Repurposing Siponimod for Alzheimer's Disease

NCT06639282 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 23-500-037-10-037R01AG073212-02
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 1

Brief Summary

Collaboration with multiple sclerosis (MS) specialty colleagues led us to formulate the central hypothesis that Siponimod could lower the rate of brain atrophy in Alzheimer's disease (AD) subjects. To test our central hypothesis, we will carry out an 18-month Phase II, double-blind, randomized, twoarmed, placebo controlled, proof-of-concept clinical study in early AD subjects (i.e. mild AD) who will be receiving an escalating dose of Siponimod or placebo in the ratio 2:1 for 12 months, followed by a 6-month washout period. The primary outcome measures are safety and tolerability of Siponimod in mild AD subjects. The secondary outcome measures are the rates of brain atrophy derived from volumetric MRI (vMRI) as a proxy for neurodegeneration conducted at baseline, 6, 12, and 18 months. The tertiary outcome measures are the changes in cognition and the levels of AD-associated (e.g., Aβ and tau) and inflammatory biomarkers in CSF after Siponimod exposure. In an exploratory effort, we will also measure plasma inflammatory markers during the entire duration of the study to investigate whether one or more of these markers can be used as dynamic surrogate markers of treatment response. Using our unique experience with the repurposing of immunomodulatory drugs for AD (and NCT #04032626), in the present project we are using elements of clinical trial design that we believe were successful and made some adjustments to fit the pharmacologic and toxic properties of Siponimod.

Conditions

Mild Alzheimer Disease; MCI With Increased Risk for Alzheimer Disease; Cognitive Impairment, Mild; Alzheimer Disease

Keywords

Alzheimer's disease; Siponimod; Cognitive Impairment; Cognition; Brain Imaging; Biomarkers; Immunomodulation

Outcome Measures

Primary Outcomes (1)

• Monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs)

  To evaluate the safety and tolerability of Siponimod titrated for up to 12 months and washed out for 6 months in mild AD subjects. (Subjects will receive gradual titration regimen of Siponimod starting at 0.25mg/day and increasing every two weeks by 0.25 mg, up to final dosage of 1 mg/day.) Safety will be assessed at each study visit through completion of comprehensive tests and procedures aimed at monitoring for potentials adverse events (AEs). Study staff will also gather direct reports from subjects regarding any adverse events.

  18 months

Secondary Outcomes (1)

• Rates of brain atrophy

  12 months

Other Outcomes (8)

• Changes in cognition assessed by Mini Mental State Examination (MMSE)

  18 months

• Changes in cognition as assessed by Alzheimer's Disease Composite Score (ADCOMS)

  18 months

• Changes in cognition assessed by Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog)

  18 months

Study Arms (2)

Drug Arm

EXPERIMENTAL

Randomly assigned subjects who will receive an escalating dose of Siponimod (0.25-1 mg/day) for 12 months.

Drug: Siponimod

Placebo Arm

PLACEBO COMPARATOR

Randomly assigned subjects who will receive a placebo daily for 12 months.

Drug: Placebo

Interventions

Placebo DRUG

A placebo that resembles siponimod will be given once daily to participants randomly assigned into the placebo arm.

Placebo Arm

Siponimod DRUG

Siponimod (formerly known as BAF312 and completed trial NCT #01665144) has been FDA approved since 2019 (IND #076122) for the treatment of multiple sclerosis. Siponimod is an immunomodulator that prevents the egression of T lymphocytes from peripheral lymphoid organs.

Also known as: Mayzent

Drug Arm

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female at least 50 years of age, but less than 85 (84 at time of screening)
• Females must be of non-childbearing potential or have negative pregnancy test at time of screening. Women of non-childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for \>12 months prior to the planned date of enrollment.
• Must have a diagnosis of mild Alzheimer's Dementia determined by medical record review.
• Vision and hearing must be sufficient to comply with study procedures.
• Be able to take oral medications.
• Must be able to attend all study visits indicated in the schedule of visits.
• Must have a collateral informant/study partner who has significant direct contact with the patient at least 10 hours per week and who is willing to accompany the patient to specified clinic visits, supervise administration of all study medication, and be available for telephone visits/interviews.
• Documented Mini Mental State Exam (MMSE) score between 20-26 at Screening Visit Day 1.
• CT or MRI scan of the brain within 12 months of Screening Visit Day 1 showing no evidence of significant focal lesions or other pathology which could contribute to dementia. If neither a CT or a MRI scan is available from the past 12 months, a scan fulfilling the requirements must be obtained before randomization.
• Hachinski ischemic score must be \< 4.
• Geriatric depression scale must be \< 10.
• Prior to dosing all randomized study subjects must show proof they have received immunization to varicella (VZV IgG).
• No active suicidality identified on Columbia-Suicide Severity Rating Scale (C-SSRS).
• Patients with stable prostate cancer may be included at the discretion of the Medical Monitor.
• Patients who are on monoclonal antibody medication for the treatment of Alzheimer's (ex. lecanemab, donanemab) for \> 6 months or have discontinued monoclonal antibody medication for the treatment of Alzheimer's for \> 6 months may be included if all other criteria has been met.

You may not qualify if:

• Taking one of the following medications: Medications for treatment of cancer or other drugs that weaken the immune system (ex. Natalizumab and Rituximab), Amiodarone, Bishydroxycoumarin, Chloramphenicol, Cimetidine, Fluconazole, Fluvastatin, Miconazole, Phenylbutazone, Sulphinpyrazone, Sulphadiazine, Sulphamethizole, Sulfamethoxazole, Sulphaphenazole, Trimethoprim, and Zafirlukast.
• Current active infection in participants including, but not limited to, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection and fungal skin infection. Siponimod may increase the risk in participants with active infections.
• If participant received mRNA COVID-19 vaccination, must have received last dose at least 3 months prior to first dose of study drug/placebo.
• Current evidence or history within the last 3 years of a neurological or psychiatric illness that could contribute to dementia, including (but not limited to) epilepsy, focal brain lesion, Parkinson's disease, seizure disorder, or head injury with loss of consciousness.
• Meets DSM IV criteria for any major psychiatric disorder including psychosis, major depression and bipolar disorder.
• Known history of or self-reported active alcohol and/ or substance abuse within the past three years.
• Isolated living circumstances which would prohibit a study partner from providing sufficient and credible information about the participant.
• Poorly controlled hypertension
• Known Atrioventricular heart block, known heart block type I-III.
• History of myocardial infarction or signs or symptoms of unstable coronary artery disease within the last year (including revascularization procedure/angioplasty).
• Severe pulmonary disease (including chronic obstructive pulmonary disease) requiring more than 2 hospitalizations within the past year.
• Untreated obstructive sleep apnea.
• Any thyroid disease (unless euthyroid on treatment for at least 6 months prior to screening).
• Active neoplastic disease (except for skin tumors other than melanoma) within five years.
• Absolute lymphocytopenia of \<1,000/mm3, or a history of lymphocytopenia within the past two years.

Sponsors & Collaborators

• St. Joseph's Hospital and Medical Center, Phoenix: lead
• Texas Tech University Health Sciences Center: collaborator
• Arizona State University: collaborator
• National Institute on Aging (NIA): collaborator
• Novartis: collaborator
• Laboratory Corporation of America: collaborator

Study Sites (1)

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

RECRUITING

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Related Links

• Additional citation
• Additional citation

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

siponimod

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Study Officials

• Marwan N Sabbagh, MD

  St. Josep's Hospital and Medical Center, Phoenix

  PRINCIPAL INVESTIGATOR

• Boris Decourt, PhD

  Texas Tech University Health Sciences Center

  STUDY CHAIR

Central Study Contacts

Marwan N Sabbagh, MD

CONTACT

602-406-7735; Marwan.Sabbagh@CommonSpirit.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The clinical research coordinator, the psychometrist, the co-investigators (Dr. Boris Decourt and Dr. Karl Golnik) will be masked. Everyone who is patient-facing will be masked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study will have 105 participants with a 2:1 ratio of drug:placebo.

Study Record Dates

• First Submitted: October 9, 2024
• First Posted: October 15, 2024
• Study Start: August 26, 2025
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: March 4, 2026

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: From 03/08/2023 to 07/31/2027
• Access Criteria: Dr. Jeffrey Wilson at Arizona State University will be given study data directly from Barrow Neurological Institute (BNI) staff to perform biostatistical analysis. Dr. Boris Decourt at Texas Tech will be given blood and saliva samples from BNI to process, store, and analyze. Dr. Mirla Avila at Texas Tech, Dr. Martin Farlow at University of Indiana, and Dr. Craig Mallinckrodt at Pentara Corporation will receive case report forms from BNI staff such as the project manager and SAE information from Dr. Sabbagh. There are current data use and material transfer agreements in place with the respective institutions. Dr. Sabbagh and Dr. Decourt also plan to present study findings in the form of peer-reviewed manuscripts and presentations at scientific meetings.

Locations

US (1)