Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial

Study Overview
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Brief Summary
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A multicenter, non-randomized, open label trial, to assess long term safety and efficacy of Arimoclomol in subjects with Amyotrophic Lateral Sclerosis (ALS) who have completed the ORARIALS-01 trial.

Detailed Description
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The planned duration of the open-label trial was 152 weeks, but the trial was terminated early as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints. Therefore, the actual mean duration of open-label treatment was approximately 28 weeks (range approximately 2 to 71 weeks).

Official Title
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Open Label, Non-randomized Extension Trial to Assess Long Term Safety and Efficacy of Arimoclomol in Subjects With Amyotropic Lateral Sclerosis Who Have Completed the ORARIALS-01 Trial

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Arimoclomol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is able to comprehend and is willing to provide written informed consent and is capable and willing to comply with trial procedures, or in the circumstance that the subject is incompetent, informed consent/assent is provided in accordance with local regulation and/or procedures Subject has completed the ORARIALS-01 trial (i.e., met one of the surrogate survival endpoints of tracheostomy or PAV or has completed the 76 weeks randomized treatment period) Subject completed ORARIALS-01 while on treatment, where on treatment is defined as having taken the last dose of IMP within 2 weeks of the End of Trial visit (whether at week 76 or prior) Exclusion Criteria: Known or suspected allergy or intolerance to the IMP (Arimoclomol or constituents) Exposure to any other investigational treatment, advanced therapy medicinal product or use of any other prohibited concomitant medications Women who are lactating or pregnant, or men or women unwilling to use a highly effective method of birth control if not surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy for women; vasectomy for men) for female participants until 4 weeks after last dose and for male participants until 3 months after last dose. Pre-menopausal women must have a negative pregnancy test prior to dosing with trial medication. Any of the following medically significant conditions: Clinically significant renal or hepatic disease OR clinical laboratory assessment (results ≥ 3 times the upper limit of normal [ULN] for aspartate aminotransferase and/or alanine aminotransferase, bilirubin ≥ 2 times the ULN, or creatinine ≥ 1.5 times the ULN). Any new condition or worsening of existing condition which, in the opinion of the investigator, would put the subject at undue risk. Any serious adverse event or moderate/severe adverse event from the ORARIALS-01 trial which is ongoing at the time of transitioning to ORARIALS-02 and assessed as probably related to IMP

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: Non-randomized open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arimoclomol<br>248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily | Drug: Arimoclomol<br>* 2 capsules (2 x 124 mg arimoclomol base; equivalent to 2 x 200 mg arimoclomol citrate) taken 3 times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period | Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. No participant was treated for 76 weeks. Participants with on-treatment TEAEs are reported. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration >14 days or the last dose at the end of trial). A participant may have several on-treatment periods separated by interruption intervals. | From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) | Standard hematology parameters. White blood cell differential count for basophils, eosinophils, leukocytes, lymphocytes, monocytes, and neutrophils, and platelet count. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) | Standard hematology parameters. Percentage of leukocytes were determined for basophils, eosinophils, lymphocytes, monocytes, and neutrophils | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Erythrocytes | Standard hematology parameter. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematocrit | Standard hematology parameter. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hemoglobin | Standard hematology parameter. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) | Standard clinical chemistry parameters. Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Creatine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) | Standard clinical chemistry parameters. Calcium, Calcium Corrected, Cholesterol, Glucose, HDL Cholesterol, LDL Cholesterol, Potassium, Sodium, Triglycerides, and Urea Nitrogen. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) | Standard clinical chemistry parameters. Bilirubin, Creatinine, Direct Bilirubin, and Indirect Bilirubin. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Albumin and Protein | Standard clinical chemistry parameters. | Week 76 | 
| Mean and Change From Baseline in Clinical Safety Laboratory Tests - Cystatin C | Standard clinical chemistry parameter. | Week 76 | 
| Mean and Change From Baseline in Vital Signs - Blood Pressure | Standard vital signs. Systolic and diastolic blood pressure. | Week 76 | 
| Mean and Change From Baseline in Vital Signs - Pulse Rate | Standard vital signs measurement. | Week 76 | 
| Mean and Change From Baseline in Vital Signs - Respiratory Rate | Standard vital signs measurement. | Week 76 | 
| Mean and Change From Baseline in Vital Signs - Temperature | Standard vital signs measurement. | Week 76 | 
| Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period | Clinical safety laboratory data and vital signs were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. No patient was treated for 76 weeks. | From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks | 
| Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period | The C-SSRS is a detailed questionnaire assessing both suicidal behavior and suicidal ideation through a series of simple, plain-language questions administered as an interview by a qualified investigator or delegate. | From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ALS Functional Rating Scale - Revised (ALSFRS-R) From Baseline to Week 76 | The ALSFRS-R is an ordinal rating scale used to determine subjects' subjective assessment of their capability and independence with 12 functional activities ('speech', 'salivation', 'swallowing', handwriting', 'cutting food and handling utensils', 'dressing and hygiene', 'turning in bed and adjusting bed clothes', 'walking', 'dyspnoea', 'orthopnoea' and 'respiratory insufficiency'). Each activity is rated on a 5-point scale (from 0 [no ability] to 4 [normal]), giving a maximal ALSFRS-R score of 48. A lower score corresponds to a lower capability and independence. | Week 76 | 
| Change in Percentage (%) Predicted Slow Vital Capacity (SVC) From Baseline to Week 76 (for Subjects Who Did Not Meet the Survival Endpoint in the ORARIALS-01 Trial) | Slow vital capacity (SVC) measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. Predicted SVC was derived per European Community of Coal and Steel (ECCS) reference equations: If male: Predicted SVC = 0.061 x height (cm) - 0.028 x age (years) - 4.65 If female: Predicted SVC = 0.0466 x height (cm) - 0.024 x age (years) - 3.28 | 76 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arimoclomol, ALS