A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)
Primary Purpose
Frontotemporal Dementia
Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
DNL593
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Frontotemporal Dementia focused on measuring FTD, FTD-GRN, granulin
Eligibility 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
Sites / Locations
- UZ LeuvenRecruiting
- Hospital de Clinicas de Porto Alegre (HCPA) - PPDSRecruiting
- Fakultni nemocnice v MotoleRecruiting
- CHU de NantesRecruiting
- CHU RouenRecruiting
- CHU ToulouseRecruiting
- ASST degli Spedali Civili di BresciaRecruiting
- Azienda Ospedaliera Universitaria CareggiRecruiting
- IRCCS Istituto Auxologico ItalianoRecruiting
- Azienda Ospedaliera Cardinale G PanicoRecruiting
- Erasmus University Medical CenterRecruiting
- Hospital de BragaRecruiting
- Hospital Pedro HispanoRecruiting
- Campus Neurológico SéniorRecruiting
- University Clinical Center NisRecruiting
- Hospital Universitario de DonostiaRecruiting
- Hospital Clinic de BarcelonaRecruiting
- Hospital Universitario La PazRecruiting
- Hospital Universitario Virgen del RocioRecruiting
- Hacettepe UniversityRecruiting
- Istanbul University Istanbul Medical FacultyRecruiting
- Dokuz Eylul University Medical FacultyRecruiting
- Ondokuz Mayis University HospitalRecruiting
- Simbec Orion
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Arm Label
DNL593 (Healthy Participant)
Placebo (Healthy Participant)
DNL593 (Participants with FTD)
Placebo (Participants with FTD)
Arm Description
Outcomes
Primary Outcome Measures
Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
Change from baseline in vital sign measurements: systolic and diastolic blood pressure
Change from baseline in vital sign measurements: heart rate
Change from baseline in vital sign measurements: respiratory rate
Change from baseline in vital sign measurements: body temperature
Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
Secondary Outcome Measures
PK Parameter: Maximum concentration (Cmax) of DNL593 in serum
PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum
PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum
PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum
PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)
PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)
PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)
PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)
Concentration of DNL593 in cerebrospinal fluid (CSF)
DNL593 CSF:serum concentration ratio
Full Information
NCT ID
NCT05262023
First Posted
February 1, 2022
Last Updated
August 21, 2023
Sponsor
Denali Therapeutics Inc.
Collaborators
Takeda
1. Study Identification
Unique Protocol Identification Number
NCT05262023
Brief Title
A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 1, 2022 (Actual)
Primary Completion Date
November 2025 (Anticipated)
Study Completion Date
November 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Denali Therapeutics Inc.
Collaborators
Takeda
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Frontotemporal Dementia
Keywords
FTD, FTD-GRN, granulin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
106 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
DNL593 (Healthy Participant)
Arm Type
Experimental
Arm Title
Placebo (Healthy Participant)
Arm Type
Placebo Comparator
Arm Title
DNL593 (Participants with FTD)
Arm Type
Experimental
Arm Title
Placebo (Participants with FTD)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
DNL593
Intervention Description
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Primary Outcome Measure Information:
Title
Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
Time Frame
up to 18 months
Title
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
Time Frame
up to 18 months
Title
Change from baseline in vital sign measurements: systolic and diastolic blood pressure
Time Frame
up to 18 months
Title
Change from baseline in vital sign measurements: heart rate
Time Frame
up to 18 months
Title
Change from baseline in vital sign measurements: respiratory rate
Time Frame
up to 18 months
Title
Change from baseline in vital sign measurements: body temperature
Time Frame
up to 18 months
Title
Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
Time Frame
up to 18 months
Title
Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
Time Frame
up to 18 months
Title
Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
Time Frame
up to 18 months
Secondary Outcome Measure Information:
Title
PK Parameter: Maximum concentration (Cmax) of DNL593 in serum
Time Frame
up to 18 months
Title
PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum
Time Frame
up to 18 months
Title
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
Title
PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum
Time Frame
up to 18 months
Title
PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)
Time Frame
up to 84 days
Title
PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)
Time Frame
up to 18 months
Title
PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)
Time Frame
up to 18 months
Title
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
Title
Concentration of DNL593 in cerebrospinal fluid (CSF)
Time Frame
up to 18 months
Title
DNL593 CSF:serum concentration ratio
Time Frame
up to 18 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials at Denali Therapeutics
Phone
Email:
Email
clinical-trials@dnli.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amy Berger, MD
Organizational Affiliation
Denali Therapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
UZ Leuven
City
Leuven
Country
Belgium
Individual Site Status
Recruiting
Facility Name
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
City
Porto Alegre
Country
Brazil
Individual Site Status
Recruiting
Facility Name
Fakultni nemocnice v Motole
City
Prague
Country
Czechia
Individual Site Status
Recruiting
Facility Name
CHU de Nantes
City
Nantes
Country
France
Individual Site Status
Recruiting
Facility Name
CHU Rouen
City
Rouen
Country
France
Individual Site Status
Recruiting
Facility Name
CHU Toulouse
City
Toulouse
Country
France
Individual Site Status
Recruiting
Facility Name
ASST degli Spedali Civili di Brescia
City
Brescia
Country
Italy
Individual Site Status
Recruiting
Facility Name
Azienda Ospedaliera Universitaria Careggi
City
Firenze
Country
Italy
Individual Site Status
Recruiting
Facility Name
IRCCS Istituto Auxologico Italiano
City
Milano
Country
Italy
Individual Site Status
Recruiting
Facility Name
Azienda Ospedaliera Cardinale G Panico
City
Tricase
Country
Italy
Individual Site Status
Recruiting
Facility Name
Erasmus University Medical Center
City
Rotterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
Hospital de Braga
City
Braga
Country
Portugal
Individual Site Status
Recruiting
Facility Name
Hospital Pedro Hispano
City
Matosinhos
Country
Portugal
Individual Site Status
Recruiting
Facility Name
Campus Neurológico Sénior
City
Torres Vedras
Country
Portugal
Individual Site Status
Recruiting
Facility Name
University Clinical Center Nis
City
Niš
Country
Serbia
Individual Site Status
Recruiting
Facility Name
Hospital Universitario de Donostia
City
Donostia-San Sebastian
State/Province
Guipúzcoa
ZIP/Postal Code
20014
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
ZIP/Postal Code
8036
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hacettepe University
City
Ankara
Country
Turkey
Individual Site Status
Recruiting
Facility Name
Istanbul University Istanbul Medical Faculty
City
Istanbul
Country
Turkey
Individual Site Status
Recruiting
Facility Name
Dokuz Eylul University Medical Faculty
City
İzmir
Country
Turkey
Individual Site Status
Recruiting
Facility Name
Ondokuz Mayis University Hospital
City
Samsun
Country
Turkey
Individual Site Status
Recruiting
Facility Name
Simbec Orion
City
Merthyr Tydfil
State/Province
Wales
ZIP/Postal Code
CF48 4DR
Country
United Kingdom
Individual Site Status
Completed
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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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