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| Name | Class |
|---|---|
| Weizmann Institute of Science | OTHER |
| Apotex Inc. | INDUSTRY |
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The study will assess the safety of the drug enoxacin at specific dose levels in adults with ALS.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Enoxacin 200mg twice daily | Experimental | 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 | Experimental | 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 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enoxacin | Drug | Oral 200mg tablet |
|
| 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 |
| 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. |
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Angela Genge, MD, FRCP | McGill University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montreal Neurological Institute-Hospital | Montreal | Quebec | H3A 2B4 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20616011 | Background | 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. | |
| 26330466 |
| Label | URL |
|---|---|
| Clinical Research Unit at The Montreal Neurological Institute-Hospital, McGill University | View source |
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| ID | Term |
|---|---|
| D000690 | Amyotrophic Lateral Sclerosis |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D016472 | Motor Neuron Disease |
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| ID | Term |
|---|---|
| D015365 | Enoxacin |
| ID | Term |
|---|---|
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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| Placebo | Drug | Oral tablet |
|
| 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 |
| 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 |
| 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. |
| 31852800 | Background | 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. |
| D019636 | Neurodegenerative Diseases |
| D057177 | TDP-43 Proteinopathies |
| D009468 | Neuromuscular Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |