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Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03757351
Recruitment Status : Terminated (Due to change in Sanofi's development strategy for DNL747/SAR443060 - not due to any safety concerns)
First Posted : November 28, 2018
Last Update Posted : July 10, 2020
Sponsor:
Collaborator:
Denali Therapeutics Inc.
Information provided by (Responsible Party):
Sanofi

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

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: DNL747 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : December 28, 2018
Actual Primary Completion Date : March 12, 2020
Actual Study Completion Date : June 18, 2020


Arm Intervention/treatment
Experimental: DNL747 First, Placebo Second Drug: DNL747
Repeating oral dose

Drug: Placebo
Repeating oral dose

Experimental: Placebo First, DNL747 Second Drug: DNL747
Repeating oral dose

Drug: Placebo
Repeating oral dose

Experimental: Open-Label Extension
Conducted in the Netherlands only.
Drug: DNL747
Repeating oral dose




Primary Outcome Measures :
  1. Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Randomization - Day 86 ]
  2. Number of Subjects with clinically significant neurological examination abnormalities [ Time Frame: Randomization - Day 86 ]
  3. Number of Subjects with laboratory test abnormalities [ Time Frame: Randomization - Day 86 ]

Secondary Outcome Measures :
  1. Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747 [ Time Frame: Randomization - Day 86 ]
  2. Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747 [ Time Frame: Randomization - Day 86 ]
  3. Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747 [ Time Frame: Randomization - Day 86 ]
  4. Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747 [ Time Frame: Randomization - Day 86 ]
  5. Pharmacokinetic measure of CSF concentrations of DNL747 [ Time Frame: Randomization - Day 86 ]
  6. Pharmacodynamic measure of pS166 in PBMCs [ Time Frame: Randomization - Day 86 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03757351


Locations
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United States, Florida
Bioclinica
Orlando, Florida, United States, 32806
United States, Utah
PRA Health Sciences
Salt Lake City, Utah, United States, 84124
Netherlands
CHDR
Leiden, South Holland, Netherlands, 2333
Sponsors and Collaborators
Sanofi
Denali Therapeutics Inc.
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03757351    
Other Study ID Numbers: TDR16536
DNLI-D-0003 ( Other Identifier: Denali Therapeutics Inc. )
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: July 10, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases