Evaluation of Lamivudine on Neurocognitive Biomarkers and Type-I IFN Genes in Mild Cognitive Impairment Due to Alzheimer's Disease
- Trial ID
- 2024-514330-20-00
- Protocol
- LAMIFERON
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the efficacy of **lamivudine** in reducing the levels of neurocognitive impairment biomarkers and type-I IFN-stimulated genes in the plasma of patients with Mild Cognitive Impairment (MCI) associated with Alzheimer's Disease over a 24-week treatment period. This is clinically relevant as it may provide insights into potential therapeutic strategies for managing cognitive decline in Alzheimer's Disease, potentially improving patient outcomes.
Secondary objectives include assessing the ability of lamivudine to lower the levels of type-I IFN-stimulated genes in the plasma and cryopreserved peripheral blood mononuclear cells (PBMCs) of patients with MCI and positive Alzheimer's Disease biomarkers over the same treatment period. Additionally, the study aims to evaluate the incidence, nature, and severity of Treatment Emergent Adverse Events (TEAE), which is crucial for understanding the safety profile of lamivudine in this patient population.
Participants
The clinical trial involves participants diagnosed with **Mild Cognitive Impairment** due to Alzheimer's Disease. The study population includes both male and female subjects aged between 55 to 90 years. Participants are required to have a Clinical Dementia Rating-Global Score of 0.5 and must have documented confirmation of Alzheimer's Disease diagnosis through positive cerebrospinal fluid (CSF) AD signature or positive amyloid-PET imaging. The trial does not involve a vulnerable population. Participants must be able to visit the study center and undergo various cognitive and functional tests. If participants are on approved medications for Alzheimer's Disease, such as donepezil or memantine, they must be on a stable dose for at least four weeks prior to the screening. Similarly, any over-the-counter supplements for cognition must also be at a stable dose. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **lamivudine** on neurocognitive impairment biomarkers and type-I interferon-stimulated genes in patients with mild cognitive impairment due to Alzheimer's disease. This is a single-center, self-controlled, single-arm pilot study. The trial will span a total duration of 24 weeks, with the recruitment period commencing on October 28, 2024, and concluding on February 21, 2025. Participants will be administered **lamivudine** orally in the form of film-coated tablets, with a maximum daily dose of 300 mg.
The study will involve several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and medication stability. Participants must be between 55 and 90 years of age and have a diagnosis of prodromal Alzheimer's disease with a Clinical Dementia Rating-Global Score of 0.5. Imaging studies and documented confirmation of Alzheimer's disease diagnosis are required. The screening visit will also ensure that participants are on stable doses of any approved Alzheimer's medications or cognitive supplements.
Following the screening, participants will undergo a baseline visit where initial measurements of neurocognitive biomarkers and type-I interferon-stimulated genes will be taken. Subsequent follow-up visits will occur at regular intervals to monitor the percentage change in biomarkers and assess the safety and tolerability of the treatment. The primary endpoint is the percentage change in specific biomarkers from the baseline to the week 24 visit. Secondary endpoints include the fold change of type-I interferon-stimulated genes.
The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. Participants are expected to remain in the study for the full 24-week duration unless conditions arise that necessitate early termination, such as the occurrence of serious adverse events or withdrawal of consent. The trial is not classified as low intervention and is categorized as a Phase 4 study, focusing on the safety and efficacy of the treatment in the specified patient population.
Treatment
The clinical trial involves the administration of **Lamivudine**, marketed as Lamivudina Aurovitas 300 mg film-coated tablets. This experimental medication is formulated as a film-coated tablet, designed for oral administration. Each tablet contains 300 mg of the active substance, lamivudine, which is a chemically synthesized compound. The maximum daily dose is set at 300 mg, with a total maximum dose of 50.4 grams over the course of the study. The treatment period is defined as 23 weeks, during which participants will receive the medication daily. Compliance with the dosing schedule will be monitored to ensure adherence to the protocol.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the effects of lamivudine on neurocognitive impairment biomarkers and type-I interferon-stimulated genes in patients with Mild Cognitive Impairment (MCI). The trial aims to assess the efficacy of lamivudine over a 24-week treatment period, as well as to monitor the incidence, nature, and severity of any treatment-emergent adverse events (TEAEs) that may occur during the study.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the impact of lamivudine on specific biomarkers associated with neurocognitive impairment and type-I interferon-stimulated genes in patients with Mild Cognitive Impairment (MCI). The primary endpoints include the percentage change in plasma levels of **pTau-217**, total Tau, NfL, GFAP, Aβ42, Aβ40, and their ratios from baseline to the week 24 visit. Safety and tolerability will also be monitored through the incidence, nature, and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events leading to withdrawal.
Secondary endpoints focus on the fold change of type-I IFN-stimulated genes in plasma and cryopreserved peripheral blood mononuclear cells (PBMCs) from baseline to week 24. These efficacy parameters will be measured and collected at specified timepoints, including the baseline and week 24 visits, using validated laboratory tests. The analysis will involve comparing the baseline and week 24 data to determine the efficacy of lamivudine in reducing neurocognitive impairment biomarkers and modulating type-I IFN-stimulated genes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants 55 to 90 years of age (both inclusive) at the time of signing the informed consent.
- Diagnosis of prodromal AD: MCI due to AD according to National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria as determined by a neurologist, geriatrician, psychiatrist, or clinician approved by the Sponsor or designee.
- Clinical Dementia Rating (CDR)-Global Score of 0.5
- Imaging studies (MRI or CT) within 2 years prior to screening that exclude secondary causes of dementia.
- Documented confirmation of AD diagnosis by positive CSF AD signature or positive amyloid-PET. CSF AD positivity established with low levels of CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 and high levels of p-Tau. A CSF examination performed within 12 months prior to screening is allowed. A positive amyloid-PET is defined as abnormal deposits of amyloid in the PET imaging.
- If receiving an approved medication for AD (i.e., donepezil, galantamine, rivastigmine, memantine, or memantine/donepezil combination product), must be on the medication with a stable dose for at least 4 weeks before the screening visit (dosing should remain stable throughout the study).
- If receiving an OTC supplement for cognition (e.g., gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin), must not be exceeding the recommended dose and be at stable dose for at least 4 weeks prior to screening visit.
- Able to visit the study center and undergo cognitive, functional, and other tests specified in the protocol.
- In the event that the participant requires a caregiver, the caregiver: a. Agrees to accompany the participant to all study visits and able to supervise the participant’s compliance with the study procedures and provide detailed information about the participant. b. Either lives with the participant or sees the participant on average for ≥ 1 hour/day ≥ 3 days/week, or in the Investigator’s opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behavior and function over time and provide information on safety and tolerability. c. Can read, understand, and speak the designated language at the study center. d. Caregiver must be cognitively able to fulfill the requirements of the study.
- A male participant must agree to use a highly effective contraception method during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR a WOCBP who agrees to use a highly effective contraception method during the treatment period and for at least 3 months after the last dose of study treatment.
- Written informed consent provided by participant (or legal representative) and caregiver prior to any study-specific procedures.
Exclusion Criteria
- Possible, probable, or definite vascular dementia according to the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) criteria.
- Concurrent malignancies or invasive cancers diagnosed within the past 3 years except for non-metastatic basal cell carcinoma or squamous cell carcinoma of skin, in situ carcinoma of the uterine cervix or non-metastatic prostate càncer.
- Sexually active WOCBP or man capable of fathering a child who do not consent to using medicinally acceptable contraception (such as surgical sterilization, intrauterine contraceptive device, condom, or diaphragm, an injectable or inserted contraceptive) during the study and for 3 months after the last dose of study treatment.
- Use of anxiolytics, narcotics, or sleep aids in a manner that would interfere with cognitive testing, in the opinion of the investigator. Atypical antipsychotics may be used at the discretion of the Investigator. Tricyclic antidepressants and monoamine oxidase (MAO) inhibitors may be used at the discretion of the investigator.
- Previous treatment with lamivudine.
- Received an investigational product for AD within the last 3 months.
- Participated in another clinical study within 4 weeks prior to this study.
- Subject has any of the following laboratory findings at screening: a. Severe liver dysfunction (Alanine aminotransferase > 2x upper limit of normal (ULN), aspartate aminotransferase > 2x ULN, or history of clinically significant liver disease in the investigator’s judgment. b. Hemoglobin ≤ 10 g/dl. c. International Normalized Ratio (INR) > 1.5 or total bilirubin > 1.5 x ULN (unless subject has evidence of Gilbert’s disease). d. Renal impairment Creatinine clearance (CrCl) < 45 ml/min. e. Poorly controlled diabetes as defined by hemoglobin A1C (HbA1C) > 8.
- Body weight ≤ 35 kg.
- Resides in a moderate to high dependency continuous care facility (residence in low grade assisted living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is allowed).
- Any other reason that in the opinion of the investigator would make the participant ineligible to participate or to complete this study.
- Evidence of significant abnormality that would suggest another potential etiology for dementia (e.g., evidence of cerebral contusion, encephalomalacia, aneurysm, vascular malformation, > 10 microhemorrhages, macrohemorrhage, single infart > 1 cm3).
- Refrain from donating blood or blood products from the screening visit until 3 months after the EOS/ET visit.
- Other central nervous system diseases that may cause cognitive impairment (e.g., cerebrovascular disease including cerebrovascular dementia, Parkinsonism, Huntington’s disease, subdural hematoma, normal pressure hydrocephalus, brain tumor, Creutzfeldt-Jakob disease).
- Concurrent or history of clinically significant psychiatric conditions (e.g., schizophrenia or bipolar affective disorder) that in the Investigator’s opinion prevents the participant from participating or is likely to confound interpretation of drug effect or affect cognitive assessments.
- Vitamin B12, folic acid, syphilis serology, and thyroid stimulating hormone (TSH) results that are thought to contribute to the severity of dementia or cause dementia. Participants may be enrolled if in the Investigator’s medical judgment, the abnormal laboratory values are not the cause of the cognitive symptoms.
- History of known or suspected seizures including febrile seizures (excluding self-limited childhood febrile seizures), a history of significant head trauma with loss of consciousness or recent unconsciousness that is not explained.
- Acute or unstable cardiovascular disease, active peptic ulcer, uncontrolled hypertension, uncontrolled diabetes or any medical condition that may interfere with the completion of the clinical study.
- Known allergies, hypersensitivity, or intolerance to lamivudine or similar products or excipients.
- History of alcohol, substance abuse or dependence as per DSM-V criteria (except nicotine dependence) within the last 3 years.
- Positive blood screen for Human Immunodeficiency Virus (HIV-1 and 2).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Sept 2024 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lamivudina Aurovitas 300 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 300 | 23 | PRD5772571 |