Dementia memory loss
Conditions
Interventions
In Part A of the study four dose level cohorts will be enrolled sequentially,
with each subject receiving a single dose of the study drug or a placebo.
Subjects enrolled in group 1 and 2 will be ran
levels through Day 15, from at least 5 patients for
Sponsors
Alnylam Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Inclusion Criteria for Participants in Part A and Replacement Patients in Parts A and B: 1. Male or female, aged 18 years or older at the time of informed consent 2. Individuals with mild cognitive impairment or mild dementia due to EOAD, where disease onset occurred at age 20 4. Able and willing to meet all study requirements: adequately supportive psychosocial circumstances, able to undergo Magnetic Resonance Imaging (MRI) scans and able to tolerate them, body Mass Index (BMI) >=18 and
Exclusion criteria
Exclusion criteria: Exclusion Criteria for Participants in Part A and Replacement Patients in Parts A and B: 1. Non-Alzheimer's disease dementia 2. Has any of the following laboratory parameter assessments at Screening: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper limit of normal (ULN), total bilirubin >1.5×ULN, international normalized ratio (INR) >1.4, platelet count 150 mmHg and/or a diastolic blood pressure >90 mmHg after 10 minutes of rest at screening 5. Has known active human immunodeficiency virus (HIV) infection 6. Has active severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection 7. Treatment with another investigational drug, biological agent, or device within 6 months of Screening, or 5 half-lives of investigational agent 8. Use of the following medications is prohibited unless the dose has been stable for at least 12 weeks prior to Screening and the dose regimen is not anticipated to change during the study: antidepressants, antipsychotics, anxiolytics, benzodiazepines, acetylcholinesterase inhibitors, memantine 9. Supplement use (eg, coenzyme Q10, vitamins, creatine), unless stable dose for 6 weeks prior to Screening 10. Antiplatelet or anticoagulant therapy within the 28 days prior to Screening or anticipated use during the study 11. Oral carbonic anhydrase inhibitors 12. Treatment with amyloid-targeting antibody within the last 3 years prior to Screening 13. Treatment with another IT administered medication within the last 1 year prior to Screening 14. Active infection requiring systemic antiviral or antimicrobial therapy 15. Prior treatment with an siRNA or antisense oligonucleotide (ASO) 16. Any history of gene therapy or cell transplantation or experimental brain surgery 17. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter 18. Any condition, including EOAD-related symptoms, that would prevent either writing or performing assessments 19. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to Screening 20. Any condition that increases risk of meningitis (eg, immunodeficient state) 21. History of bleeding diathesis or coagulopathy 22. A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment 23. History of uncontrolled seizures within the last 6 months prior to Screening 24. Hospitalization for any major medical or surgical procedure 25. Clinically relevant hematological, hepatic, cardiac or renal disease or event 26. History of intolerance to IT injection(s) 27. Is not willing to comply with the contraceptive requirements during the study period 28. Female patient is pregnant, planning a pregnancy, or breast-feeding and history of drug/chemical or alcohol abuse Exclusion Criteria for Participants Who Transition from Part A to Part B: 1. Has any of the following laboratory parameter assessments at Screening: international normalized rat
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A - Single-dose Period: To evaluate frequency of adverse events. Safety will also be evaluated through vital signs, physical exams, neurological assessment, cognitive and suicide severity assessment, neuroimaging, electrocardiograms (ECGs), and clinical laboratory assessments. Part B - Multi-dose Period: To evaluate frequency of adverse events. Safety will also be evaluated through vital signs, physical exams, neurological assessment, cognitive and suicide severity assessment, and clinical laboratory assessments. | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A - Single-dose Period: Change from baseline in levels of CSF sAPPa and sAPPβ and evaluate PK parameters of ALN-APP and of potential metabolites in plasma (area under the concentration-time curve [AUC], maximum plasma concentration [Cmax]), urine (fraction excreted in the urine [fe]) and CSF (concentration at time 't' [Ct]). Part B - Multi-dose Period: Change from baseline in levels of CSF sAPPa and sAPPβ and evaluate PK parameters of ALN-APP and of potential metabolites in plasma (area under the concentration-time curve [AUC], maximum plasma concentration [Cmax]), and CSF (concentration at time 't' [Ct]). | — |
Countries
Netherlands
Outcome results
None listed