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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Active
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Enoxacin
Placebo
Sponsored by
McGill University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Enoxacin

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of familial or sporadic ALS
  • 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

Sites / Locations

  • Montreal Neurological Institute-Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Enoxacin 200mg twice daily

Enoxacin 400mg twice daily

Enoxacin 600mg twice daily

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Incidence of adverse events (AEs) and serious adverse events (SAEs)
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.
Incidence of abnormalities in clinical laboratory assessments
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.
Incidence of abnormalities in vital signs
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.
Incidence of abnormalities in physical and neurological examinations
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.
Incidence of abnormalities in electrocardiograms (ECGs)
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.
Ability of participants to remain on their assigned dose for the full 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

Maximum plasma concentration (Cmax) of enoxacin after administration on day 1 and 30
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.
Time of maximum plasma concentration (Tmax) of enoxacin after administration on day 1 and 30
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.
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
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.
Area under the plasma concentration-time curve extrapolated to infinity (AUC 0-inf) of enoxacin after administration on day 1 and 30
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.
Terminal half-life (t1/2) of enoxacin after administration on day 1 and 30
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.
Accumulation ratio (R) of enoxacin after administration on day 1 and 30
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.
Trough plasma concentration at pre-dose of enoxacin on day 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.
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score at baseline and at the end of the follow-up period
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.
King's College (KINGS) stage at baseline and at the end of the follow-up period
The KINGS staging system for ALS will be used to assess the course of the disease and is based on the number of involved regions (where the three possible regions are bulbar, upper limb or lower limb) for the first three stages and the need for gastrostomy and non-invasive ventilation for the subsequent stages. The possible stages in the KINGS staging system are as follows: Stage 1: First Region Involved; Stage 2: Second Region Involved; Stage 3: Third Region Involved; Stage 4a: Nutritional Failure (need for gastrostomy); Stage 4b: Respiratory Failure (need for non-invasive ventilation); and Stage 5: Death.
Forced Vital Capacity (FVC) measurements at baseline and at the end of the follow-up period

Full Information

First Posted
March 29, 2021
Last Updated
March 21, 2023
Sponsor
McGill University
Collaborators
Weizmann Institute of Science, Apotex Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04840823
Brief Title
Enoxacin for Amyotrophic Lateral Sclerosis (ALS)
Acronym
REALS-1
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 26, 2021 (Actual)
Primary Completion Date
May 2023 (Anticipated)
Study Completion Date
May 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
McGill University
Collaborators
Weizmann Institute of Science, Apotex Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
Enoxacin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Enoxacin 200mg twice daily
Arm Type
Experimental
Arm Description
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.
Arm Title
Enoxacin 400mg twice daily
Arm Type
Experimental
Arm Description
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.
Arm Title
Enoxacin 600mg twice daily
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Enoxacin
Intervention Description
Oral 200mg tablet
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral tablet
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs) and serious adverse events (SAEs)
Description
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.
Time Frame
From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
Title
Incidence of abnormalities in clinical laboratory assessments
Description
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.
Time Frame
From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
Title
Incidence of abnormalities in vital signs
Description
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.
Time Frame
From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
Title
Incidence of abnormalities in physical and neurological examinations
Description
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.
Time Frame
From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
Title
Incidence of abnormalities in electrocardiograms (ECGs)
Description
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.
Time Frame
From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
Title
Ability of participants to remain on their assigned dose for the full 30 day treatment period
Description
The ability of participants to remain on each dose level will be measured by the mean number of missed doses.
Time Frame
From the beginning (day 1) to the end (day 30) of the 30 day treatment period
Secondary Outcome Measure Information:
Title
Maximum plasma concentration (Cmax) of enoxacin after administration on day 1 and 30
Description
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.
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.
Title
Time of maximum plasma concentration (Tmax) of enoxacin after administration on day 1 and 30
Description
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.
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.
Title
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
Description
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.
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.
Title
Area under the plasma concentration-time curve extrapolated to infinity (AUC 0-inf) of enoxacin after administration on day 1 and 30
Description
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.
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.
Title
Terminal half-life (t1/2) of enoxacin after administration on day 1 and 30
Description
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.
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.
Title
Accumulation ratio (R) of enoxacin after administration on day 1 and 30
Description
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.
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.
Title
Trough plasma concentration at pre-dose of enoxacin on day 7, 14, 21, and 30
Description
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.
Time Frame
Prior to morning dosing on days 7, 14, 21, and 30.
Title
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score at baseline and at the end of the follow-up period
Description
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.
Time Frame
At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit
Title
King's College (KINGS) stage at baseline and at the end of the follow-up period
Description
The KINGS staging system for ALS will be used to assess the course of the disease and is based on the number of involved regions (where the three possible regions are bulbar, upper limb or lower limb) for the first three stages and the need for gastrostomy and non-invasive ventilation for the subsequent stages. The possible stages in the KINGS staging system are as follows: Stage 1: First Region Involved; Stage 2: Second Region Involved; Stage 3: Third Region Involved; Stage 4a: Nutritional Failure (need for gastrostomy); Stage 4b: Respiratory Failure (need for non-invasive ventilation); and Stage 5: Death.
Time Frame
At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit
Title
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 Pre-specified Outcome Measures:
Title
Ability of enoxacin to modulate the expression of one or more miRNA species in cerebrospinal fluid (CSF) and/or plasma
Description
Expression levels of miRNA species will be measured in 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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of familial or sporadic ALS 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Angela Genge, MD, FRCP
Organizational Affiliation
McGill University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montreal Neurological Institute-Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 2B4
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
20616011
Citation
Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R Jr, Chen A, Hornstein E. miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13111-6. doi: 10.1073/pnas.1006151107. Epub 2010 Jun 29.
Results Reference
background
PubMed Identifier
26330466
Citation
Emde A, Eitan C, Liou LL, Libby RT, Rivkin N, Magen I, Reichenstein I, Oppenheim H, Eilam R, Silvestroni A, Alajajian B, Ben-Dov IZ, Aebischer J, Savidor A, Levin Y, Sons R, Hammond SM, Ravits JM, Moller T, Hornstein E. Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS. EMBO J. 2015 Nov 3;34(21):2633-51. doi: 10.15252/embj.201490493. Epub 2015 Sep 1.
Results Reference
background
PubMed Identifier
31852800
Citation
Reichenstein I, Eitan C, Diaz-Garcia S, Haim G, Magen I, Siany A, Hoye ML, Rivkin N, Olender T, Toth B, Ravid R, Mandelbaum AD, Yanowski E, Liang J, Rymer JK, Levy R, Beck G, Ainbinder E, Farhan SMK, Lennox KA, Bode NM, Behlke MA, Moller T, Saxena S, Moreno CAM, Costaguta G, van Eijk KR, Phatnani H, Al-Chalabi A, Basak AN, van den Berg LH, Hardiman O, Landers JE, Mora JS, Morrison KE, Shaw PJ, Veldink JH, Pfaff SL, Yizhar O, Gross C, Brown RH Jr, Ravits JM, Harms MB, Miller TM, Hornstein E. Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. Sci Transl Med. 2019 Dec 18;11(523):eaav5264. doi: 10.1126/scitranslmed.aav5264.
Results Reference
background
Links:
URL
https://cru.mcgill.ca/
Description
Clinical Research Unit at The Montreal Neurological Institute-Hospital, McGill University

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Enoxacin for Amyotrophic Lateral Sclerosis (ALS)

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