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

• ClinicalTrials.gov Identifier: NCT03815916
• Recruitment Status: Completed
• First Posted: January 24, 2019
• Last Update Posted: November 22, 2021
• Sponsor: Clene Nanomedicine
• Collaborator: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Clene Nanomedicine

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Parkinson's Disease	Drug: Gold Nanocrystals	Phase 2

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:

1. A six-week screening period (Screening Period);
2. A twelve-week treatment period (Treatment Period);
3. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open Label, Investigator Blinded, Sequential Cohort (max of 2 cohorts amongst the possible 4 interventions)
• Masking: None (Open Label)
• Masking Description: Research participants and site personnel are not masked to study drug, but will be blinded to study dose for each cohort (single-blinded).
• Primary Purpose: 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
• Actual Study Start Date: December 19, 2019
• Actual Primary Completion Date: June 7, 2021
• Actual Study Completion Date: June 7, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 7.5mg CNM-Au8; 7.5mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water	Drug: Gold Nanocrystals; 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.; Other Name: CNM-Au8
Experimental: 15mg CNM-Au8; 15mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water	Drug: Gold Nanocrystals; 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.; Other Name: CNM-Au8
Experimental: 30mg CNM-Au8; 30mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water	Drug: Gold Nanocrystals; 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.; Other Name: CNM-Au8
Experimental: 60mg CNM-Au8; 60mg suspension of clean-surfaced, faceted, gold nanocrystals in 120ml of sodium bicarbonate buffered water	Drug: Gold Nanocrystals; 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.; Other Name: CNM-Au8

Outcome Measures

Primary Outcome Measures :

1. Change in 31P-MRS Redox Ratio (NAD+/NADH) [ Time Frame: At 12 Weeks ]
   Mean change in average NAD+/NADH measured brain Redox Ratio by treatment group

Other Outcome Measures:

1. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NAD+ [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of NAD+ [mmol/kg] by treatment group
2. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NADH [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of NADH [mmol/kg] by treatment group
3. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Pooled NAD+/NADH [ Time Frame: At 12 Weeks ]
   Mean change in average CNS concentration of pooled NAD+/NADH [mmol/kg] by treatment group
4. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of ATP [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of ATP [mmol/kg] (as internal reference) by treatment group
5. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Phosphocreatine (PCr) [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of PCr [mmol/kg] by treatment group
6. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Intracellular Inorganic Phosphate (Pi(in)) [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of Pi(in) [mmol/kg] by treatment group
7. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Extracellular Inorganic Phosphate (Pi(ex)) [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of Pi(ex) [mmol/kg] by treatment group
8. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Uridine Diphosphate Glucose (UDPG) [ Time Frame: At 12 Week ]
   Mean change in average CNS concentration of UDPG [mmol/kg] by treatment group
9. Mean Change in 31P-MRS Membrane Component Tissue Concentration of Phosphoethanolamine (PE) [ Time Frame: At 12 Weeks ]
   Mean change in average CNS concentration of PE [mmol/kg] by treatment group
10. Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Phosphocholine (PC) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of PC [mmol/kg] by treatment group
11. Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerolphophoethanolamine (GPE) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of GPE [mmol/kg] by treatment group
12. Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerophosphocholine (GPC) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of GPC [mmol/kg] by treatment group
13. Measures of Gait [ Time Frame: at 12 weeks ]
    Measured by APDM instrumented Timed up and go test.
14. Measures of Balance [ Time Frame: at 12 weeks ]
    Measured by APDM Instrumented Postural Sway Test
15. Measure of Mobility [ Time Frame: at 12 weeks ]
    Measured by APDM instrumented Walk Test
16. Measurements of Global Impression of Disease Improvement [ Time Frame: at 12 weeks ]
    Using Clinician Global Impression Scale. Scale is rated from 1-7, with 1 representing Very much improved and 7 representing very much worse.
17. Measurements of Global Impression of Disease Severity [ Time Frame: at 12 weeks ]
    Using Patient Global Impression Scale. Scale is rated from 1-7, with 1 representing very mush improved, and 7 representing very much worse.
18. Measurements of disease progression [ Time Frame: at 12 weeks ]
    Using Unified Parkinson's Disease Rating Scale. The scale is based off of participants symptoms, with a lower value representing a being closer to no impairments.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Able to understand and give written informed consent and follow study procedures.
2. Male or female, aged 30 - 80 years or age (inclusive) at the time of PD diagnosis.

3. PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for

   PD:

   1. Parkinsonism present (bradykinesia + either rest tremor or rigidity)
   2. 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

4. Duration of PD since diagnosis is </= 3 years (inclusive)
5. Modified Hoehn and Yahr stage </= 3
6. Treatment with dopaminergic therapy for at least 12-weeks and with no change in current medications within the prior 6-weeks

Exclusion Criteria:

1. Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease.

2. The presence of any of the following:

   1. Unequivocal cerebellar abnormalities
   2. Downward vertical gaze limitation or slowing of downward saccades
   3. Diagnosis of behavioral variant frontotemporal dementia or primary progressive aphasia
   4. Parkinsonian features restricted to the lower limbs for > 3 years
   5. Treatment with dopamine blockers or depleters in a time course consistent with drug-induced parkinsonism
   6. Absence of an observable response to high dose levodopa despite moderate disease severity
   7. Expert considers a diagnosis of alternative syndrome more likely than PD
   8. Rapid progression of gait impairment requiring wheelchair within 5 years of onset
   9. Complete absence of progression of motor symptoms over 3 years unless due to treatment
   10. Early bulbar dysfunction within the first 5 years since diagnosis
   11. Inspiratory respiratory dysfunction (stridor or frequent sighs)
   12. Severe autonomic failure in the first 5 years
   13. Recurrent falls (>1 per year) because of impaired balance in the first 3 years
   14. Disproportionate dystonic anterocollis or hand contractures of hands or feet within 10 years
   15. Absence of any of the common non-motor features of PD despite 5 years of disease
   16. Otherwise unexplained pyramidal tract signs (weakness, hyperreflexia, or extensor toe signs)
   17. Bilateral symmetric parkinsonism
3. Mini-Mental State Exammination (MMSE) score of less than 19.
4. Patient with a history of any clinically significant or unstable medical condition based on the Investigator's judgment.
5. History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody.
6. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures.
7. 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.
8. 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.
9. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter)
10. Positive screen for drugs of abuse or known history of alcohol abuse.
11. 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.
12. 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.
13. Patients with implanted metal objects in their body that may be affected by an MRI procedure.
14. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures.
15. History of allergy to gold in any form.
16. 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.

Contacts and Locations

Locations

United States, Texas

UT Southwestern

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Clene Nanomedicine

University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Richard Dewey, MD; UT Southwestern

More Information

• Responsible Party: Clene Nanomedicine
• ClinicalTrials.gov Identifier: NCT03815916
• Other Study ID Numbers: CNMAu8.202
• First Posted: January 24, 2019
• Last Update Posted: November 22, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Clene Nanomedicine:

neurodegeneration; gold; nanocrystal; NAD+; redox; 31P-MRS; Parkinson's Disease; magnetic resonance spectroscopy; nanoparticle; nanomedicine; NADH

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases