Clinical trial NCT03993171: 31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Multiple Sclerosis.
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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: neurodegeneration
gold
nanoparticle
NAD+
redox
31P-MRS
multiple sclerosis
magnetic resonance spectroscopy
nanocrystal
NADH
primary progressive multiple sclerosis
relapsing multiple sclerosis
Lead sponsor: Clene Nanomedicine
Sponsor class: INDUSTRY
Collaborators: name: University of Texas Southwestern Medical Center
First posted: 2019-06-20
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Open Label, Investigator Blinded, Sequential Cohort (max of 2 cohorts amongst the possible 4 interventions)
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Patients enrolled in Cohort 1 must meet the following 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.

Patients enrolled in Cohort 2 must meet the following Inclusion Criteria:

1. Male or female, aged 18 - 70 years or age (inclusive);
2. Diagnosis of primary progressive multiple sclerosis (PPMS) or nonactive secondary progressive multiple sclerosis (SPMS), according to revised 2017 McDonald criteria at the Screening visit;
3. EDSS score at the Screening visit of less than or equal to 6.5 (inclusive);
4. Participants must be taking either B-cell depleting therapy (e.g., ocrelizumab, rituximab) or S1P modulator therapy (e.g., siponimod) with consistent stable dosing for at least 48 weeks prior to the Screening visit;
5. 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; and
6. Able to understand and give written informed consent.

Patients enrolled in Cohort 1 must meet the following 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.

Patients enrolled in Cohort 2 must meet the following Exclusion Criteria:

1. History of MS relapses or gadolinium-enhancing lesions seen on brain MRI scans within the five (5) years prior to the Screening visit.
2. History of AQP4, MOG Ab(+) status, or documented ≥ 3 contiguous segment lesion in the spinal cord.
3. Any diagnosis other than PPMS or SPMS that could explain a participant's signs and symptoms.
4. Participants taking any MS disease-modifying therapy other than Bcell depleting therapy (e.g., ocrelizumab, rituximab) or S1P modulator therapy (e.g., siponimod), or not taking disease modifying therapy.
5. 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.
6. Based on the Investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures.
7. 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.
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. 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).
10. Patients participating in any other investigational drug trial or using an investigational drug (within 12 weeks prior to screening and thereafter).
11. Positive screen for drugs of abuse or known alcohol abuse.
12. 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.
13. 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.
14. Patients with implanted metal objects in their body that may be affected by an MRI procedure.
15. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures.
16. Patients with a history of gold allergy.
17. 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.

Primary outcomes:
measure: The change from baseline to week 12 in CNS metabolic changes, based on 31P-MRS Redox Ratio.
timeFrame: At 12 Weeks
Secondary outcomes:
Other outcomes:
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of ATP (a, B, y) by subject per dosing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NAD+/NADH pool by subject per dosing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Phosphocreatine (PCr) by subject per dosing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Intracellular inorganic phosphate (Pi(in)) by subject per doing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Extracellular inorganic phosphate (Pi(ex)) by subject per dosing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Uridine Diphosphate Glucose (UDPG) by subject per dosing group.
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Membrane Component Tissue Concentration of Phosphoethanolamine (PE)
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Phosphocholine (PC)
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of glycerophosphoethanolamine (GPE)
timeFrame: At 12 Weeks
measure: Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerophosphocholine (GPC)
timeFrame: At 12 Weeks
measure: 9-Hole Peg Test
timeFrame: At 12 weeks
measure: Timed 25 foot walk test.
timeFrame: At 12 weeks
measure: Mean Change in Symbol Digit Modality Test (SDMT)
timeFrame: At 12 Weeks
measure: EDSS
timeFrame: At 12 weeks
measure: Mean Change in Optical Coherence Tomography (OCT) Retinal Layers of ganglion cell + inner plexiform layer (GCIPL)
timeFrame: At 12 Weeks
measure: Mean Change in Optical Coherence Tomography (OCT) Retinal Layer of Outer nuclear layer (ONL).
timeFrame: At 12 Weeks
measure: Mean Change in Optical Coherence Tomography (OCT) Retinal Layer of Inner nuclear layer (INL).
timeFrame: At 12 Weeks
measure: Mean Change in Optical Coherence Tomography (OCT) Retinal Nerve Fiber Layer by Peripapillary scan.
timeFrame: At 12 Weeks
measure: Mean Change in Myelin Volume Fraction (MVF)
timeFrame: At 12 Weeks
measure: Mean Change in Restricted Volume Fraction (F_R)
timeFrame: At 12 Weeks
measure: Mean Change in CSF Volume Fraction (F_CSF)
timeFrame: At 12 Weeks
measure: Mean Change in Axonal Volume Fraction (AVF)
timeFrame: At 12 Weeks
measure: Mean Change in G-Ratio
timeFrame: At 12 Weeks
measure: Mean Change in G-Ration Susceptibility
timeFrame: At 12 Weeks
measure: Low contrast letter acuity by eye
timeFrame: At 12 weeks
measure: Clinical Global Impression Scale
timeFrame: At 12 weeks
measure: Patient Global Impression Scale
timeFrame: At 12 weeks
measure: Pharmacokinetic Endpoint
timeFrame: Through 18 weeks
measure: Pharmacodynamic Endpoint
timeFrame: Through 18 weeks
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
Study officials:
affiliation: University of Texas Southwestern Medical Center
name: Peter Sguigna, MD
role: PRINCIPAL_INVESTIGATOR
References: