Therapeutic Nanocatalysis to Slow Disease Progression of Amyotrophic Lateral Sclerosis (ALS) (RESCUE-ALS)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study in Early Symptomatic Amyotrophic Lateral Sclerosis Patients on Stable Background Therapy to Assess Bioenergetic Catalysis With CNM-Au8 to Slow Disease Progression in ALS.

The objective of this trial was to assess the efficacy, safety, and PK/PD effects of CNM-Au8 as a disease-modifying agent for the treatment of ALS by utilizing electrophysiological measures to detect preservation of motor neuron function. The primary endpoint was the mean change in the average difference between active treatment and placebo from Baseline through Week 36 evaluated by electromyography.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: CNM-Au8; Drug: Placebo

Detailed Description

This was a multi-centre randomized, double-blind, parallel group, placebo-controlled study of the efficacy, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who are newly symptomatic within 24-months of Screening and with a clinically probable or possible or definite ALS diagnosis per the Awaji-Shima criteria.

Patients were screened over up to a 6-week period. Patients who met the inclusion criteria and none of the exclusionary criteria were enrolled into the clinical study. Patients were randomized 1:1 into one of two groups: either active treatment with CNM-Au8 30 mg or Placebo.

All patients received their randomized oral treatment daily over thirty-six (36) consecutive weeks during the Treatment Period.

There were up to four study periods:

1. Up to a six (6) week screening period (Screening Period);
2. A thirty-six (36) week blinded randomized treatment period (Treatment Period);
3. Up to a forty-eight (48) week optional open-label extension period (Open-Label Period);
4. A four (4) week safety follow-up period following completion of either the Treatment or Open-Label period or in the case of Early Termination (Safety Follow-Up Period).

Per protocol, all patients received their blinded and randomized oral treatment daily over at least 36 consecutive weeks during the Treatment Period.

For those patients not transitioning into the optional OLE period, patients completed a safety follow-up visit 4-weeks following study drug discontinuation.

An independent DSMB was responsible for monitoring the safety of the study on a quarterly basis and ad hoc at the request of the DSMB or the Sponsor (e.g., in the event of unexpected SAEs) to review data throughout the Treatment Period. The DSMB may make recommendations on the conduct of the study, including study termination. Appropriate procedures will be detailed in a DSMB Charter.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2050
      • University of Sydney Brain and Mind Centre

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Able to understand and give written informed consent.
2. Male or female patients aged 30 years or greater (inclusive) and less than 80 years of age at the time of Screening.
3. Patients whose conditions are defined as possible or probable or definite ALS per the diagnostic criteria by Awaji-Shima criteria as determined by a neurologist sub- specialising in ALS (e.g., the Principal Investigator by study site).
4. For patients taking riluzole, stable dosing of riluzole over the prior 30-days from Screening.
5. At the time of Screening either disease duration less than or equal to 24-months from symptom onset, or disease duration less than or equal to 12-months from diagnosis.
6. Forced vital capacity (FVC) 60% of predicted value as adjusted for gender, height, and age at the Screening Visit.
7. Patient who has established care with a neurologist at one of the specialized ALS clinics involved in the study and will maintain this clinical care throughout the study. If a patient is referred from a third party (neurologist or a State based ALS organization) they must be willing to transfer care to the neurologist participating in the study.

Following completion of the 36-week randomized placebo controlled treatment period, interested participants must meet the following inclusion criteria to enroll in the open-label extension:

1. Participants must have completed the randomized placebo controlled Treatment Period without compliance issues
2. Able to understand and give written informed consent to participant in the open-label extension.
3. If referred from a third party (neurologist or a State based ALS organization), participant agrees to maintain transfer of care to a neurologist participating in the study.

Exclusion Criteria:

1. Patients will be excluded from the study if they meet any of the following criteria:

2. At Screening patients who utilize, or in the Investigator's judgment will be imminently dependent upon:

   1. Non-invasive ventilation > 22 hours per day, or
   2. Tracheostomy Note: If the patient requires non-invasive ventilation postrandomisation, they will be allowed to continue in the study.
3. Patients with Familial ALS (e.g., 2 or more family members with ALS or motor neuron disease)
4. Patients with a history of carpal tunnel syndrome, polyneuropathy, or in the investigators judgement diseases that could induce polyneuropathy and interfere with electromyography (EMG) recordings.
5. Patients with too severe atrophy of the Abductor Digiti Minimi (ADM), Abductor Pollicis Brevis (APB), Biceps Brachii (BB), or Tibialis Anterior (TA) muscles in the least clinically affected hand and leg, respectively, to allow for reliable EMG recordings.
6. Patient with a history of significant other major medical conditions based on the Investigator's judgment.
7. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.
8. Patient with clinically significant abnormalities in haematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator can interfere with study participation.
9. 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.
10. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter).
11. 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.
12. Females of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control.
13. Active inflammatory condition or autoimmune disorder.
14. Positive screen for drugs of abuse.
15. History of gold allergy.
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.

Following completion of the 36-week randomized placebo controlled treatment period, interested participants will be excluded from participating in the open-label extension phase if they meet any of the following criteria:

1. Lack of treatment compliance during the randomized placebo controlled Treatment Period.
2. Positive pregnancy test at the Week 36 visit, or, females who plan to get pregnant during the course of this extension or within 6 months of the end of this extension.
3. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.
4. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination identified during the W36 visit which according to Investigator may interfere with continued participation.

5. 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 the Week 36 visit.

6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 30 mg CNM-Au8; 30mg suspension of clean-surfaced, faceted, gold nanocrystals in 60ml of sodium bicarbonate buffered water	Drug: CNM-Au8; 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 nominal concentration of 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 60 mL HDPE containers.
Placebo Comparator: Placebo; The matched placebo used in this study consisted of water, sodium bicarbonate, and food coloring to match volume and color of the experimental treatment	Drug: Placebo; Placebo was liquid with identical color and taste

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electromyography Measures of Disease Progression.	The Motor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with ALS. Mean change in the average difference between active treatment and placebo from Baseline through Week 36 for the MUNIXscore(4), which is the sum of the respective MUNIX values for the Abductor Digiti Minimi (ADM), Abductor Pollicis Brevis (APB), Biceps Brachii (BB), and Tibialis Anterior (TA). The average baseline summed values will be indexed to 100%. Changes will be calculated as the percent change from the Baseline index of 100%.	36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Mean Change in the Average Difference Between Active Treatment and Placebo From Baseline for Respiratory Function as Measured by Forced Vital Capacity (FVC).	Mean change in FVC - Forced Vital Capacity.	36 weeks
Mean Absolute Change of the Average Difference Between Active Treatment and Placebo From Baseline Through Week 36 for the MUNIXscore(4).	The Motor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with ALS. MUNIX will be reviewed via electromyography for the Abductor Pollicus Brevis (APB), Abductor Digiti Minimi (ADM), Biceps Brachii (BB), and Tibialis Anterior (TA). MUNIXscore(4) is the sum of the respective MUNIX values for the above mentioned muscle groups. A higher MUNIX value signifies greater muscle function. A greater decrease in the Mean absolute change signifies worsening muscle function.	36 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in the Average Difference Between Active Treatment and Placebo From Baseline Through Week 36 (Overall Difference at All Time Points) as Measured by MScanFit MUNE (Jacobsen et al., 2017) of the APB.	The baseline average will be indexed to 100%, and changes at Week 12 and Week 36 will be calculated as the percent change from the Baseline index of 100%.	36 weeks
Mean Change in the Average Difference Between Active Treatment and Placebo From Baseline Through Week 36 for the MUSIXscore(4) (Neuwirth et al., 2015), Which is the Mean of the Respective MUSIX Values for the ADM, APB, BB, and TA.	MUNIXscore(4) is the mean of the respective MUSIX values for the ADM, APB, BB, and TA. The average baseline mean values will be indexed to 100%. Changes will be calculated as the percent change from the Baseline index of 100%.	36 weeks
Mean Change in the Average Difference Between Active Treatment and Placebo From Baseline for the Neurophysiological Index (NPI) of the ADM.	NPI is a method to quantify peripheral disease burden in ALS. NPI is defined as the ulnar nerve (ADM [CMAP peak amplitude] / ADM [distal motor latency]) x (ADM [f-wave %]).	36 weeks
Mean Change in the Average Difference Between Active Treatment and Placebo From Baseline for the Split Hand Index (SI).	The SI is an early clinical feature that is used as a neurophysiological biomarker for evaluating ALS. Split Hand Index, defined as the first dorsal interosseous (FDI)Peak CMAP Amplitude * APBPeak CMAP Amplitude/ADMPeak CMAP Amplitude.	36 weeks
Mean Change in Average ALSFRS-R Score	The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated rating instrument for monitoring the progression of disability in patients with ALS. Maximum score is 40, minimum is 0. A higher score signifies greater function.	36 weeks
Mean Change Between Active Treatment and Placebo in the Proportion of Patients Experiencing a > 6-point Decline in the ALSFRS-R Between Active Treatment and Placebo.	Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)	36 weeks
Mean Change in Slope of the Decline of the ALSFRS-R	The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated rating instrument for monitoring the progression of disability in patients with ALS.	36 weeks
Mean Change Between Active Treatment and Placebo for the Combined Assessment of Function and Survival (CAFS), a Joint-rank Analysis of Function (ALSFRS-R) and Overall Survival	the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. There is no maximum or minimum due to ranking.	36 weeks
Time to ALS Clinical Worsening	ALS Clinical Worsening is defined as the occurrence of death, tracheostomy, use of non-invasive ventilatory respiratory support, insertion of a gastrostomy tube, or a 6-point drop in the ALSFRS-R score. This outcome measures the number of participants that experienced ALS clinical worsening event within the 36 week time frame.	36 weeks
Mean Change in Rate of Disease Progression Defined as the Average Change in the Functional Survival (FS) Score ([Max ALSFRS-R Minus Current ALSFRS-R Score]/Symptom Duration in Months)	Change in FS score = (Max ALSFRS-R minus current ALSFRS-R score) divided by symptom duration in months.	36 weeks
Mean Change in Average Difference Between Active Treatment and Placebo for the ALSSQOL-Short Form Questionnaire (ALSSQOL-SF)	ALS Specific Quality of Life - Short Form (ALSSQOL-SF) Questionnaire will be completed at multiple times during the trial and the scores will be averaged. Maximum score is 10, minimum score is 0. A higher score signifies a higher quality of life.	36 weeks
Mean Change in Average Difference Between Active Treatment and Placebo for the Clinician's Global Impression (CGI)	The CGI scales (assessing both severity [CGI-S] and improvement [CGI-I]) provides a brief assessment of the clinician's view of the patient's global functioning and severity of current disease state and can be utilized to assess for changes in disease progression over the course of a clinical trial.	36 weeks
Mean Change in Average Difference Between Active Treatment and Placebo for the Patient's Global Impression (PGI)	The PGI scales (assessing both severity [PGI-S] and improvement [PGI-I]) provides a brief assessment of the patient's view global functioning and severity of current disease state and can be utilized to assess for changes in disease progression over the course of a clinical trial.	36 weeks
Difference in the Proportion of Patients Utilizing Health Economic Outcome Measures		36 weeks

Collaborators and Investigators

• Sponsor: Clene Nanomedicine
• Collaborators: Clene Australia Pty Ltd
• Investigators: Principal Investigator: Parvarthi Menon, PhD, MD, MBBS, Westmead Hospital; Principal Investigator: William Huynh, MD, University of Sydney, Brain and Mind Centre

Publications and helpful links

General Publications

• Vucic S, Kiernan MC, Menon P, Huynh W, Rynders A, Ho KS, Glanzman R, Hotchkin MT. Study protocol of RESCUE-ALS: A Phase 2, randomised, double-blind, placebo-controlled study in early symptomatic amyotrophic lateral sclerosis patients to assess bioenergetic catalysis with CNM-Au8 as a mechanism to slow disease progression. BMJ Open. 2021 Jan 11;11(1):e041479. doi: 10.1136/bmjopen-2020-041479.
• Vucic S, Menon P, Huynh W, Mahoney C, Ho KS, Hartford A, Rynders A, Evan J, Evan J, Ligozio S, Glanzman R, Hotchkin MT, Kiernan MC. Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension. EClinicalMedicine. 2023 Jun 8;60:102036. doi: 10.1016/j.eclinm.2023.102036. eCollection 2023 Jun.

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2019
• Primary Completion (Actual): July 13, 2021
• Study Completion (Actual): July 13, 2021

Study Registration Dates

• First Submitted: September 19, 2019
• First Submitted That Met QC Criteria: September 19, 2019
• First Posted (Actual): September 23, 2019

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: June 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: ALS; electromyography; Nanoparticle; Gold; Nanocrystal
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Disease Progression; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: CNMAu8.205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No