Ignite Creation Date:
2024-05-06 @ 8:05 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06249867
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-08
First Post:
2024-01-22
Brief Title:
A Study to Assess the Safety Tolerability and Pharmacology of Darifenacin in Patients With ALS
Sponsor:
McGill University
Organization:
McGill University
Study Overview
Official Title:
A Randomized Double-blind Single Center Phase 2 Study to Assess the Safety Tolerability Pharmacokinetics and Pharmacodynamics of 15 mg of Darifenacin Daily in Patients With Amyotrophic Lateral Sclerosis
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Amyotrophic lateral sclerosis ALS is a progressive neurological disorder characterized by selective death of upper and lower motor neurons which leads to severe disability and fatal outcomes One of the major hallmarks of ALS is the denervation of neuromuscular junctions NMJs which is one of the earliest events seen in ALS patients and mouse models of ALS Under healthy conditions glial cells called Perisynaptic Schwann Cells PSCs have a key role in regulating the stability and maintenance of NMJs but they only participate in NMJ repair once denervation occurs Denervation and the subsequent decline in synaptic activity triggers a loss of muscarinic acetylcholine receptors mAChRs in the PSC and the resulting decrease in mAChR-mediated gene expression drives the repair mode of the PSC In assessing the NMJ under conditions of ALS a scarcity of process extensions in PSCs was observed for months prior to disease onset in the superoxide dismutase 1 SOD1 mouse model of ALS indicating inadequate glial repair Collectively these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated repair response of PSCs in the NMJ Hence the use of a selective M3 muscarinic receptor antagonist Darifenacin as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function resulting in a beneficial impact on the autonomy and quality of life of ALS patients
The purpose of the current Phase 2 trial is therefore to test the safety tolerability and pharmacology of Darifenacin in patients with ALS Specifically 30 eligible subjects between 18 and 85 years of age will take 75 mg of darifenacin or placebo daily by mouth for two weeks followed by an increased dose of 15 mg for the next 22 weeks The trial will evaluate the effects of this medication on several outcome measures including patient safety physical and neurological function muscle strength depression levels and NMJ innervation of patients with ALS Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives
The purpose of the current Phase 2 trial is therefore to test the safety tolerability and pharmacology of Darifenacin in patients with ALS Specifically 30 eligible subjects between 18 and 85 years of age will take 75 mg of darifenacin or placebo daily by mouth for two weeks followed by an increased dose of 15 mg for the next 22 weeks The trial will evaluate the effects of this medication on several outcome measures including patient safety physical and neurological function muscle strength depression levels and NMJ innervation of patients with ALS Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives
Detailed Description:
ALS is a rapidly progressive neurodegenerative disorder caused by the selective death of motor neurons within the brain brainstem and spinal cord leading to paralysis and death within 2-5 years after diagnosis A limited number of disease-modifying treatments are available for patients with ALS namely Riluzole Rilutek Edaravone Radicava and AMX0035 Relyvrio in the USA and Albrioza in Canada and novel therapeutic approaches are being investigated to tackle several aspects of ALS pathological features
One of the major hallmarks of ALS is the denervation of neuromuscular junctions NMJs which is one of the earliest events seen in ALS patients and murine models that recapitulate ALS-like aspects of the disease due to ALS-causing mutations in the SOD1 TDP-43 and FUS genes It has been shown that an extensive and extended period of NMJ denervation-reinnervation cycles occurs months prior to disease onset in SOD1 ALS mice To be specific scarce Perisynaptic Schwann Cell PSC process extensions were observed which indicates inadequate glial repair Therefore while PSCs are responsive to NMJ alterations in ALS their response does not support NMJ repair PSCs have a key role in regulating the stability and maintenance of NMJs They actively participate in NMJ repair once denervation and loss of muscarinic acetylcholine receptors mAChRs occur Additionally regulation of PSC gene expression governed by mAChR activation drives the dynamic adaptation of the PSC in a synaptic activity-dependent manner PSCs will switch to a repair mode when mAChR activation is reduced such as following a sciatic nerve crush injury and during synapse formation
Collectively these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated repair response of PSCs in the NMJ Hence the use of a selective M3 muscarinic receptor antagonist Darifenacin as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function resulting in a beneficial impact on the autonomy and quality of life of ALS patients The purpose of the current Phase 2 trial is therefore to test the safety tolerability and pharmacology of Darifenacin in patients with ALS
APO-DARIFENACIN Darifenacin Extended Release Tablets darifenacin as darifenacin hydrobromide is a known active substance with the chemical name S-2-1-2-23-Dihydrobenzofuran-5-ylethyl-3-pyrrolidnyl-22-diphenylacetamide hydrobromide For the purposes of this trial darifenacin has been formulated by Apotex Inc as an extended release tablet Darifenacin will be produced and formulated into 75 mg coated tablets extended-release and a placebo film-coated tablet will be manufactured without the active substance
Patient enrollment for this trial will consist of 30 eligible ALS patients between 18 and 85 years of age During the first two weeks titration period patients will receive a daily dose of either a placebo or a 75 mg darifenacin extended-release tablet After the titration period the dose will be increased to 15 mg once daily which consists of two 75 mg tablets together Depending on the patients response to the medication they may be asked to temporarily or permanently stop taking the drug or reduce their dose from 15 mg to 75 mg for safety reasons This treatment period has been selected as a standard for phase 2 trials to study the endpoints and observe significant differences in the outcome measures
The trial will evaluate the effects of this medication and dosing regimen on several outcome measures including patient safety physical and neurological function muscle strength depression levels and NMJ innervation of patients with ALS Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives
One of the major hallmarks of ALS is the denervation of neuromuscular junctions NMJs which is one of the earliest events seen in ALS patients and murine models that recapitulate ALS-like aspects of the disease due to ALS-causing mutations in the SOD1 TDP-43 and FUS genes It has been shown that an extensive and extended period of NMJ denervation-reinnervation cycles occurs months prior to disease onset in SOD1 ALS mice To be specific scarce Perisynaptic Schwann Cell PSC process extensions were observed which indicates inadequate glial repair Therefore while PSCs are responsive to NMJ alterations in ALS their response does not support NMJ repair PSCs have a key role in regulating the stability and maintenance of NMJs They actively participate in NMJ repair once denervation and loss of muscarinic acetylcholine receptors mAChRs occur Additionally regulation of PSC gene expression governed by mAChR activation drives the dynamic adaptation of the PSC in a synaptic activity-dependent manner PSCs will switch to a repair mode when mAChR activation is reduced such as following a sciatic nerve crush injury and during synapse formation
Collectively these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated repair response of PSCs in the NMJ Hence the use of a selective M3 muscarinic receptor antagonist Darifenacin as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function resulting in a beneficial impact on the autonomy and quality of life of ALS patients The purpose of the current Phase 2 trial is therefore to test the safety tolerability and pharmacology of Darifenacin in patients with ALS
APO-DARIFENACIN Darifenacin Extended Release Tablets darifenacin as darifenacin hydrobromide is a known active substance with the chemical name S-2-1-2-23-Dihydrobenzofuran-5-ylethyl-3-pyrrolidnyl-22-diphenylacetamide hydrobromide For the purposes of this trial darifenacin has been formulated by Apotex Inc as an extended release tablet Darifenacin will be produced and formulated into 75 mg coated tablets extended-release and a placebo film-coated tablet will be manufactured without the active substance
Patient enrollment for this trial will consist of 30 eligible ALS patients between 18 and 85 years of age During the first two weeks titration period patients will receive a daily dose of either a placebo or a 75 mg darifenacin extended-release tablet After the titration period the dose will be increased to 15 mg once daily which consists of two 75 mg tablets together Depending on the patients response to the medication they may be asked to temporarily or permanently stop taking the drug or reduce their dose from 15 mg to 75 mg for safety reasons This treatment period has been selected as a standard for phase 2 trials to study the endpoints and observe significant differences in the outcome measures
The trial will evaluate the effects of this medication and dosing regimen on several outcome measures including patient safety physical and neurological function muscle strength depression levels and NMJ innervation of patients with ALS Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None