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

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ClinicalTrials.gov Identifier: NCT03815916
Recruitment Status : Not yet recruiting
First Posted : January 24, 2019
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Clene Nanomedicine

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=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:

  1. A four-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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 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
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 5 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. Montreal Cognitive Assessment (MoCA) score of 20 or less.
  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. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter)
  9. Positive screen for drugs of abuse or known history of alcohol abuse.
  10. 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.
  11. 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.
  12. Patients with implanted metal objects in their body that may be affected by an MRI procedure.
  13. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures.
  14. History of allergy to gold in any form.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03815916


Contacts
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Contact: Glen Frick, MD (801) 676-9695 info@clene.com
Contact: Austin Rynders, RN (801) 676-9695 info@clene.com

Locations
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United States, Texas
UT Southwestern Not yet recruiting
Dallas, Texas, United States, 75390
Contact: Richard Dewey, MD    214-648-5437    Richard.Dewey@UTSouthwestern.edu   
Contact: Ben Greenberg, MD    (214) 648 5437    Benjamin.Greenberg@UTSouthwestern.edu   
Principal Investigator: Richard Dewey, MD         
Sub-Investigator: Ben Greenberg, MD         
Sub-Investigator: Jimin Ren, PhD         
Sponsors and Collaborators
Clene Nanomedicine
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Richard Dewey, MD UT Southwestern

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Responsible Party: Clene Nanomedicine
ClinicalTrials.gov Identifier: NCT03815916     History of Changes
Other Study ID Numbers: CNMAu8.202
First Posted: January 24, 2019    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Clene Nanomedicine:
NAD+
NADH
neurodegeneration
gold
nanocrystal
redox
31P-MRS
Parkinson's Disease
magnetic resonance spectroscopy
nanoparticle
nanomedicine

Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases