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Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
DNL747
Placebo
Sponsored by
Sanofi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria (Double-Blind Part):

  • Women of non-childbearing potential and men, aged 21-80 years
  • Willingness and ability to complete all aspects of the study; participant should be capable of completing assessments either alone or with help of a caregiver
  • Diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria
  • Less than 3 years since symptom onset
  • Forced vital capacity (FVC) >50% predicted measured within 30 days of screening
  • If subject is taking approved ALS treatments (riluzole and/or edaravone), doses must be stable for ≥2 months prior to screening and subject is expected to stay on a stable regimen throughout the study

Key Exclusion Criteria (Double-Blind Part):

  • History of a clinically significant non-ALS neurologic disorder (other than frontal temporal lobe dementia), including, but not limited to, muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson's disease, Lewy body dementia, vascular dementia, Huntington's disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection or abscess
  • Unstable or poorly controlled comorbid disease process of any organ system currently requiring active treatment or likely to require treatment adjustment during the study

Key Inclusion Criteria (Open-Label Extension):

  • Successful completion of both periods of the the double-blind, crossover part of the study
  • Continued diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria

Key Exclusion Criteria (Open-Label Extension):

  • Presence of laboratory abnormalities, physical examination findings, or AEs determined to be clinically significant by the investigator from the double-blind part of the study that have not resolved by the final follow-up visit as part of the double-blind study period
  • New diagnosis of clinically significant neurological disorder (other than frontal temporal lobe dementia)

Sites / Locations

  • Bioclinica
  • PRA Health Sciences
  • CHDR

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

DNL747 First, Placebo Second

Placebo First, DNL747 Second

Open-Label Extension

Arm Description

Conducted in the Netherlands only.

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

First Posted
November 27, 2018
Last Updated
May 11, 2022
Sponsor
Sanofi
Collaborators
Denali Therapeutics Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03757351
Brief Title
Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis
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 Amyotrophic Lateral Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Terminated
Why Stopped
Due to change in Sanofi's development strategy for DNL747/SAR443060 - not due to any safety concerns
Study Start Date
December 14, 2018 (Actual)
Primary Completion Date
June 18, 2020 (Actual)
Study Completion Date
June 18, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi
Collaborators
Denali Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

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 Amyotrophic Lateral Sclerosis in a cross-over design

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DNL747 First, Placebo Second
Arm Type
Experimental
Arm Title
Placebo First, DNL747 Second
Arm Type
Experimental
Arm Title
Open-Label Extension
Arm Type
Experimental
Arm Description
Conducted in the Netherlands only.
Intervention Type
Drug
Intervention Name(s)
DNL747
Intervention Description
Repeating oral dose
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Repeating oral dose
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
21 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria (Double-Blind Part): Women of non-childbearing potential and men, aged 21-80 years Willingness and ability to complete all aspects of the study; participant should be capable of completing assessments either alone or with help of a caregiver Diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria Less than 3 years since symptom onset Forced vital capacity (FVC) >50% predicted measured within 30 days of screening If subject is taking approved ALS treatments (riluzole and/or edaravone), doses must be stable for ≥2 months prior to screening and subject is expected to stay on a stable regimen throughout the study Key Exclusion Criteria (Double-Blind Part): History of a clinically significant non-ALS neurologic disorder (other than frontal temporal lobe dementia), including, but not limited to, muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson's disease, Lewy body dementia, vascular dementia, Huntington's disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection or abscess Unstable or poorly controlled comorbid disease process of any organ system currently requiring active treatment or likely to require treatment adjustment during the study Key Inclusion Criteria (Open-Label Extension): Successful completion of both periods of the the double-blind, crossover part of the study Continued diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria Key Exclusion Criteria (Open-Label Extension): Presence of laboratory abnormalities, physical examination findings, or AEs determined to be clinically significant by the investigator from the double-blind part of the study that have not resolved by the final follow-up visit as part of the double-blind study period New diagnosis of clinically significant neurological disorder (other than frontal temporal lobe dementia)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Bioclinica
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
PRA Health Sciences
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84124
Country
United States
Facility Name
CHDR
City
Leiden
State/Province
South Holland
ZIP/Postal Code
2333
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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
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Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

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