Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)

• ClinicalTrials.gov Identifier: NCT06022068
• Recruitment Status: Enrolling by invitation
• First Posted: September 1, 2023
• Last Update Posted: March 26, 2024
• Sponsor: Karolinska Institutet
• Collaborator: Karolinska University Hospital
• Information provided by (Responsible Party): Jonas Svensson, Karolinska Institutet

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: Sirolimus	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)
• Actual Study Start Date: September 1, 2023
• Estimated Primary Completion Date: January 31, 2025
• Estimated Study Completion Date: January 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rapamycin; Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks	Drug: Sirolimus; 7 mg taken once per week during 26 weeks.; Other Name: Rapamycin

Outcome Measures

Primary Outcome Measures :

1. Change in cerebral glucose metabolism [ Time Frame: From baseline to six months ]
   Cerebral glucose uptake measured through [18F]FDG positron emission tomography

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: From baseline to six months ]
   Safety and tolerability of intermittent sirolimus treatment
2. Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42 [ Time Frame: From baseline to six months ]
   CSF biomarker for Alzheimers disease
3. Change in CSF concentration of phosphorylated tau [ Time Frame: From baseline to six months ]
   CSF biomarker for Alzheimers disease
4. Change in CSF concentration of total tau [ Time Frame: From baseline to six months ]
   CSF biomarker for Alzheimers disease
5. Change in cerebral blood flow [ Time Frame: From baseline to six months ]
   Cerebral blood flow measured with MRI using arterial spin labeling
6. Area under the concentration versus time curve (AUC) of sirolimus [ Time Frame: Tested at one occasion between baseline to six months ]
   Whole blood measurements of sirolimus concentration.
7. Peak Plasma Concentration (Cmax) of sirolimus [ Time Frame: Tested at one occasion between baseline to six months ]
   Whole blood measurements of sirolimus concentration.
8. Trough Plasma Concentration (Cmin) of sirolimus [ Time Frame: Tested at one occasion between baseline to six months ]
   Whole blood measurements of sirolimus concentration.
9. Change in Montreal Cognitive Assessment (MoCA) rating [ Time Frame: From baseline to six months ]
   Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance)

Other Outcome Measures:

1. Change in composite z-score of neuropsychological tests [ Time Frame: From baseline to six months ]
   Cognition assessed with a composite score of the following tests: Rey Auditory Verbal Learning Test; Rey-Osterrieth Complex Figure; Hagman test; Trail Making Test A + B; Wechsler Adult Intelligence Scale (subtest to assess processing speed/attention). A composite score will be calculated using z-score approach..
2. Change in concentration of neurofilament light in CSF [ Time Frame: From baseline to six months ]
   Neuronal damage assessed using concentraion of neurofilament light in CSF.
3. Change in quotient of albumin concentration in serum and CSF [ Time Frame: From baseline to six months ]
   Blood-brain barrier integrity assessed using quotient of concentration albumin in serum and CSF
4. Change in hand-grip strength [ Time Frame: From baseline to six months ]
   Measured using a hand-grip dynamometer
5. Change in chair stand test [ Time Frame: From baseline to six months ]
   Number of completed chair stands in 30 seconds
6. Change in walking speed [ Time Frame: From baseline to six months ]
   Timed 10-metre dual task walking test
7. Change in ratio of CSF concentration of amyloid beta 42 and 40 [ Time Frame: From baseline to six months ]
   CSF biomarker for Alzheimers disease

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Sweden

Karolinska University Hospital Memory clinic

Solna, Stockholm, Sweden, 171 64

Sponsors and Collaborators

Karolinska Institutet

Karolinska University Hospital

Investigators

• Study Director: Pontus Plavén Sigray, PhD; Karolinska Institutet
• Principal Investigator: Jonas Svensson, MD, PhD; Karolinska Institutet

More Information

• Responsible Party: Jonas Svensson, MD, Karolinska Institutet
• ClinicalTrials.gov Identifier: NCT06022068
• Other Study ID Numbers: 2023-00611-01
• First Posted: September 1, 2023
• Last Update Posted: March 26, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: We aim to share pseudonymized individual participant data that underlie results in a publication in accordance with institutional regulations.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs