary: repair-als is a single-center open label pilot, sequential group, investigator and patient blinded study to assess the cns metabolic effects, safety, pharmacokinetics, and pharmacodynamics of cnm-au8 in patients who have been diagnosed with amyotrophic lateral sclerosis (als) within twelve (12) months of screening. the primary endpoint is the ratio of the oxidized to reduced form of nicotinamide adenine dinucleotide (nad+:nadh) measured non-invasively by 31phosphorous magnetic resonance spectroscopy (31p-mrs).

this is a single-center open label pilot, sequential group, investigator blinded study of the cns metabolic effects, safety, pharmacokinetics, and pharmacodynamics of cnm-au8 in patients who have been diagnosed with amyotrophic lateral sclerosis within twelve months of screening. the sponsor will select a starting treatment dose of cnm-au8 for the initial treatment. investigators and patients will be blinded to each cohort's study dose. upon completion of the first treatment cohort, the sponsor will select a single dose or two different doses for the subsequent second cohort from a pre-specified dosing selection plan based on the evaluation of the 31p-magnetic resonance spectroscopy (31p-mrs) changes versus baseline in the first cohort. up to a total of two treatment cohorts may be studied (n=12 patients/cohort, total n=24 patients). all patients will receive daily oral treatment over twelve consecutive weeks during each cohort's treatment period. there will be three study periods per treatment cohort: a four-week screening period (screening period); a twelve-week treatment period (treatment period); a four-week follow-up period (end-of-study assessment). the primary study outcome, cns metabolic changes, will be assessed based upon each patient's week 12 study visit versus the pre-treatment baseline. the primary endpoint is the brain metabolic effects of treatment with cnm-au8 as assessed by an improvement of 31p-mrs assessment of brain tissue cellular redox potential defined by the measured tissue ratio of nad+:nadh concentrations following 12 weeks of once daily treatment.

Eligibility criteria:
inclusion criteria: 1. able to understand and give written informed consent. 2. male or female patients aged 35 years or greater (inclusive) and less than 75 years of age at the time of als diagnosis. 3. patients with a confirmed als diagnosis: "definite als" or "probable als" or "possible" diagnostic criteria per the revised el escorial criteria as determined by a neurologist subspecializing in als (e.g., the principal investigator by study site). 4. stable background therapy (e.g., stable dosing of riluzole within the prior 6-weeks) per investigator discretion. 5. at the time of screening disease duration less than or equal to 24-months from symptom onset or within 12-moths of a confirmed als diagnosis. 6. forced vital capacity (fvc) \>/= 60% of predicted value as adjusted for gender, height, and age at the screening visit. 7. patients who are ambulatory (e.g., normal ambulation, early ambulation difficulties, or walks with assistance) on the alsfrs-r scale. exclusion criteria: 1. at screening patients who utilize, or in the investigator's judgment will be imminently dependent upon during the course of this study: 1. non-invasive ventilation 2. gastrostomy (e.g., use of percutaneous endoscopic gastrostomy tube) 3. use of wheel chair 2. patient who have previously undergone tracheostomy. 3. patient with a history of significant other major medical condition based on the investigator's judgment. 4. based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures. 5. patient with clinically significant abnormalities in hematology, blood chemistry, ecg, or physical examination not resolved by the baseline visit which according to investigator can interfere with study participation. 6. patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter) 7. females who are pregnant or nursing or who plan to get pregnant during the course of this clinical trial or within 6 months of the end of this trial. 8. positive screen for drugs of abuse or known alcohol abuse. 9. women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control during the study or for 6 months following completion of study participation. 10. women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study. 11. patients with implanted metal objects in their body that may be affected by an mri procedure. 12. patients who are claustrophobic or otherwise unlikely to be able to complete the mri scanning procedures. 13. patients with a history of gold allergy.

Keywords: neurodegeneration gold nanocrystal nad+ nadh redox redox ratio als amyotrophic lateral sclerosis 31p-mrs mrs magnetic resonance spectroscopy nanoparticle nanomedicine