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Enoxacin for Amyotrophic Lateral Sclerosis (ALS) (REALS-1)

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ClinicalTrials.gov Identifier: NCT04840823
Recruitment Status : Recruiting
First Posted : April 12, 2021
Last Update Posted : April 12, 2021
Sponsor:
Collaborators:
Weizmann Institute of Science
Apotex Inc.
Information provided by (Responsible Party):
Angela Genge, McGill University

Brief Summary:
The study will assess the safety of the drug enoxacin at specific dose levels in adults with ALS.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Enoxacin 200mg Oral Tablet Drug: Placebo Phase 1 Phase 2

Detailed Description:
Participants will be randomized to one of three doses of enoxacin (200, 400, or 600mg twice daily) for 30 days. On day 1, 7, 14, 21, and 30 of treatment and at a follow-up visit 14 days after the last dose, participants will be assessed for safety measures and blood will be collected to assist with the determination of enoxacin pharmacokinetics (PK) and pharmacodynamics (PD). On day 1 and day 30 of dosing, participants will only take one dose of study medication (the morning dose) to assist with determination of enoxacin single dose PK over a 24-hour period. A lumbar puncture (LP) to collect cerebrospinal fluid (CSF) for PD assessments will occur on day 1 and day 30.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Parallel Group, Single Centre, Phase 1b/2 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Three Orally Administered Doses of Enoxacin (200mg Twice Daily, 400mg Twice Daily and 600mg Twice Daily) in Adults With Amyotrophic Lateral Sclerosis
Estimated Study Start Date : April 2021
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Enoxacin 200mg twice daily
Enoxacin 200mg twice daily (one dose in the morning and one dose in the evening) for 30 days, except day 1 and day 30 when only the morning dose will be taken. Participants will take 1 active 200mg enoxacin tablet and 2 placebo tablets per dose.
Drug: Enoxacin 200mg Oral Tablet
Enoxacin 200mg film coated tablet

Drug: Placebo
Placebo 200mg film coated tablet

Experimental: Enoxacin 400mg twice daily
Enoxacin 400mg twice daily (one dose in the morning and one dose in the evening) for 30 days, except day 1 and day 30 when only the morning dose will be taken. Participants will take 2 active 200mg enoxacin tablets and 1 placebo tablet per dose.
Drug: Enoxacin 200mg Oral Tablet
Enoxacin 200mg film coated tablet

Drug: Placebo
Placebo 200mg film coated tablet

Experimental: Enoxacin 600mg twice daily
Enoxacin 600mg twice daily (one dose in the morning and one dose in the evening) for 30 days, except day 1 and day 30 when only the morning dose will be taken. Participants will take 3 active 200mg enoxacin tablets per dose.
Drug: Enoxacin 200mg Oral Tablet
Enoxacin 200mg film coated tablet




Primary Outcome Measures :
  1. Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit ]
    The incidence of adverse events (new or worsened from baseline (where baseline refers to those AEs recorded prior to dosing on day 1 of dosing)) will be summarized by primary system organ class and preferred term as frequency count and percentage of participants with AEs.

  2. Incidence of abnormalities in clinical laboratory assessments [ Time Frame: From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit ]
    Clinical laboratory data will be characterized by abnormalities in values and in changes from baseline values, where baseline refers to measurements taken prior to dosing on day 1 of dosing.

  3. Incidence of abnormalities in vital signs [ Time Frame: From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit ]
    Vital sign data will be characterized by abnormalities in values and in changes from baseline values, where baseline refers to measurements taken prior to dosing on day 1 of dosing.

  4. Incidence of abnormalities in physical and neurological examinations [ Time Frame: From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit ]
    Physical and neurological examinations will be characterized by abnormalities and in changes from baseline, where baseline refers to measurements taken prior to dosing on day 1 of dosing.

  5. Incidence of abnormalities in electrocardiograms (ECGs) [ Time Frame: From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit ]
    ECG data will be characterized by abnormalities in values and in changes from baseline values, where baseline refers to measurements taken prior to dosing on day 1 of dosing.

  6. Ability of participants to remain on their assigned dose for the full 30 day treatment period [ Time Frame: From the beginning (day 1) to the end (day 30) of the 30 day treatment period ]
    The ability of participants to remain on each dose level will be measured by the mean number of missed doses.


Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the Cmax.

  2. Time of maximum plasma concentration (Tmax) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the Tmax.

  3. Area under the plasma concentration-time curve from time zero until the time corresponding with the last observed quantifiable concentration (AUC 0-last) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the (AUC) 0-last.

  4. Area under the plasma concentration-time curve extrapolated to infinity (AUC 0-inf) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the AUC 0-inf.

  5. Terminal half-life (t1/2) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the t1/2.

  6. Accumulation ratio (R) of enoxacin after administration on day 1 and 30 [ Time Frame: Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing. ]
    Enoxacin plasma concentrations measured in each individual participant prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing will be used to derive the R.

  7. Trough plasma concentration at pre-dose of enoxacin on day 7, 14, 21, and 30 [ Time Frame: Prior to morning dosing on days 7, 14, 21, and 30. ]
    Enoxacin plasma concentrations measured in each individual participant prior to morning dosing on days 7, 14, 21, and 30 will be used to derive the trough plasma concentration at pre-dose.

  8. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score at baseline and at the end of the follow-up period [ Time Frame: At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit ]
    The ALSFRS-R will be used to measure activities of daily living (ADL) and global function across four domains (respiratory, bulbar function, gross motor skills, and fine motor skills) and consists of 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function.

  9. KINGS stage at baseline and at the end of the follow-up period [ Time Frame: At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit ]
  10. Forced Vital Capacity (FVC) measurements at baseline and at the end of the follow-up period [ Time Frame: At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit ]

Other Outcome Measures:
  1. Ability of enoxacin to modulate the expression of one or more miRNA species in cerebrospinal fluid (CSF) and/or plasma [ Time Frame: Blood: prior to morning dosing on days 1, 7 (+/- 2 days), 14 (+/- 2 days), 21 (+/- 2 days) and 30, and at the 14 day +/- 2 day follow-up visit. CSF: prior to dosing on day 1, and 2 hours (+/-1 hour) post dosing on day 30. ]
    Expression levels of miRNA species will be measured in CSF and/or plasma



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of familial or sporadic ALS
  • Disease duration less than 36 months from symptom onset
  • FVC of ≥ 50 percent predicted
  • If female, is not breastfeeding and is not pregnant
  • Has been on a stable dose of riluzole, or has not taken riluzole, for at least 30 days prior to screening
  • If taking concomitant edaravone at study entry, must have completed at least one cycle of edaravone therapy prior to screening
  • Not currently taking and has not taken for at least 30 days prior to screening any Theophylline containing medications, clozapine, or duloxetine
  • No active infection in the 30 days prior to randomization
  • Has not taken any fluoroquinolone antibiotics for at least 30 days prior to screening

Exclusion Criteria:

  • Hypersensitivity/allergy to fluoroquinolones
  • Diagnosed with another neurodegenerative disease
  • Significant pulmonary disorder not attributed to ALS, central nervous system disorder associated with seizures, myasthenia gravis, active rheumatologic disease, tendinopathy, or any severe uncontrolled medical condition (other than ALS)
  • Severe renal impairment or impaired liver function
  • Baseline prolongation of QT interval/corrected QT interval (QTc) at screening, treatment with any agent that may prolong Qt/QTc interval, or history of any other at-risk other cardiac condition
  • Currently enrolled in another clinical trial involving an experimental drug or device

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04840823


Contacts
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Contact: Yousra Khalfallah, PhD 514-398-6188 yousra.khalfallah@mcgill.ca

Locations
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Canada, Quebec
Montreal Neurological Institute-Hospital Recruiting
Montreal, Quebec, Canada, H3A 2B4
Principal Investigator: Angela Genge         
Sponsors and Collaborators
McGill University
Weizmann Institute of Science
Apotex Inc.
Investigators
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Principal Investigator: Angela Genge, MD, FRCP McGill University
Additional Information:
Publications:
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Responsible Party: Angela Genge, Associate Professor, Neurologist, Neurology and Neurosurgery, McGill University
ClinicalTrials.gov Identifier: NCT04840823    
Other Study ID Numbers: REALS-1
First Posted: April 12, 2021    Key Record Dates
Last Update Posted: April 12, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Angela Genge, McGill University:
Enoxacin
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Enoxacin
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors