A Double-blind Randomised, Placebo-controlled Clinical Trial to Test Ambroxol Treatment in ALS

Study Overview
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Brief Summary
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Ambroxol is a simple cough medicine that is predicted to slow ALS disease progression. This study aims to investigate if ambroxol in high doses is effective in treating ALS. This study will be carried out across 5 research sites in Australia (2 NSW, 1 VIC, 1 SA and 1 TAS), where newly diagnosed ALS patients will be asked to participate. Participation will be over a 32-week period, where they will come in for a 4-week screening, 24-week treatment, and 4-week end of study safety follow-up period. The participants will receive either the placebo or drug solution that they will take three times a day, up-dosing each week until they reach the maximum dose or highest dose they can tolerate. Throughout the study their disease progression will be assessed using tests, questionnaires, and blood biomarkers.

Detailed Description
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This study is a double-blind, randomised, placebo-controlled phase 2 clinical trial, to assess the safety, tolerability and efficacy of ambroxol therapy in ALS patients by using electrophysiological and functional measures to detect preservation of motor units. The study design will have participants be randomised to either ambroxol or placebo at a 2:1 ratio (ambroxol (n=34) and placebo (n=16)). Participants randomised to the active arm will receive various doses of ambroxol in solution, taken orally, three times a day. Doses will be increased pending a safety review for each participant. The doses will be 180mg per day, 260mg per day, 540mg per day, 900mg per day, and 1260 mg per day. Each week safety bloods will be performed to assess tolerance to the dose. Participants randomised to the control arm will receive a placebo for the duration of the study. Disease progression will be assessed by the following, time to event (death, need for tracheostomy, the need for gastrostomy feeding or non-invasive ventilation support (≥12 hours a day in a 24-hour period), or ≥6-point progression (ALS functional rating score-revised).

Official Title
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AMBroxol Therapy for ALS (AMBALS) Trial: a Double-blind, Randomised, Placebo-controlled Phase 2 Clinical Trial of Ambroxol for ALS

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Ambroxol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have given written informed consent before any study related assessments are performed and must be able to understand purpose of the study, including any possible risks and adverse events. ALS as diagnosed according to the recently proposed Gold Coast diagnostic criteria. First symptom of ALS less than or equal to 18 months prior to screening. The qualifying first symptoms of ALS are limited to manifestations of weakness in extremity, bulbar, or respiratory muscles. Cramps, fasciculations, or fatigue should not be taken in isolation as a first symptom of ALS. Forced vital capacity (FVC) greater than or equal to 60% of predicted value as adjusted for gender, height and age at the Screening Visit. Male or female patients aged 18 years or greater (inclusive) and less than 85 years at the time of ALS diagnosis. Able to swallow liquid. Able to perform reproducible pulmonary function tests Female patients must be post-menopausal or sterilized or must not be breastfeeding, have no intention to become pregnant during the study, and use acceptable methods of contraception or abstain from intercourse. Male patients who have not had a vasectomy and confirmed zero sperm count must agree after receiving the first dose of study drug either to use acceptable methods of contraception or abstain from intercourse. If on riluzole, stable dosing for 30-days prior to screening. Pre-study ALSFRS-R progression between disease onset and screening of greater than or equal to 0.5 points/month (calculated by ALSFRS-R total score decline from 48 divided by the months since onset of ALS symptoms). Exclusion Criteria: Use of non-invasive ventilation (NIV) support for ALS only or gastrostomy tube at time of screening. Exposure to investigational drug within 12-weeks prior to screening. At screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or data. Patient with a history of significant other major medical conditions based on the Investigator's judgment. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures. Any person who is an employee or an Investigator or Sponsor, or an immediate relative of an Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised controlled trial. Participants will be randomised at a 2:1 ratio to the drug solution or placebo respectively.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Active<br>Ambroxol taken 3x daily. Variation in doses as follow-up progresses. For detailed information, see Intervention Description. | Drug: Ambroxol<br>* Participants in the study will receive varying doses of ambroxol in solution, 3 times per day. Doses will be increased pending a safety review, up to a maximum of 1260mg/day. Blood tests will be conducted weekly to assess tolerance. Compliance will be monitored by returning used bottles. The study will last 32 weeks, including 24 weeks of drug administration and follow-up visits. After the final follow-up, there will be an end of study safety visit occurring 4 weeks later. The total time of participation will be 32 weeks. This includes a screening visit up to 4 weeks prior to Baseline, then a Baseline visit, followed by 24 weeks of follow-up (3x in clinic follow-up visits). These 24 weeks will be the drug administration period, meaning that the total duration of drug administration is 24 weeks. Following this drug administration and follow-up period, there will be an EoS safety-follow up visit that will occur 4 weeks after the final follow-up visit (28 weeks from baseline).<br>* Other names: Ambroxol Hydrochloride;|
| Placebo Comparator: Placebo Comparator: Control<br>Glucose Placebo, taken 3x daily. Variation in doses as follow-up progresses. For detailed information, see Intervention Description. | Drug: Placebo<br>* Participants randomised to the control arm will receive a placebo for the duration of the study. The placebo will look and taste like ambroxol, but will have no active ingredient. Participants will not be told which arm they have been randomised to. The placebo will primarily be a glucose solution, however it will also have flavouring (e.g. bitters) and colouring, so as to make it look and taste like ambroxol, to maintain blinding.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to event | Time to event (death, need for tracheostomy, the need for gastrostomy feeding or non-invasive ventilation (NIV) support (greater than or equal to 12 hours a day in a 24-hour period), or greater than or equal to 6-point progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS)) This will be measured by patient medical records, and the completion of the ALSFRS by investigators. | Time to event for a maximum of 24 weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALS functional rating score-revised (ALSFRS-R) | Change in ALSFRS-R Score | 24 weeks from Baseline | 
| Motor unit number estimation (MUNIX) | Change in MUNIX values | 24 weeks from Baseline | 
| Split Hand Index (SI) | Change in SI value | 24 weeks from Baseline | 
| Neurophysiology Index (NPI) | Change in NPI Value | 24 weeks from Baseline | 
| Kings staging system | Change in Kings stage | 24 weeks from Baseline | 
| Muscle strength assessment as measured by the Medical Research Council (MRC) Scale for Muscle Strength | Change in Muscle strength, where Grade 0 is no visible contraction and Grade 5 is Normal | 24 weeks from Baseline | 
| Respiratory function (FVC) as measure by a Spirometer | Change in FVC | 24 weeks from Baseline | 
| Survival | Overall survival rate | 24 weeks from Baseline | 
| Serum NFL levels | Change in Serum NFL Levels | 24 weeks from Baseline | 
| Assessment of Quality of Life (AQoL) | Change in AQoL score | 24 weeks from Baseline |