RESCUE-ALS: Therapeutic Nanocatalysis to Slow Disease Progression of Amyotrophic Lateral Sclerosis (ALS)
Study Details
Study Description
Brief Summary
The objective of this trial is 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 is the mean change in the average difference between active treatment and placebo from Baseline through Week 36 evaluated by electromyography.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is 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 may be screened over up to a 6-week period. Patients who meet the inclusion criteria and none of the exclusionary criteria will be enrolled into the clinical study. Patients will be randomized 1:1 into one of two groups: either active treatment with CNM-Au8 30 mg or Placebo.
All patients will receive their randomized oral treatment daily over thirty-six (36) consecutive weeks during the Treatment Period.
There will be up to four study periods:
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Up to a six (6) week screening period (Screening Period);
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A thirty-six (36) week blinded randomized treatment period (Treatment Period);
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Up to a forty-eight (48) week optional open-label extension period (Open-Label Period);
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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 will receive 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 will complete a safety follow-up visit 4-weeks following study drug discontinuation.
An independent DSMB will be 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo The matched placebo to be used in this study will consist of water, sodium bicarbonate, and food coloring to match volume and color of the experimental treatment |
Drug: Placebo
Placebo is liquid with identical color and taste
|
| 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.
|
Outcome Measures
Primary Outcome Measures
- Electromyography measures of disease progression. [36 weeks]
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%.
Secondary Outcome Measures
- Mean change in the average difference between active treatment and placebo from Baseline for respiratory function as measured by forced vital capacity (FVC). [36 weeks]
FVC - Forced Vital Capacity.
- Mean absolute change of the average difference between active treatment and placebo from Baseline through Week 36 for the MUNIXscore(4). [36 weeks]
The Motor Unit Number Index (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.
Other Outcome Measures
- 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. [36 weeks]
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%.
- 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. [36 weeks]
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%.
- Mean change in the average difference between active treatment and placebo from Baseline for the Neurophysiological Index (NPI) of the ADM. [36 weeks]
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 %]).
- Mean change in the average difference between active treatment and placebo from Baseline for the Split Hand Index (SI). [36 weeks]
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.
- Mean change in average ALSFRS-R score [36 weeks]
The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated rating instrument for monitoring the progression of disability in patients with ALS. The revised version incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support.
- 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. [36 weeks]
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
- Mean change in slope of the decline of the ALSFRS-R [36 weeks]
The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated rating instrument for monitoring the progression of disability in patients with ALS. The revised version incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support.
- 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 [36 weeks]
CAFS and ALSFRS-R
- Mean change in the proportion of patients experiencing ALS clinical composite disease progression [36 weeks]
Disease progression 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.
- 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) [36 weeks]
Change in FS score = (Max ALSFRS-R minus current ALSFRS-R score) divided by symptom duration in months.
- Mean change in the average difference between active treatment and placebo for respiratory function as measured by forced vital capacity (FVC) [36 weeks]
FVC - Forced Vital Capacity
- Mean change in average difference between active treatment and placebo for the ALSSQOL-Short Form questionnaire (ALSSQOL-SF) [36 weeks]
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.
- Mean change in average difference between active treatment and placebo for the Clinician's Global Impression (CGI) [36 weeks]
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.
- Mean change in average difference between active treatment and placebo for the Patient's Global Impression (PGI) [36 weeks]
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.
- Difference in the proportion of patients utilizing health economic outcome measures [36 weeks]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Able to understand and give written informed consent.
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Male or female patients aged 30 years or greater (inclusive) and less than 80 years of age at the time of Screening.
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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).
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For patients taking riluzole, stable dosing of riluzole over the prior 30-days from Screening.
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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.
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Forced vital capacity (FVC) 60% of predicted value as adjusted for gender, height, and age at the Screening Visit.
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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:
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Participants must have completed the randomized placebo controlled Treatment Period without compliance issues
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Able to understand and give written informed consent to participant in the open-label extension.
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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:
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Patients will be excluded from the study if they meet any of the following criteria:
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At Screening patients who utilize, or in the Investigator's judgment will be imminently dependent upon:
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Non-invasive ventilation > 22 hours per day, or
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Tracheostomy Note: If the patient requires non-invasive ventilation postrandomisation, they will be allowed to continue in the study.
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Patients with Familial ALS (e.g., 2 or more family members with ALS or motor neuron disease)
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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.
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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.
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Patient with a history of significant other major medical conditions based on the Investigator's judgment.
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Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.
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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.
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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.
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Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter).
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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.
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Females of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control.
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Active inflammatory condition or autoimmune disorder.
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Positive screen for drugs of abuse.
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History of gold allergy.
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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:
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Lack of treatment compliance during the randomized placebo controlled Treatment Period.
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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.
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Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.
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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.
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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.
- 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Sydney Brain and Mind Centre | Sydney | New South Wales | Australia | 2050 |
| 2 | Westmead Hospital | Sydney | New South Wales | Australia | 2145 |
Sponsors and Collaborators
- Clene Nanomedicine
- 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CNMAu8.205