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

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

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

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Enoxacin

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute-Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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: Placebo; Oral tablet; Drug: Enoxacin; Oral 200mg 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: Placebo; Oral tablet; Drug: Enoxacin; Oral 200mg 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; Oral 200mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
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.	From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
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.	From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
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.	From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
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.	From baseline (prior to dosing on day 1 of dosing) to 14 day +/- 2 day follow up visit
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.	From the beginning (day 1) to the end (day 30) of the 30 day treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to dosing and at 1, 2, 4, 6, 8 and 24 hours post morning dosing on days 1 and 30 of dosing.
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.	Prior to morning dosing on days 7, 14, 21, and 30.
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.	At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit
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.	At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit
Forced Vital Capacity (FVC) measurements at baseline and at the end of the follow-up period		At baseline (prior to dosing on day 1 of dosing) and at the 14 day +/- 2 day follow-up visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability of enoxacin to modulate the expression of one or more miRNA species in cerebrospinal fluid (CSF) and/or plasma	Expression levels of miRNA species will be measured in CSF and/or plasma	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.

Collaborators and Investigators

• Sponsor: McGill University
• Collaborators: Weizmann Institute of Science; Apotex Inc.
• Investigators: Principal Investigator: Angela Genge, MD, FRCP, McGill University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Clinical Research Unit at The Montreal Neurological Institute-Hospital, McGill University

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Actual): November 15, 2023
• Study Completion (Actual): November 15, 2023

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: April 8, 2021
• First Posted (Actual): April 12, 2021

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Enoxacin
• 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; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Enoxacin
• Other Study ID Numbers: REALS-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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