Study to Evaluate DNL747 in Subjects With Alzheimer's Disease

Phase 1

Completed

• Conditions: Alzheimer Disease
• Interventions: Drug: DNL747; Drug: Placebo

• Registration Number: NCT03757325
• Lead Sponsor: Denali Therapeutics Inc.

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)

Study Timeline

• Study First Submitted: 2018-11-27
• Study First Submitted QC: 2018-11-27
• Study First Posted: 2018-11-28
• Study Start: 2019-02-13
• Primary Completion: 2019-12-05
• Study Completion: 2019-12-05
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-25
• Last Update Posted: 2020-02-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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

Key

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo First, DNL747 Second	DNL747	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.
Placebo First, DNL747 Second	Placebo	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.
DNL747 First, Placebo Second	DNL747	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.
DNL747 First, Placebo Second	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Number of Subjects with laboratory test abnormalities	Randomization - Day 86
Number of Subjects with clinically significant neurological examination abnormalities	Randomization - Day 86
Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Randomization - Day 86

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Clinical Site(s); 🇳🇱 Groningen, Netherlands