A Phase 2a, dose-finding, randomized, double-blinded, placebo-controlled study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Efavirenz in Patients with Early Alzheimer’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amsterdam UMC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Oct 2024 → ongoing

Decision date (initial)

2024-06-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic

The primary PD endpoint is the change from baseline in levels in 24-hydroxycholesterol in CSF at Day 84 compared with baseline.

Secondary objectives 2

1. The secondary objective of this study is to evaluate the pharmacodynamics (PD) of efavirenz in plasma in patients with early Alzheimer’s Disease (AD). Any changes from levels in 24-hydroxycholesterol at 3h, 6h, 24h, 7d, 28d, 56d, and 84d
2. AD Biomarkers CSF: pTau181, Ab42, Ab40, Ab42/40, NFL, NRGN, GFAP, YKL-40, inflammatory cytokines; AD biomarkers plasma: pTau181, Ab42, Ab40, Ab42/40, NFL

Conditions and MedDRA coding

Alzheimer's Disease

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age range: 50-75 years of age at the Screening Visit.
2. Males, or females who are post-menopausal or otherwise not of child-bearing potential.
3. Diagnosis of AD based on the NIA-AA Research Framework criteria: Biomarker classification A+T+N+ or A+T+N- based upon: a. CSF profile consistent with AD (an Aβ42 concentration of <1000 pg/mL AND phosphorylated tau (p-Tau) >19 pg/mL, or a ratio of p-Tau/Aβ42 of ≥0.020) taken during the Screening period prior to the day of the first dose of study medication or, b. Documented evidence of a CSF profile consistent with AD obtained within the previous 12 months, or c. Documented amyloid positron emission tomography (PET) scan evidence acquired within the previous 12 months.
4. AD Clinical Stage 3 or 4 based on the NIA-AA Research Framework criteria a. Have a mini-mental state examination (MMSE) score at Screening and baseline ≥20. b. CDR global score 0.5 up to 1.0
5. Able to speak, read and write the local language fluently.
6. Patients should either be: a. Not treated with any approved treatments for AD with a reasonable expectation that, based on the course of illness, need for treatment is not imminent and the patient should not be initiated on treatment for the length of the study, or b. Stabilized on an approved medication(s) for the treatment of AD for at least 3 months prior to baseline. The dose of the AD treatment should remain the same after entering the study.
7. Patient and care partner are willing to consent to all study procedures.

Exclusion criteria 12

1. Other than AD, neurologic or medical disorder which may impair cognition including: head trauma, seizure disorder, neurodegenerative disease, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, central nervous system infection (eg, encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes), or endocrine disorder, or any significant medical conditions that, in the opinion of the Investigator, would prohibit their participation in the study.
2. Any contra-indication to undergo magnetic resonance imaging (MRI), as judged by Investigator or radiologist.
3. MRI of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, deep white matter lesions corresponding to a Fazekas score of 3, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (eg, abscess or brain tumor such as meningioma). Small incidental meningiomas may be allowed if discussed and approved by the PI.
4. History of any of the following neurological, psychiatric or medical conditions: a. History of large vessel stroke b. History of myocardial infarction or unstable angina within the previous 12 months c. Type 1 diabetes or uncontrolled type 2 diabetes (hemoglobin A1c [HbA1c] >8%) d. Systemic blood pressure >150/90 mmHg on 3 separate determinations e. History of hyperaldosteronism f. Significant renal or hepatic dysfunction g. Current or previous hepatitis B infection (defined as positive test for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBc)+. Subjects with immunity to hepatitis B (if due to natural infection defined as negative HBsAg, positive hepatitis B antibody [anti-HBs] and positive anti-HBc; if due to vaccination defined as negative HBsAg, negative anti-HCV and positive anti-HBs) are eligible to participate in the study h. History or positive test at Screening for hepatitis C virus antibody (anti-HCV) i. History or positive test at Screening for human immunodeficiency virus (HIV) j. Diagnosed with cancer with metastatic potential within the last 5 years other than carcinoma in situ of the breast or cervix, or basal cell carcinoma of the skin that has been completely excised k. Major depressive episode requiring initiation of medication or hospitalization within the previous 90 days l. Presence of hallucinations or delusions m. Surgery within 12 weeks of Screening
5. Any of the following laboratory abnormalities at Screening a. Clinically significant (as determined by a cardiologist or local PI) 12-lead ECG abnormalities b. Any serum chemistry value (eg, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, creatine kinase [CK], total bilirubin etc) >2x the upper limit of normal (ULN) on 2 successive determinations less than 2 weeks apart c. Serum creatinine above the ULN or estimated glomerular filtration rate (eGFR) <60 mL/min d. Platelet count, international normalized ratio (INR), prothrombin time (PT) or partial thromboplastin time (PTT) not within the normal range or other risk for increased or uncontrolled bleeding
6. Presence of contraindication to lumbar puncture as judged by local PI.
7. Any other significant medical conditions that, in the opinion of the Investigator, would prohibit participation in the study, including inability to tolerate the MRI scan or lumbar puncture procedures.
8. Taking any of the following medications a. Antipsychotic agents, including pimavanserin b. Stimulant medications c. Antidepressant medications whose dose has not been stable for at least 90 days d. Immunosuppressant medications, including chronic corticosteroids e. Injected or infused antibody therapies, including but not limited antibodies directed against tumor necrosis factor (TNF), anti-interleukin(IL)-6, natalizumab, rituximab and similar agents f. Anticoagulant or anti-platelet medications including warfarin, heparanoids and direct coagulation factor inhibitors (eg, apixaban, dagibatran, rivaroxaban); either aspirin at a dose of ≤100 mg/day or clopidogrel at a dose of 75 mg/day, but not both in combination is permitted. g. Any lipid-altering therapies h. CYP3A4 inhibitors i. terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine)
9. Participation in any other interventional clinical trial, or treatment with any investigational drug or investigational use of an approved therapy within 30 days (or 5 half-lives of such agent) prior to the first Screening visit.
10. Regular use of cannabis or cannabis products, including non-prescription products containing cannabidiol.
11. History of drug (including cannabis) or alcohol abuse within the last 5 years.
12. Has an active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection a. Note: A subject being screened for this study who had a documented, positive polymerase chain reaction (PCR) or serology test for SARS-CoV-2 may be enrolled provided the subject has: i. Recovered from COVID-19 ie, all COVID-19 related symptoms and major clinical findings which could potentially affect the safety of the subject should be resolved to baseline, and ii. A negative result from a health authority-authorized nucleic acid amplification (PCR) test for SARS-CoV-2 taken.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change From Baseline Levels in 24-Hydroxycholesterol in CSF

Secondary endpoints 5

1. Changes from levels in 24-hydroxycholesterol at 3h, 6h, 24h, 7d, 28d, 56d, and 84d
2. Change From Baseline Levels in AD Biomarkers in CSF: pTau, tTau, Ab42, Ab40, Ab42/40, NFL, NRGN, GFAP, YKL-40, inflammatory cytokines
3. Change From Baseline Levels in AD Biomarkers in Plasma: pTau, tTau, Ab40, Ab42, Ab42/40m NFL
4. Exploratory cognition endpoints: MSSE
5. PK in plasma and CSF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amsterdam UMC

Sponsor organisation

Amsterdam UMC

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Amsterdam UMC

Contact name

Marlies Oosthoek

Public contact point

Organisation

Amsterdam UMC

Contact name

Marlies Oosthoek

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications