Enoxacin for Amyotrophic Lateral Sclerosis (ALS)

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

Detailed Description
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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.

Official Title
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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

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Enoxacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enoxacin 200mg twice daily<br>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<br>* Oral 200mg tablet<br>Drug: Placebo<br>* Oral tablet<br>|
| Experimental: Enoxacin 400mg twice daily<br>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<br>* Oral 200mg tablet<br>Drug: Placebo<br>* Oral tablet<br>|
| Experimental: Enoxacin 600mg twice daily<br>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<br>* Oral 200mg tablet<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Enoxacin