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Alzheimer DiseasePhase 2SIPO1-ADNCT06639282

Repurposing Siponimod for Alzheimer's Disease

A Phase 2 study testing Siponimod in people with Alzheimer Disease and Mild Alzheimer Disease, run by St. Joseph's Hospital and Medical Center, Phoenix at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 50 to 85 years
What is being tested?
Siponimod
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
105 participants
Where
1 siteUnited States
Study dates
26 Aug 2025to Oct 2029
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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).
  • Each patient must be assessed for capacity to consent by the principal or sub-investigators in order to provide informed consent. If the patient is deemed unable to provide informed consent, they must have a legally authorized representative (LAR), and the LAR must review and sign the informed consent form. If the patient does not have a LAR, the patient must appear able to provide informed consent and must review and sign the informed consent form. If the patient is deemed unable to provide informed consent and does not have a LAR, they cannot participate in the study. In addition, the patient's study partner/informant (as defined in the study inclusion criteria) must sign the informed consent form. If the LAR and the patient's study partner/informant are the same individual, he/she should sign under both.
  • 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.

Who cannot join

  • 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.
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  • 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.
  • Absolute neutropenia of <1,000/mm3, or a history of neutropenia within the past two years.
  • History of/ or current thromboembolism (including deep venous thrombosis).
  • Any clinically significant hepatic or renal disease (including presence of Hepatitis B or C surface antigen or an elevated transaminase levels of greater than 2x the upper limit of normal (ULN) or creatinine greater than 1.5 x upper limit of normal (ULN)).
  • Clinically significant hematologic or coagulation disorder including any unexplained anemia, or a platelet count less than 100,000/µL at screening.
  • Use of any investigational drug within 30 days or within five half-lives of the investigational agent, whichever is longer.
  • Unwilling or unable to undergo CT or MRI imaging.
  • In the opinion of the investigator, participation would not be in the best interest of the subject.
  • Subjects with CYP2C9*3/*3 genotyping

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Marwan N Sabbagh, MD contact

602-406-7735

Marwan.Sabbagh@CommonSpirit.org

United States1 site, 1 recruiting

  • St. Joseph's Hospital and Medical Center

    Phoenix, Arizona, 85013

    Connie Hillis, 602-406-5128, connie.hillis@commonspirit.org

    Marwan Sabbagh, MD

    Recruiting

Other trials in United States

About this study

Official title: SIPO1-AD: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Siponimod in Patients With Mild Alzheimer's Disease

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.

Read the detailed description

Alzheimer's disease (AD) is a neurodegenerative disorder with several complex neuropathologies suspected to develop sequentially but that overlap over time as symptoms progress to dementia. Thus, to be effective, future intervention strategies will likely require combination therapies or pleiotropic agents to tackle several AD molecular pathogenic pathways simultaneously. For more than a decade, our group has been exploring the repurposing of immunomodulators for AD. Recent discussions with collaborators who specialize in multiple sclerosis suggest that sphingosine-1-phosphate receptor (S1PR) modulators are strong candidates for repurposing in AD. Indeed, S1PR modulators are blood brain barrier (BBB) penetrant and display pleiotropic actions, including immunomodulation and neuroprotective properties. S1P is a versatile endogenous molecule that regulates several signaling pathways by binding to five G-protein-coupled receptors, which are expressed in high levels in cardiac, vascular, immune, and brain cells. This widespread localization of S1PR was the historical basis for Novartis Pharmaceuticals, Inc, to develop oral formulations of S1PR modulators for multiple sclerosis (MS), which proved successful and resulted in two marketed oral compounds (i.e., fingolimod and Siponimod). In the present project, we intend to collaborate with Novartis to use the most recently FDA-approved S1PR modulator, Siponimod. Based on MS and animal experimentation literature, we hypothesize that Siponimod could alter the rate of neurodegeneration as measured by lowering the rate of brain atrophy in mild AD dementia subjects. In this Phase II, proof-of-concept, translational clinical study, mild AD dementia subjects will be randomized 2:1 and will receive gradual titration regimen of Siponimod starting at 0.25mg/day and increasing up to final dosage of 1 mg/day (N=70) or placebo (N=35) for 12 months. This will be followed by a 6-month washout period. Siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS patients, and because its toxicity profile is favorable for use in older individuals, Siponimod has a strong potential to alter markers of mild AD dementia pathology and disease trajectory.

Being tested
Siponimod, Placebo
Keywords
Alzheimer's disease, Siponimod, Cognitive Impairment, Cognition, Brain Imaging, Biomarkers, Immunomodulation
Medical subject headings
Alzheimer Disease, Cognitive Dysfunction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SiponimodDrug

    Also called Mayzent

    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.

  • PlaceboDrug

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

Study groups in NCT06639282
Study groupRoleWhat they receive
Drug ArmExperimentalRandomly assigned subjects who will receive an escalating dose of Siponimod (0.25-1 mg/day) for 12 months.
Receives: Drug: Siponimod
Placebo ArmPlacebo comparatorRandomly assigned subjects who will receive a placebo daily for 12 months.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 18 months

Secondary outcomes (1)

  1. Rates of brain atrophy

    The secondary outcome measures are the rates of brain atrophy derived from volumetric MRI (vMRI) as a proxy for neurodegeneration conducted at baseline. The aim is to assess the medical benefits of the drug in mild AD dementia subjects by assessing whether brain atrophy slows with Siponimod treatment 1 mg/day titrated for up to 12 months. (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.)

    Subjects will undergo volumetric MRI (vMRI) measurements of the hippocampus, cortical thickness, and global thickness as indicators of neurodegeneration.

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Oct 2024
  2. Study start26 Aug 2025
  3. Primary completionOct 2029 (estimated)
  4. Study completionOct 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
The study will have 105 participants with a 2:1 ratio of drug:placebo.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
105 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06639282
Sponsor's protocol ID
23-500-037-10-03
Other IDs
7R01AG073212-02
Acronym
SIPO1-AD
Status last verified
May 2025
First submitted
9 Oct 2024
Last updated
4 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Information from the study such as SAEs, the study protocol, case report forms, study results, Statistical Analysis Plan, Informed Consent Form, and findings that might alter the current benefit-risk profile of the Study Drug or that would be sufficient to consider changes in the Study Drug's administration or in the overall conduct of the Study, and the Clinical Study Report, will be shared with the drug manufacturer Novartis, and the subaward institutions, Arizona State University and Texas Tech, and the members of the Data Safety and Monitoring Board, who are associated with University of Indiana, Pentara Corporation, and Texas Tech, and the internal medical monitor and clinical monitoring team who are part of Barrow Neurological Institute (BNI).

Publications

  • Kahle-Wrobleski K, Coley N, Lepage B, Cantet C, Vellas B, Andrieu S; Plasa DSA Group. Understanding the complexities of functional ability in Alzheimer's disease: more than just basic and instrumental factors. Curr Alzheimer Res. 2014 May;11(4):357-66. doi: 10.2174/1567205011666140317101419.

    PubMed 24635843

  • Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001 Mar;58(3):397-405. doi: 10.1001/archneur.58.3.397.

    PubMed 11255443

  • Tahami Monfared AA, Houghton K, Zhang Q, Mauskopf J; Alzheimer's Disease Neuroimaging Initiative. Staging Disease Severity Using the Alzheimer's Disease Composite Score (ADCOMS): A Retrospective Data Analysis. Neurol Ther. 2022 Mar;11(1):413-434. doi: 10.1007/s40120-022-00326-y. Epub 2022 Jan 31.

    PubMed 35099758

  • Decourt B, Wilson J, Ritter A, Dardis C, DiFilippo FP, Zhuang X, Cordes D, Lee G, Fulkerson ND, St Rose T, Hartley K, Sabbagh MN. MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer's Disease. Open Access J Clin Trials. 2020;12:1-13. doi: 10.2147/oajct.s221914. Epub 2020 Jan 7.

    PubMed 32123490

  • Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. doi: 10.1136/jnnp-2015-312383. Epub 2016 Mar 23.

    PubMed 27010616

  • Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther. 2014 Dec 24;6(9):89. doi: 10.1186/s13195-014-0089-7. eCollection 2014.

    PubMed 25621019

  • Tur C, Kalincik T, Oh J, Sormani MP, Tintore M, Butzkueven H, Montalban X. Head-to-head drug comparisons in multiple sclerosis: Urgent action needed. Neurology. 2019 Oct 29;93(18):793-809. doi: 10.1212/WNL.0000000000008319. Epub 2019 Oct 7.

    PubMed 31591277

  • Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L. gamma-Secretase inhibitors and modulators. Biochim Biophys Acta. 2013 Dec;1828(12):2898-907. doi: 10.1016/j.bbamem.2013.06.005. Epub 2013 Jun 17.

    PubMed 23791707

  • Frost GR, Jonas LA, Li YM. Friend, Foe or Both? Immune Activity in Alzheimer's Disease. Front Aging Neurosci. 2019 Dec 10;11:337. doi: 10.3389/fnagi.2019.00337. eCollection 2019.

    PubMed 31920620

  • Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou SH. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines. 2019 Dec 9;7(4):97. doi: 10.3390/biomedicines7040097.

    PubMed 31835422

  • Xie HG, Prasad HC, Kim RB, Stein CM. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev. 2002 Nov 18;54(10):1257-70. doi: 10.1016/s0169-409x(02)00076-5.

    PubMed 12406644

  • Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006346. doi: 10.1101/cshperspect.a006346.

    PubMed 22315714

  • Shakeri-Nejad K, Aslanis V, Veldandi UK, Mooney L, Pezous N, Brendani B, Juan A, Allison M, Perry R, Legangneux E. Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects. Clin Ther. 2015 Nov 1;37(11):2489-2505.e2. doi: 10.1016/j.clinthera.2015.09.006. Epub 2015 Oct 27.

    PubMed 26519230

  • Sabbagh MN, Shi J, Lee M, Arnold L, Al-Hasan Y, Heim J, McGeer P. Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer's disease dementia from normal controls: preliminary findings. BMC Neurol. 2018 Sep 26;18(1):155. doi: 10.1186/s12883-018-1160-y.

    PubMed 30257642

  • Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. doi: 10.1176/ajp.141.11.1356.

    PubMed 6496779

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Siponimod in people with Alzheimer Disease and Mild Alzheimer Disease, run by St. Joseph's Hospital and Medical Center, Phoenix at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Marwan N Sabbagh, MD (602-406-7735, Marwan.Sabbagh@CommonSpirit.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs) (time frame: 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06639282, which also lists 46 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2026.

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