Study to Evaluate DNL747 in Subjects With Alzheimer's Disease

NCT03757325 | Completed Phase 1 FDA Drug

• 1 other identifier: DNLI-D-0002
• Study Type: interventional
• Target: 16
• Locations: 2 countries
• Sites: 5

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

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (3)

• Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Randomization - Day 86

• Number of Subjects with clinically significant neurological examination abnormalities

  Randomization - Day 86

• Number of Subjects with laboratory test abnormalities

  Randomization - Day 86

Secondary Outcomes (6)

• Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747

  Randomization - Day 86

• Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747

  Randomization - Day 86

• Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747

  Randomization - Day 86

• Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747

  Randomization - Day 86

• Pharmacokinetic measure of CSF concentrations of DNL747

  Randomization - Day 86

Study Arms (2)

DNL747 First, Placebo Second

EXPERIMENTAL

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.

Drug: DNL747; Drug: Placebo

Placebo First, DNL747 Second

EXPERIMENTAL

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.

Drug: DNL747; Drug: Placebo

Interventions

DNL747 DRUG

DNL747

DNL747 First, Placebo Second; Placebo First, DNL747 Second

Placebo DRUG

Placebo

DNL747 First, Placebo Second; Placebo First, DNL747 Second

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Denali Therapeutics Inc.: lead

Study Sites (5)

Clinical Site(s)

Miami, Florida, 33143, United States

Location

Clinical Site(s)

Orlando, Florida, 32806, United States

Location

Clinical Site(s)

Dallas, Texas, 75231, United States

Location

Clinical Site(s)

Salt Lake City, Utah, 84124, United States

Location

Clinical Site(s)

Groningen, 9713, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 35649245 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: November 28, 2018
• Study Start: February 13, 2019
• Primary Completion: December 5, 2019
• Study Completion: December 5, 2019
• Last Updated: February 26, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); NL (1)