Clinical trial NCT03757325: Study to Evaluate DNL747 in Subjects With Alzheimer's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer Disease
Lead sponsor: Denali Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2018-11-28
Enrollment: 16
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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)

Eligibility criteria: Key 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 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

Primary outcomes:
measure: Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Randomization - Day 86
measure: Number of Subjects with clinically significant neurological examination abnormalities
timeFrame: Randomization - Day 86
measure: Number of Subjects with laboratory test abnormalities
timeFrame: Randomization - Day 86
Secondary outcomes:
measure: Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of CSF concentrations of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacodynamic measure of pS166 in PBMCs
timeFrame: Randomization - Day 86
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Site(s)
state: Florida
city: Orlando
country: United States
facility: Clinical Site(s)
state: Florida
city: Dallas
country: United States
facility: Clinical Site(s)
state: Texas
city: Salt Lake City
country: United States
facility: Clinical Site(s)
state: Utah
city: Groningen
country: Netherlands
facility: Clinical Site(s)
Study officials:
References:
citation: Vissers MFJM, Heuberger JAAC, Groeneveld GJ, Oude Nijhuis J, De Deyn PP, Hadi S, Harris J, Tsai RM, Cruz-Herranz A, Huang F, Tong V, Erickson R, Zhu Y, Scearce-Levie K, Hsiao-Nakamoto J, Tang X, Chang M, Fox BM, Estrada AA, Pomponio RJ, Alonso-Alonso M, Zilberstein M, Atassi N, Troyer MD, Ho C. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. Clin Transl Sci. 2022 Aug;15(8):2010-2023. doi: 10.1111/cts.13317. Epub 2022 Jun 1.