31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
REPAIR-PD 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 Parkinson's Disease (PD) within three (3) years 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).

Detailed Description
-----------------
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 Parkinson's Disease within three years 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=15 patients/cohort, total n=30 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 six-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.

Official Title
-----------------
A Phase 2, Pilot Open Label, Sequential Group, Investigator Blinded Study of Magnetic Resonance Spectroscopy (31P-MRS) to Assess the Effects of CNM-Au8 for the Bioenergetic Improvement of Impaired Neuronal Redox State in Parkinson's Disease

Conditions
-----------------
Parkinson's Disease

Intervention / Treatment
-----------------
* Drug: Gold Nanocrystals


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to understand and give written informed consent and follow study procedures. Male or female, aged 30 - 80 years or age (inclusive) at the time of PD diagnosis. PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for PD: Parkinsonism present (bradykinesia + either rest tremor or rigidity) 2 of the following 4 supportive criteria: i. Clear and dramatic beneficial response to dopaminergic medication ii. Presence of levodopa-induced dyskinesias iii. Rest tremor of a limb iv. Olfactory loss or cardiac sympathetic denervation seen on prior MIBG SPECT Duration of PD since diagnosis is </= 3 years (inclusive) Modified Hoehn and Yahr stage </= 3 Treatment with dopaminergic therapy for at least 12-weeks and with no change in current medications within the prior 6-weeks Exclusion Criteria: Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease. The presence of any of the following: Unequivocal cerebellar abnormalities Downward vertical gaze limitation or slowing of downward saccades Diagnosis of behavioral variant frontotemporal dementia or primary progressive aphasia Parkinsonian features restricted to the lower limbs for > 3 years Treatment with dopamine blockers or depleters in a time course consistent with drug-induced parkinsonism Absence of an observable response to high dose levodopa despite moderate disease severity Expert considers a diagnosis of alternative syndrome more likely than PD Rapid progression of gait impairment requiring wheelchair within 5 years of onset Complete absence of progression of motor symptoms over 3 years unless due to treatment Early bulbar dysfunction within the first 5 years since diagnosis Inspiratory respiratory dysfunction (stridor or frequent sighs) Severe autonomic failure in the first 5 years Recurrent falls (>1 per year) because of impaired balance in the first 3 years Disproportionate dystonic anterocollis or hand contractures of hands or feet within 10 years Absence of any of the common non-motor features of PD despite 5 years of disease Otherwise unexplained pyramidal tract signs (weakness, hyperreflexia, or extensor toe signs) Bilateral symmetric parkinsonism Mini-Mental State Exammination (MMSE) score of less than 19. Patient with a history of any clinically significant or unstable medical condition based on the Investigator's judgment. History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator may interfere with study participation. Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (<150 x 109 per liter) or eosinophilia (absolute eosinophil count of ≥500 eosinophils per microliter) at Screening. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter) Positive screen for drugs of abuse or known history of alcohol abuse. Women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control for up to 6 months following study participation. Women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study or within 6 months of the end of this trial. Patients with implanted metal objects in their body that may be affected by an MRI procedure. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures. History of allergy to gold in any form. Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Open Label, Investigator Blinded, Sequential Cohort (max of 2 cohorts amongst the possible 4 interventions)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 7.5mg CNM-Au8<br>7.5mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water | Drug: Gold Nanocrystals<br>* CNM-Au8 is a dark red/purple-colored liquid formulation consisting of a stable suspension of faceted clean surfaced elemental gold nanocrystals in buffered deionized water with a concentration of up to 0.5 mg/mL of gold. The formulation is buffered by sodium bicarbonate present at a concentration of 0.546 mg/mL. There are no other excipients. The drug product is formulated to be taken orally and will be provided in single dose HDPE containers. The study doses vary by the concentration of gold nanocrystals per milliliter in a volume of 60 mL.<br>* Other names: CNM-Au8;|
| Experimental: 15mg CNM-Au8<br>15mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water | Drug: Gold Nanocrystals<br>* CNM-Au8 is a dark red/purple-colored liquid formulation consisting of a stable suspension of faceted clean surfaced elemental gold nanocrystals in buffered deionized water with a concentration of up to 0.5 mg/mL of gold. The formulation is buffered by sodium bicarbonate present at a concentration of 0.546 mg/mL. There are no other excipients. The drug product is formulated to be taken orally and will be provided in single dose HDPE containers. The study doses vary by the concentration of gold nanocrystals per milliliter in a volume of 60 mL.<br>* Other names: CNM-Au8;|
| Experimental: 30mg CNM-Au8<br>30mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water | Drug: Gold Nanocrystals<br>* CNM-Au8 is a dark red/purple-colored liquid formulation consisting of a stable suspension of faceted clean surfaced elemental gold nanocrystals in buffered deionized water with a concentration of up to 0.5 mg/mL of gold. The formulation is buffered by sodium bicarbonate present at a concentration of 0.546 mg/mL. There are no other excipients. The drug product is formulated to be taken orally and will be provided in single dose HDPE containers. The study doses vary by the concentration of gold nanocrystals per milliliter in a volume of 60 mL.<br>* Other names: CNM-Au8;|
| Experimental: 60mg CNM-Au8<br>60mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water | Drug: Gold Nanocrystals<br>* CNM-Au8 is a dark red/purple-colored liquid formulation consisting of a stable suspension of faceted clean surfaced elemental gold nanocrystals in buffered deionized water with a concentration of up to 0.5 mg/mL of gold. The formulation is buffered by sodium bicarbonate present at a concentration of 0.546 mg/mL. There are no other excipients. The drug product is formulated to be taken orally and will be provided in single dose HDPE containers. The study doses vary by the concentration of gold nanocrystals per milliliter in a volume of 60 mL.<br>* Other names: CNM-Au8;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 31P-MRS Redox Ratio (NAD+/NADH) | Mean change in average NAD+/NADH measured brain Redox Ratio by treatment group | At 12 Weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neurodegeneration, gold, nanocrystal, NAD+, redox, 31P-MRS, Parkinson's Disease, magnetic resonance spectroscopy, nanoparticle, nanomedicine, NADH