Clinical trial NCT06022068: Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography
Official title: Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE1
PHASE2
Conditions: Alzheimer Disease
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
First posted: 2023-09-01
Enrollment: 15
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This single-center, uncontrolled pilot study aims to evaluate the efficacy, safety, and tolerability of six months of intermittently dosed oral rapamycin (sirolimus) in subjects with early-stage Alzheimer's disease.

Fifteen participants will be recruited. Following a set of baseline measurements, all participants will receive a weekly oral dose of 7 mg rapamycin for six months. Participants will be continuously monitored for safety and side effects. At the termination of the treatment, follow-up measurements will be taken.

The primary endpoint will be change in cerebral glucose metabolism, measured using 18F labeled fluorodeoxyglucose (\[18F\]FDG) positron emission tomography (PET).

In addition to the registered outcome measures this pilot trial will explore the feasibility of acquiring data on the effect of sirolimus treatment on age-related tissue changes in the body using a variety of imaging modalities, such as bone mineral density assessed using quantitative computed tomography, retinal structures assessed using optical coherence tomography, periodontal tissue assessed using MRI and FDG-PET, cardiac function assessed using MRI, vessel wall in large arteries using MRI and \[18F\]FDG PET.


Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis of mild cognitive impairment (MCI), or dementia of Alzheimer's type
2. Amyloid positivity established with either amyloid positron emission tomography or cerebrospinal fluid analysis.
3. For subjects with dementia, the disease should be in an early stage, operationalized as:

   * Stage 4 (Mild dementia) or lower, according to the National Institute on Aging - Alzheimer's Association 2018 clinical staging criteria, AND
   * Clinical Dementia Rating Scale (CDR) global score of 1 or lower, AND
   * Montreal Cognitive Assessment (MoCA) score of ≥ 18 OR Rey Auditory Verbal Learning Test (RAVLT) \>4 words after 30 minutes
4. Capable of giving, and has the capacity to give informed consent
5. Availability of a responsible study partner who can accompany the subject to all planned visits
6. Male or female between 50 and 80 years
7. Normal or clinically acceptable medical history, physical examination, and vital signs

Exclusion Criteria:

1. History of any major disease that may interfere with safe engagement in the intervention (especially severe liver or kidney disease, or uncontrolled diabetes).
2. Central nervous system infarct, infection, or focal lesions of clinical significance on MRI scans.
3. Fulfills any contraindication for the use of sirolimus as per the summary of product characteristics, including but not restricted to:

   * Current or planned medication with a strong inhibitor of CYP3A4 or P-gp
   * Current or planned medication with a strong inducer of CYP3A4 or P-gp
   * Other current medications with known serious interaction risks with sirolimus
   * Known allergy or hypersensitivity to sirolimus
4. Significant obesity
5. Untreated and clinically significant hyperlipidemia
6. Treatment with immunosuppressive medications within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted), or chemotherapeutic agents for malignancy within the last 3 years
7. Major surgery within 3 months prior to the planned start of sirolimus treatment, OR has major surgery planned during the period of the trial.
8. Use of experimental medications for Alzheimer's or any other investigational medication or device within 60 days. Participants who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial

Primary outcomes:
measure: Change in cerebral glucose metabolism
timeFrame: From baseline to six months
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: From baseline to six months
measure: Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42
timeFrame: From baseline to six months
measure: Change in CSF concentration of phosphorylated tau
timeFrame: From baseline to six months
measure: Change in CSF concentration of total tau
timeFrame: From baseline to six months
measure: Change in cerebral blood flow
timeFrame: From baseline to six months
measure: Area under the concentration versus time curve (AUC) of sirolimus
timeFrame: Tested at one occasion between baseline to six months
measure: Peak Plasma Concentration (Cmax) of sirolimus
timeFrame: Tested at one occasion between baseline to six months
measure: Trough Plasma Concentration (Cmin) of sirolimus
timeFrame: Tested at one occasion between baseline to six months
measure: Change in Montreal Cognitive Assessment (MoCA) rating
timeFrame: From baseline to six months
Other outcomes:
measure: Change in composite z-score of neuropsychological tests
timeFrame: From baseline to six months
measure: Change in concentration of neurofilament light in CSF
timeFrame: From baseline to six months
measure: Change in quotient of albumin concentration in serum and CSF
timeFrame: From baseline to six months
measure: Change in hand-grip strength
timeFrame: From baseline to six months
measure: Change in chair stand test
timeFrame: From baseline to six months
measure: Change in walking speed
timeFrame: From baseline to six months
measure: Change in ratio of CSF concentration of amyloid beta 42 and 40
timeFrame: From baseline to six months
Locations:
city: Solna
country: Sweden
facility: Karolinska University Hospital Memory clinic
state: Stockholm
Study officials:
affiliation: Karolinska Institutet
name: Pontus Plavén Sigray, PhD
role: STUDY_DIRECTOR
affiliation: Karolinska Institutet
name: Jonas Svensson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: