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Study to Evaluate DNL747 in Subjects With Alzheimer's Disease

Primary Purpose

Alzheimer Disease

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

DNL747

Placebo

About this trial

This is an interventional treatment trial for Alzheimer Disease

Eligibility Criteria

55 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Clinical Site(s)
Clinical Site(s)
Clinical Site(s)
Clinical Site(s)
Clinical Site(s)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

DNL747 First, Placebo Second

Placebo First, DNL747 Second

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Number of Subjects with clinically significant neurological examination abnormalities

Number of Subjects with laboratory test abnormalities

Secondary Outcome Measures

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

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

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

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

Pharmacokinetic measure of CSF concentrations of DNL747

Pharmacodynamic measure of pS166 in PBMCs

Full Information

NCT ID

NCT03757325

First Posted

November 27, 2018

Last Updated

February 25, 2020

Sponsor

Denali Therapeutics Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03757325

Brief Title

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

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Completed

Study Start Date

February 13, 2019 (Actual)

Primary Completion Date

December 5, 2019 (Actual)

Study Completion Date

December 5, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Denali Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DNL747 First, Placebo Second

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo First, DNL747 Second

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

DNL747

Intervention Description

DNL747

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

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

Time Frame

Randomization - Day 86

Title

Number of Subjects with clinically significant neurological examination abnormalities

Time Frame

Randomization - Day 86

Title

Number of Subjects with laboratory test abnormalities

Time Frame

Randomization - Day 86

Secondary Outcome Measure Information:

Title

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

Time Frame

Randomization - Day 86

Title

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

Time Frame

Randomization - Day 86

Title

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

Time Frame

Randomization - Day 86

Title

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

Time Frame

Randomization - Day 86

Title

Pharmacokinetic measure of CSF concentrations of DNL747

Time Frame

Randomization - Day 86

Title

Pharmacodynamic measure of pS166 in PBMCs

Time Frame

Randomization - Day 86

10. Eligibility

Sex

All

Minimum Age & Unit of Time

55 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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

Facility Information:

Facility Name

Clinical Site(s)

City

Miami

State/Province

Florida

ZIP/Postal Code

33143

Country

United States

Facility Name

Clinical Site(s)

City

Orlando

State/Province

Florida

ZIP/Postal Code

32806

Country

United States

Facility Name

Clinical Site(s)

City

Dallas

State/Province

Texas

ZIP/Postal Code

75231

Country

United States

Facility Name

Clinical Site(s)

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84124

Country

United States

Facility Name

Clinical Site(s)

City

Groningen

ZIP/Postal Code

9713

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35649245

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.

Results Reference

derived

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Study to Evaluate DNL747 in Subjects With Alzheimer's Disease

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