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.
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.
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.
Parallel
Siponimod
DrugSiponimod (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.
Placebo
DrugA placebo that resembles siponimod will be given once daily to participants randomly assigned into the placebo arm.
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.
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.
Changes in cognition assessed by Mini Mental State Examination (MMSE)
To evaluate how siponimod 1 mg/day titrated for up to 12 months and washed out for 6 months affects changes in cognition assessed by the Mini Mental State Examination (MMSE). (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.) MMSE Scores range from 0 to 30, with 30 being the score assigned to cognitively normal individuals. The range for mild AD is 21-26. A higher score is better.
Changes in cognition as assessed by Alzheimer's Disease Composite Score (ADCOMS)
To evaluate the effect on cognition Alzheimer's Disease Composite Score (ADCOMS) of siponimod 1mg/day titrated for up to 12 months and washed out for 6 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.) The lowest ADCOMS score is 0, while the highest is 1.97. A lower score is better.
Changes in cognition assessed by Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog)
To evaluate how siponimod 1 mg/day titrated for up to 12 months and washed out for 6 months affects changes in cognition assessed by the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) assessment. (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.) A higher ADAS-cog score indicates more impairment; the range is 0 to 89.
Changes in cognition assessed by Clinical Dementia Rating - Sum of Boxes (CDR-SOB)
To evaluate how siponimod 1 mg/day titrated for up to 12 months and washed out for 6 months affects changes in cognition assessed by the Clinical Dementia Rating - Sum of Boxes (CDR-SOB) test. (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.) The CDR-SOB ratings of degree of impairment obtained on each of the 6 categories of function are synthesized into one global rating of dementia (ranging from 0 to 3). A score of 0 indicates no dementia, while higher scores indicate increasingly higher levels of dementia.
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St. Joseph's Hospital and Medical Center, Phoenix
Lead sponsor
Texas Tech University Health Sciences Center
Collaborator
Arizona State University
Collaborator
National Institute on Aging (NIA)
Collaborator
Novartis
Collaborator
Laboratory Corporation of America
Collaborator
