Clinical trial NCT03533257: Study to Assess the Safety and Biological Activity of AMX0035 for the Treatment of Alzheimer's Disease
Official title: Phase II Study to Assess the Safety, Tolerability, and Target Engagement of AMX0035, a Fixed Combination of Sodium Phenylbutyrate and Tauroursodeoxycholic Acid for the Treatment of Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Lead sponsor: Amylyx Pharmaceuticals Inc.
Sponsor class: INDUSTRY
Collaborators: name: Alzheimer's Drug Discovery Foundation
name: Alzheimer's Association
First posted: 2018-05-23
Enrollment: 95
Sex: ALL
Minimum age (years): 55
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Placebo-Controlled, Double-Blind, Parallel-Group
Primary purpose: TREATMENT

Brief summary: The study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in participants with mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD).

Detailed description: The study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in participants with mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD). The study is designed to evaluate the safety, tolerability, drug target engagement and neurobiological effects of treatment with AMX0035 over 24 weeks. The study is designed to yield deep phenotyping insight for the purposes of demonstrating the effects of AMX0035 on mechanistic targets of engagement and disease biology. The study will evaluate diverse disease-relevant markers and produce an informative dataset that will allow for evaluation and correlation of imaging-based markers, neurobiological changes, functional measures, and cognitive outcomes. Participants receive orally administered study drug twice daily for a treatment duration of approximately 24 weeks and attend clinic visits at Screening, Baseline, Week 6, Week 12, Week 18, and Week 24.

Eligibility criteria: Inclusion Criteria:

1. Ages 55-89, inclusive, male or female
2. Diagnosis of "Probable Alzheimer's Disease" or Mild Cognitive Impairment (amnestic or amnestic plus other) with biomarkers that suggest intermediate or high likelihood that the syndrome is due to AD, according to 2011 NIA-AA Workgroup criteria
3. MoCA score \>/=8
4. Able to read and write in English sufficiently to complete all study procedures
5. Geriatric Depression Scale \<7
6. Willing and able to complete all assessments and study procedures
7. Not pregnant, lactating or of child-bearing potential (women must be \>2 years post-menopausal or surgically sterile)
8. Study partner with at least two days per week with contact with patient willing to accompany patient to visits and complete partner study forms
9. No known hypersensitivity to TURSO or Phenylbutyrate
10. If on cholinesterase inhibitor and/or memantine, treatment must have started for no less than 3 months (84 days) prior to baseline and the dosing regimen must have remained stable for 6 weeks (42 days) prior to baseline. The Investigator anticipated that the dosing regimen at baseline would remain unchanged throughout participation in the study.

Exclusion Criteria:

1. Any CNS disease other than suspected AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases
2. Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of normal
3. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal
4. Recent (less than 1 year) cholecystectomy or the presence of post-cholecystectomy syndrome or biliary obstruction
5. Clinically significant unstable medical condition (other than AD) that in the Site Investigator opinion would pose a risk to the participant if they were to participate in the study
6. Any contraindication to undergo MRI studies such as:

   1. History of a cardiac pacemaker or pacemaker wires
   2. Metallic particles in the body
   3. Vascular clips in the head
   4. Prosthetic heart valves
   5. Severe claustrophobia impeding ability to participate in an imaging study, or

   MRI findings that show one or more of the following:
   1. More than 4 incidental microhemorrhages
   2. Incidental lacunar infarct with attributable signs or symptoms and with history of stroke
   3. Incidental meningiomas with attributable signs or symptoms
   4. Newly recognized meningioma
7. Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) that is not stable or well controlled within the previous year prior to baseline
8. Any significant neurodevelopmental disability
9. Current suicidal ideation or history of suicide attempt within 5 years of baseline or significant change from the screening and baseline C-SSRS at the discretion of the Site Investigator
10. History of alcohol or other substance abuse or dependence within the past 2 years
11. Any significant systemic illness or medical condition that could affect safety or compliance with study at the discretion of the Site Investigator
12. Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction
13. Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, centrally-acting antihistamines, antipsychotics, sedative hypnotics, anxiolytics)
14. Use of any investigational therapy being used or evaluated for the treatment of AD is prohibited beginning 3 months (90 days) prior to the Baseline Visit and throughout the study.
15. Use of other investigational agents 1 month (28 days) prior to the Baseline Visit and for the duration of the trial.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Event (TEAEs)
timeFrame: From first dose to 24 weeks
measure: Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST)
timeFrame: 24 weeks
Secondary outcomes:
measure: Effect of Treatment on Cognition
timeFrame: 24 weeks
measure: Effect of Treatment on Functioning
timeFrame: 24 weeks
measure: Effect of Treatment on Dementia Severity
timeFrame: 24 weeks
measure: Effect of Treatment on Cognitive Impairment
timeFrame: 24 weeks
measure: Effect of Treatment on Neuropsychiatric Symptoms
timeFrame: 24 weeks
measure: Regional Brain Volume
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Clinical Neuroscience Solutions, Inc. - Jacksonville
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc. - Orlando
state: Florida
city: Palmetto Bay
country: United States
facility: International Medical Investigational Centers (IMIC)
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Stratford
country: United States
facility: Rowan University School of Osteopathic Medicine
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Alzheimer's Disease Research Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania, Penn Memory Center
state: Pennsylvania
city: Knoxville
country: United States
facility: Genesis NeuroScience Clinic
state: Tennessee
Study officials:
affiliation: Amylyx Pharmaceuticals Inc.
name: Patrick Yeramian, MD
role: STUDY_DIRECTOR
References:
citation: Arnold SE, Hendrix S, Nicodemus-Johnson J, Knowlton N, Williams VJ, Burns JM, Crane M, McManus AJ, Vaishnavi SN, Arvanitakis Z, Neugroschl J, Bell K, Trombetta BA, Carlyle BC, Kivisakk P, Dodge HH, Tanzi RE, Yeramian PD, Leslie K. Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease. Alzheimers Dement (N Y). 2024 Aug 9;10(3):e12487. doi: 10.1002/trc2.12487. eCollection 2024 Jul-Sep.