Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial

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

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.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Arimoclomol

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Catholic University Leuven
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
• France
  • Montpellier, France, 34295
    • Centre Hospitalier Regional Universitaire (CHRU) Montpellier - Hopital Gui De Chauliac
  • Paris, France, 75013
    • Groupe Hospitalier Pitie-Salpetriere - Centre d'Investigation Clinique Neurosciences 1422
• Germany
  • Berlin, Germany, 13353
    • Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum (CVK) - Ambulanz fuer ALS und andere Motoneuronenerkrankungen
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover (MHH) - Klinik fuer Neurologie
  • Ulm, Germany, 89081
    • Universitaetsklinikum Ulm - Klinik fuer Neurologie
• Italy
  • Milano, Italy, 20138
    • Instituti Clinica Scientifici Maugeri
  • Torino, Italy, 10126
    • Azienda Ospedaliero Universitaria (AUO) di Torino - Citta'della Salute e della Scienza di Torino
• Netherlands
  • Utrecht, Netherlands, 3584CX
    • University Medical Center Utrecht
• Poland
  • Warsaw, Poland, 01-684
    • Centrum Medyczne NeuroProtect
  • Warsaw, Poland, 02-473
    • Citi Clinic
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron ALS Unit. Consultas Externas; Office: 9-10-11
  • Madrid, Spain, 28046
    • Hospital Carlos III - Hospital Universitario La Paz, ALS Unit
• Sweden
  • Umeå, Sweden, 90737
    • Umeå University Hospital
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Leonard Wolfson Experimental Neurology Centre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center (SJHMC) - Barrow Neurological Institute (BNI) - The Gregory W. Fulton ALS and Neuromuscular Disease Center
  • California
    • Orange, California, United States, 92868
      • UC Irvine Health ALS and Neuromuscular Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Brain & Spine Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • University of Pensylvania, Perelman Center for Advanced Medicine - Penn Neuroscience Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. 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).
  2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ZevraDenmark
• Investigators: Principal Investigator: Michael Benatar, MD PhD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2019
• Primary Completion (Actual): July 2, 2021
• Study Completion (Actual): July 2, 2021

Study Registration Dates

• First Submitted: February 7, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): August 24, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: ALS; Arimoclomol
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: ORARIALS-02

Drug and device information, study documents

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