31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Amyotrophic Lateral Sclerosis (REPAIR-ALS) (REPAIR-ALS)

• ClinicalTrials.gov Identifier: NCT03843710
• Recruitment Status: Withdrawn
• First Posted: February 18, 2019
• Last Update Posted: January 26, 2022
• Sponsor: Clene Nanomedicine
• Collaborator: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Clene Nanomedicine

Study Description

Brief Summary:

REPAIR-ALS 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 Amyotrophic Lateral Sclerosis (ALS) within twelve (12) months 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
Amyotrophic Lateral Sclerosis	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 Amyotrophic Lateral Sclerosis within twelve months 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:

A four-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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 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 Amyotrophic Lateral Sclerosis
• Estimated Study Start Date: March 2020
• Estimated Primary Completion Date: February 2022
• Estimated Study Completion Date: March 2022

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 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 ATP [ Time Frame: At 12 Weeks ]
   Mean change in average CNS concentration of ATP [mmol/kg] (as internal reference) 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

Eligibility Criteria

• Ages Eligible for Study: 35 Years to 75 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.
2. Male or female patients aged 35 years or greater (inclusive) and less than 75 years of age at the time of ALS diagnosis.
3. Patients with a confirmed ALS diagnosis: "definite ALS" or "probable ALS" or "possible" diagnostic criteria per the revised El Escorial Criteria as determined by a neurologist subspecializing in ALS (e.g., the Principal Investigator by study site).
4. Stable background therapy (e.g., stable dosing of riluzole within the prior 6-weeks) per Investigator discretion.
5. At the time of Screening disease duration less than or equal to 24-months from symptom onset OR within 12-moths of a confirmed ALS diagnosis.
6. Forced vital capacity (FVC) >/= 60% of predicted value as adjusted for gender, height, and age at the Screening Visit.
7. Patients who are ambulatory (e.g., normal ambulation, early ambulation difficulties, or walks with assistance) on the ALSFRS-R scale.

Exclusion Criteria:

1. At Screening patients who utilize, or in the Investigator's judgment will be imminently dependent upon during the course of this study:

   1. Non-invasive ventilation
   2. Gastrostomy (e.g., use of percutaneous endoscopic gastrostomy tube)
   3. Use of wheel chair
2. Patient who have previously undergone tracheostomy.
3. Patient with a history of significant other major medical condition based on the Investigator's judgment.
4. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures.
5. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator can interfere with study participation.
6. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter)
7. Females who are pregnant or nursing or who plan to get pregnant during the course of this clinical trial or within 6 months of the end of this trial.
8. Positive screen for drugs of abuse or known alcohol abuse.
9. Women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control during the study or for 6 months following completion of study participation.
10. Women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study.
11. Patients with implanted metal objects in their body that may be affected by an MRI procedure.
12. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures.
13. Patients with a history of gold allergy.

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: Jeffery Elliott, MD; UT Southwestern

More Information

• Responsible Party: Clene Nanomedicine
• ClinicalTrials.gov Identifier: NCT03843710
• Other Study ID Numbers: CNMAu8.203
• First Posted: February 18, 2019
• Last Update Posted: January 26, 2022
• Last Verified: January 2022

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:

ALS; Amyotrophic Lateral Sclerosis; Neurodegeneration; gold; nanocrystal; NAD+; NADH; Redox; Redox Ratio; 31P-MRS; MRS; magnetic resonance spectroscopy; nanoparticle; nanomedicine

Additional relevant MeSH terms:

Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases