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A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)

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ClinicalTrials.gov Identifier: NCT05262023
Recruitment Status : Recruiting
First Posted : March 2, 2022
Last Update Posted : March 2, 2022
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Denali Therapeutics Inc.

Brief Summary:

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period.

Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.


Condition or disease Intervention/treatment Phase
Frontotemporal Dementia Drug: DNL593 Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension
Actual Study Start Date : February 1, 2022
Estimated Primary Completion Date : November 2025
Estimated Study Completion Date : November 2025


Arm Intervention/treatment
Experimental: DNL593 (Healthy Participant) Drug: DNL593
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Placebo Comparator: Placebo (Healthy Participant) Drug: Placebo
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Experimental: DNL593 (Participants with FTD) Drug: DNL593
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Placebo Comparator: Placebo (Participants with FTD) Drug: Placebo
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)




Primary Outcome Measures :
  1. Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) [ Time Frame: up to 18 months ]
  2. Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values [ Time Frame: up to 18 months ]
  3. Change from baseline in vital sign measurements: systolic and diastolic blood pressure [ Time Frame: up to 18 months ]
  4. Change from baseline in vital sign measurements: heart rate [ Time Frame: up to 18 months ]
  5. Change from baseline in vital sign measurements: respiratory rate [ Time Frame: up to 18 months ]
  6. Change from baseline in vital sign measurements: body temperature [ Time Frame: up to 18 months ]
  7. Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals [ Time Frame: up to 18 months ]
  8. Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings [ Time Frame: up to 18 months ]
  9. Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only) [ Time Frame: up to 18 months ]

Secondary Outcome Measures :
  1. PK Parameter: Maximum concentration (Cmax) of DNL593 in serum [ Time Frame: up to 18 months ]
  2. PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum [ Time Frame: up to 18 months ]
  3. PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum [ Time Frame: up to 18 months ]
  4. PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum [ Time Frame: up to 18 months ]
  5. PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only) [ Time Frame: up to 84 days ]
  6. PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only) [ Time Frame: up to 18 months ]
  7. PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only) [ Time Frame: up to 18 months ]
  8. PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only) [ Time Frame: up to 18 months ]
  9. Concentration of DNL593 in cerebrospinal fluid (CSF) [ Time Frame: up to 18 months ]
  10. DNL593 CSF:serum concentration ratio [ Time Frame: up to 18 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Key Inclusion Criteria:

Part A:

  • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 55 years
  • BMI of ≥ 18 to ≤ 32 kg/m²
  • When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception

Part B:

  • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 80 years. Women who are of childbearing potential but on highly effective, low user dependent contraceptive methods will be allowed.
  • BMI of ≥ 18 to ≤ 32 kg/m²
  • Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5
  • Have confirmed granulin (GRN) mutation via genetic testing or historical records available for review by investigator
  • When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception

Part C:

  • All participants who completed Part B of this trial are eligible for an 18-month OLE if the participant has no unresolved clinically significant TEAEs, where continued dosing may represent a risk to participant safety.

Key Exclusion Criteria:

  • Have any history of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders
  • Have a history of malignancy, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence
  • Have a clinically significant history of stroke, cognitive impairment due to causes other than FTD, seizure within 5 years of screening, or head trauma with loss of consciousness within 2 years of screening
  • Have a positive serum pregnancy test or are currently lactating or breastfeeding

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): NCT05262023


Locations
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United Kingdom
Clinical Site Recruiting
Merthyr Tydfil, Wales, United Kingdom, CF48 4DR
Contact: Study Coordinator    Email:    Enrolmentservices@simbecorion.com   
Principal Investigator: Annelize Koch, MD         
Sponsors and Collaborators
Denali Therapeutics Inc.
Takeda
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Responsible Party: Denali Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT05262023    
Other Study ID Numbers: DNLI-H-0001
2021-005733-16 ( EudraCT Number )
First Posted: March 2, 2022    Key Record Dates
Last Update Posted: March 2, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Denali Therapeutics Inc.:
FTD
FTD-GRN
granulin
Additional relevant MeSH terms:
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Dementia
Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Frontotemporal Lobar Degeneration
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations