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31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Multiple Sclerosis. (REPAIR-MS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03993171
Recruitment Status : Recruiting
First Posted : June 20, 2019
Last Update Posted : November 4, 2020
Sponsor:
Collaborator:
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Clene Nanomedicine

Brief Summary:
REPAIR-MS is a single-center open label, 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 Multiple Sclerosis (MS) within fifteen (15) years of Screening. The primary endpoint for this study changes from baseline to week 12 in CNS metabolic changes, based on 31P-MRSimaging.

Condition or disease Intervention/treatment Phase
Relapsing Remitting Multiple Sclerosis Drug: gold nanocrystals Phase 2

Detailed Description:

This is a single-center open-label, sequential group, investigator blinded study of the CNS metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who have been diagnosed with relapsing multiple sclerosis (RMS) within fifteen (15) years of Screening. Patients will be screened over up to a 6-week period.Patients who meet inclusion criteria and none of the exclusion criteria may be enrolled into the clinical study. The initial cohort of patients (Cohort 1) will begin treatment at a dose of 15mg or 30mg CNM-Au8. Upon completion of the first Treatment Period, dose(s) will be selected for the subsequent cohort (Cohort 2), based on the results of the 31P-MRS change versus baseline from the first cohort. A total of two treatment cohorts may be studied. Investigators and patients will remain blinded to study dose until the study database is formally locked. All patients will receive daily oral treatment over twelve (12) consecutive weeks during each cohort's Treatment Period.

There will be three study periods per treatment cohort:

  1. A (6) six week screening period (Screening Period);
  2. A (12) twelve-week treatment period (Treatment Period);
  3. A (6) six-week follow-up period (End-of-Study Assessment).

Patients will be contacted by phone to assess safety and tolerability at Week 2. At Weeks 4, 8, and 12 patients will return to the clinic to complete PK, PD, visual acuity testing, and safety assessments. At the Baseline and Week 12 visits patients will complete 31P-MRS, MRI, and OCT imaging assessments, the 9-Hole Peg Test, Timed 25-Foot Walk Test, Visual Acuity (high and low contrast letter/visual acuity) and the Symbol Digit Modalities Test (SDMT). Following treatment discontinuation at Week 12, patients will complete an end-of-study (EOS) visit at Week 18. All patients who are prematurely discontinued from treatment will complete the end-of-study visit 4-weeks after discontinuation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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, 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 Multiple Sclerosis.
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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: Second dose determined by results of Cohort 1 of CNM-Au8
Second dose determined by results of Cohort 1 of CNMAu8 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: Dose determined by results of Cohort 1 of CNM-Au8
Dose determined by results of Cohort 1 of CNMAu8 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. The change from baseline to week 12 in CNS metabolic changes, based on 31P-MRS imaging. [ Time Frame: At 12 Weeks ]
    Mean change in average NAD+/NADH measured brain Redox Ratio by treatment cohort from Baseline to Week 12.


Other Outcome Measures:
  1. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NAD+ [ Time Frame: At 12 Weeks ]
    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 Weeks ]
    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 Phosphocreatine (PCr) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of PCr [mmol/kg] by treatment group

  5. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Intracellular Inorganic Phosphate (Pi(in)) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of Pi(in) [mmol/kg] by treatment group

  6. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Extracellular Inorganic Phosphate (Pi(ex)) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of Pi(ex) [mmol/kg] by treatment group

  7. Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Uridine Diphosphate Glucose (UDPG) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of UDPG [mmol/kg] by treatment group

  8. 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

  9. 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

  10. Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of glycerophosphoethanolamine (GPE) [ Time Frame: At 12 Weeks ]
    Mean change in average CNS concentration of GPE [mmol/kg] by treatment group

  11. 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

  12. Mean Change in Symbol Digit Modality Test (SDMT) [ Time Frame: At 12 Weeks ]
    Mean change in Symbol Digit Modality Test (SDMT) by treatment group from Baseline to Week 12

  13. Mean Change in Optical Coherence Tomography (OCT) Retinal Layers [ Time Frame: At 12 Weeks ]
    Mean change in Optical Coherence Tomography (OCT) retinal layers by macular scan of Ganglion Cell + inner plexiform layer (GCIPL), Outer nuclear layer (ONL) and Inner nuclear layer (INL)

  14. Mean Change in Optical Coherence Tomography (OCT) Retinal Nerve Fiber Layer [ Time Frame: At 12 Weeks ]
    Mean change in Retinal Nerve Fiber Layer by Peripapillary Scan (pRNFL)

  15. Mean Change in Myelin Volume Fraction (MVF) [ Time Frame: At 12 Weeks ]
    Mean change in Myelin volume fraction (MVF) in baseline lesions and in normal appearing white matter (NAWM).

  16. Mean Change in Restricted Volume Fraction (F_R) [ Time Frame: At 12 Weeks ]
    Mean Change in Restricted Volume Fraction (F_R) in baseline lesions and in normal appearing white matter (NAWM).

  17. Mean Change in CSF Volume Fraction (F_CSF) [ Time Frame: At 12 Weeks ]
    Mean change in CSF Volume Fraction (F_CSF) between Baseline and Week 12 MRI

  18. Mean Change in Axonal Volume Fraction (AVF) [ Time Frame: At 12 Weeks ]
    Mean Change in Axonal Volume Fraction (AVF) in baseline lesions and in normal appearing white matter (NAWM).

  19. Mean Change in G-Ratio [ Time Frame: At 12 Weeks ]
    Mean change in g-ratio in baseline lesion and in normal appearing white matter (NAWM) represented as an aggregate measure calculated on a per-voxel basis

  20. Mean Change in G-Ration Susceptibility [ Time Frame: At 12 Weeks ]
    Mean change in the g-ratio susceptibility (ppm) in baseline lesion and in normal appearing white matter (NAWM).

  21. 9-Hole Peg Test [ Time Frame: At 12 weeks ]
    Mean change from Baseline to Week 12 by treatment cohort for the 9-Hole Peg Test by hand.

  22. Timed 25 foot walk test. [ Time Frame: At 12 weeks ]
    Mean change from Baseline to Week 12 by treatment cohort for the Timed 25-Foot Walk Test.

  23. SDMT [ Time Frame: At 12 weeks ]
    Mean change from Baseline to Week 12 by treatment cohort for the Symbol Digit Modalities Test.

  24. EDSS [ Time Frame: At 12 weeks ]
    Mean change from Baseline to Week 12 by treatment cohort for the Expanded Disability Status Scale. The scale is rated 0-10 with 0 representing normal neurological function, and 10 representing death.



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:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. At least 18 years of age and up to 55 years (inclusive) of age at Screening.
  2. Clinical diagnosis of Relapsing Multiple Sclerosis (RMS) (meeting McDonald criteria, 2017).
  3. Diagnosis of MS no longer than 15 years prior to Screening.
  4. Stable treatment with natalizumab, defined as a stable dose maintained at the standard infusion interval of 28-days (±5 days) for at least the prior six (6) months.
  5. Stable disease activity based on the Investigator's judgment over the prior three (3) months.
  6. Any hematological parameters and/or biochemical parameters that fall outside the Within Normal Limits range at Screening must be assessed as Not Clinically Significant (NCS) and deemed stable or transient in nature.
  7. Able to understand and give written informed consent.

Exclusion Criteria:

  1. Patients with a clinical relapse requiring systemic steroid treatment within the prior three (3) months.
  2. Patients treated with any other MS therapy other than natalizumab; or treated with clemastine fumarate.
  3. Based on the Investigator's judgment, patients with a history of significant other major medical condition that may interfere with the conduct of the study or interpretation of the study results.
  4. Based on the Investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures.
  5. History of any clinically significant abnormality in hematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator can interfere with study participation.
  6. 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.
  7. Patients with a prior history of, or positive serological assay for the presence of HIV infection, or laboratory evidence of active or chronic infection with hepatitis C (HCV) or hepatitis B (HBV). Note, participants who have been vaccinated for HBV and have detectable HB antibodies are not excluded unless positive for hepatitis surface antigen (HBsAg).
  8. Patients participating in any other investigational drug trial or using an investigational drug (within 12 weeks prior to screening and thereafter).
  9. Positive screen for drugs of abuse or known alcohol abuse.
  10. Females who are pregnant, have a positive pregnancy test, are nursing, or who plan to get pregnant during the course of this clinical trial or within 6 months of the end of this trial.
  11. Women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control during the study and for 6 months following completion of study participation.
  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. Patients with a history of gold allergy.
  15. 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.
  16. Any active ophthalmological cause for retinal damage other than MS (e.g. cataracts, uveitis, macular degeneration, macular exudate, macular edema, glaucoma, severe astigmatism, ocular trauma, neuromyelitis optica, ischemic optic neuropathy, congenital nystagmus, retinal detachment, amblyopia, optic disk drusen).
  17. Severe refractive defects: refractive errors (-5 dioptres to +5 dioptres or more in either eye, or axial eye length >26 mm), hypermetropia (> 5 dioptres; cylinder > 3 dioptres); or based on the Investigator's judgment any other ophthalmic diseases that might confound the study results or optical coherence tomography assessment.
  18. PRN use of stimulant medications including: amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate, or modafinil; however, stimulant medications, taken on a consistent daily dose for at least 12-weeks are allowed. No changes in the dose of any stimulant medications are allowed during the study.

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): NCT03993171


Contacts
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Contact: Robert Glanzman (801) 676-9695 Robert@clene.com
Contact: Austin Rynders, RN (801) 676-9695 Austin@clene.com

Locations
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United States, Texas
University of Texas Southwestern Recruiting
Dallas, Texas, United States, 75390
Contact: Benjamin Greenberg, MD    214-645-0563    Benjamin.Greenberg@UTSouthwestern.edu   
Sponsors and Collaborators
Clene Nanomedicine
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Benjamin Greenberg, MD University of Texas Southwestern Medical Center
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Responsible Party: Clene Nanomedicine
ClinicalTrials.gov Identifier: NCT03993171    
Other Study ID Numbers: CNMAu8.207
First Posted: June 20, 2019    Key Record Dates
Last Update Posted: November 4, 2020
Last Verified: November 2020
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:
neurodegeneration
gold
nanoparticle
NAD+
redox
31P-MRS
multiple sclerosis
magnetic resonance spectroscopy
nanocrystal
NADH
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases