A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL747 in Subjects With Alzheimer's Disease
Overview
- Phase
- Phase 1
- Intervention
- DNL747
- Conditions
- Alzheimer Disease
- Sponsor
- Denali Therapeutics Inc.
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of DNL747 in subjects with Alzheimer's disease when administered for 29 days in a cross-over design
Detailed Description
This is a Phase 1b randomized, placebo-controlled, double-blind, crossover study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL747 in subjects with Alzheimer's disease (AD)
Investigators
Eligibility Criteria
Inclusion Criteria
- •Women of non-childbearing potential and men, aged 55-85 years
- •AD diagnosis based on the 2011 National Institute on Aging-Alzheimer's Association Guidelines
- •Supportive evidence for diagnosis of AD based upon positive CSF Aβ42 test, or documented history of positive amyloid-specific PET scan
- •Screening MMSE score of 16-26 points
- •Screening CDR Global Score of 0.5-1.0
- •Availability of a person ("caregiver") who, in the investigator's judgment, has frequent and sufficient contact with the participant and is able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits that require input for scale completion, assists the participant with compliance for at-home study treatment administration, and signs the necessary consent form (note: the caregiver is not required to stay in the unit)
- •Approved AD treatments (acetylcholinesterase inhibitors ± memantine) and other prescription medications must be stable for ≥1 month prior to screening and anticipated to be stable over the duration of the study
Exclusion Criteria
- •Clinical history within 2 years of the screening visit or current evidence of any neurological or neurodegenerative disorder other than AD that is associated with transient or sustained alterations in cognition
- •Magnetic resonance imaging (MRI) at screening (or within 1 year of screening visit) consistent with any neurological or neurodegenerative disorder other than AD that is associated with transient or sustained alterations in cognition
Arms & Interventions
DNL747 First, Placebo Second
Subjects will receive DNL747 for 29 days for the first period and then will switch to placebo for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
Intervention: DNL747
DNL747 First, Placebo Second
Subjects will receive DNL747 for 29 days for the first period and then will switch to placebo for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
Intervention: Placebo
Placebo First, DNL747 Second
Subjects will receive placebo for 29 days for the first period and then will switch to DNL747 for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
Intervention: DNL747
Placebo First, DNL747 Second
Subjects will receive placebo for 29 days for the first period and then will switch to DNL747 for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Randomization - Day 86
Number of Subjects with clinically significant neurological examination abnormalities
Time Frame: Randomization - Day 86
Number of Subjects with laboratory test abnormalities
Time Frame: Randomization - Day 86
Secondary Outcomes
- Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747(Randomization - Day 86)
- Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747(Randomization - Day 86)
- Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747(Randomization - Day 86)
- Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747(Randomization - Day 86)
- Pharmacokinetic measure of CSF concentrations of DNL747(Randomization - Day 86)
- Pharmacodynamic measure of pS166 in PBMCs(Randomization - Day 86)