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van CCT (UK)


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van CCT (UK)


A study to investigate the safety, tolerability, blood concentrations and effects of multiple doses of DNL104 in healthy volunteers.


- candidate number26941
- NTR NumberNTR6257
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR21-mrt-2017
- Secondary IDsCHDR1634 / DNLI-A-002  NL59310.056.16 / 2016-003859-30
- Public TitleA study to investigate the safety, tolerability, blood concentrations and effects of multiple doses of DNL104 in healthy volunteers.
- Scientific TitleA Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of DNL104 in Healthy Subjects
- ACRONYMMultiple Ascending Doses of DNL104
- hypothesis•To investigate the safety and tolerability of multiple ascending oral doses of DNL104 in healthy subjects
•To characterize the pharmacokinetics (PK) of DNL104 in plasma and measure the trough concentrations of DNL104 in CSF.
•To Explore the pharmacodynamics of DNL104 using an ex vivo stimulation assay to measure the inhibition of phosphorylation of the target protein and downstream markers that are directly impacted by RIP1 kinase inhibition
•To explore the pharmacodynamics of DNL104 in CSF
- Healt Condition(s) or Problem(s) studiedNeurodegenerative disorders
- Inclusion criteria1. Healthy men or women between 18 and 55 years of age at screening (inclusive);
2. Subjects must be willing and able to give written informed consent, and must sign an ethics-committee-approved Informed Consent Form prior to any study-related procedures being performed;
3. Body mass index between 19 to 32 kg/m2 (inclusive) and a weight of at least 50 kg;
4. For males: When engaging in sexual activity with a woman of childbearing potential, both the subject and his female partner must use highly effective contraception, consisting of 2 forms of birth control (1 of which must be a male barrier method such as latex or polyurethane condoms) from screening, throughout the clinical study period, and for 90 days after the final study drug administration;
5. For males: The subject must not donate sperm from screening, throughout the clinical study period, and for 90 days after the final study drug administration;
6. For females: The subject must have been surgically sterilized (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; proper documentation required) at least 6 months before screening, or be postmenopausal (defined as 24 months without menses before screening, with an estradiol level of < 200 pmol/L and a follicle-stimulating hormone level of > 40 IU/L at screening);
7. Able to communicate with the investigator and study staff;
8. Willing and able to comply with the requirements of the study, scheduled visits, laboratory tests, and other study procedures;
9. Agrees to abide by study restrictions and agrees to remain in the study unit for the confinement period.
- Exclusion criteria1. History of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders;
2. Current significant medical or psychiatric condition, including suicidal ideation in the last 6 months (as assessed by the C-SSRS) or a lifetime suicide attempt;
3. Clinical laboratory test values outside the normal range at screening or baseline unless assessed by the investigator as clinically non-significant values;
4. Supine systolic blood pressure <90 or >140 mmHg, supine diastolic blood pressure <50 or >90 mmHg, pulse rate <40 or >110 bpm, or elevated body temperature at screening or baseline;
5. History of serious adverse reaction or serious hypersensitivity to any drug;
6. Evidence of clinically significant hepatic or renal impairment including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 x the upper limit of normal (ULN), or bilirubin >1.2 x ULN, or GGT >2.5 x ULN, or creatinine clearance (determined by the MDRD study equation) of <70 mL/min/1.73 m2;
7. History of seizures;
8. History or presence of an abnormal ECG, including, but not limited to, complete left bundle branch block, second- or third-degree heart block, evidence of prior myocardial infarction, or any other abnormality that is clinically significant in the investigator’s opinion or precludes accurate interpretation and calculations of cardiac intervals (e.g., QT, QRS);
9. A QTcF value >450 msec or QRS >120 msec demonstrated in at least two ECGs recorded more than 30 min apart;
10. Hemoglobin level <7.5 mmol/L;
11. Any blood donation or other loss of blood greater than 500 mL within 3 months of screening or plasma donation within 2 weeks of screening;
12. Participation in any other investigational drug study within 90 days of first study drug administration, or previous participation in a study with DNL104.
13. Use of any prescription drug within 7 days or 5 half-lives (whichever is longer) of the first dose administration and anticipated use through the follow-up 1 visit;
14. Use of any over-the-counter medication (including vitamin/mineral supplements, and herbal medicines such as St. John's Wort) within 7 days of the first dose administration and anticipated use through the follow-up 1 visit;
15. Any surgical or medical condition possibly affecting drug absorption (e.g., gastrectomy);
16. Poor peripheral venous access;
17. Alcohol, caffeine, or grapefruit consumption within 48 h before dosing;
18. Average daily caffeine intake greater than 450 mg/ day (equivalent to 4 cups per day);
19. History of alcoholism, drug abuse, or drug addiction in the last 2 years;
20. Positive drug or alcohol test at screening or upon admission to the unit;
21. Use of tobacco or nicotine products within the previous month before the first dose administration;
22. Positive serology for HIV, HBV, or HCV, by HIV1 and HIV2 antibodies, Hepatitis B antigen or Hepatitis C antibodies, respectively;
23. Subjects who are part of the clinical staff personnel or family members of the clinical site staff;
24. Any other issue which, in the opinion of the Investigator, will make the subject ineligible for study participation;
25. Subjects who are unwilling to agree to any food restrictions that may be required.
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupParallel
- Type[default]
- Studytypeintervention
- planned startdate 11-jan-2017
- planned closingdate31-mrt-2017
- Target number of participants30
- InterventionsDNLI-A-002 or placebo
- Primary outcome*Treatment-emergent (serious) adverse events ((S)AEs).
*Concomitant medication
*Clinical laboratory tests
o Hematology
o Chemistry
o Coagulation
o Urinalysis
*Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Temperature (degrees Celsius)
o Respiratory rate (breaths per minute)
*Electrocardiogram (ECG)
o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF, QtcB
*Cardiac Holter
o Heart rate
o Arrhythmias (4 or more successive beats)
o Ectopy (up to three successive beats)
-Pharmacokinetic
*The area under the plasma concentration-time curve from zero to infinity(AUC0-inf);
*The maximum plasma concentration (Cmax);
*The area under the plasma concentration-time curve from zero to t of the last measured concentration above the limit of quantification (AUC0-last);
*The time to reach maximum plasma concentration (tmax);
*The terminal disposition rate constant (λz) with the respective half-life (t˝).
*Other parameters, including Vz/F, CL/F, and other parameters as appropriate, as well as dose adjusted parameters, may be determined.
- Secondary outcome-Pharmacodynamic
*pS166-RIP1 kinase level in stimulated PBMCs.
*Total RIP1 kinase protein level in stimulated PBMCs.
*Cytokine levels in stimulated plasma (exploratory).
*Possible other relevant markers such as MLKL, pMLKL and other exploratory biomarkers.
-Pharmacogenomic
A blood sample for DNA isolation will be collected from each subject pre-dose on Day 1 for potential pharmacogenetic analysis of genes that may affect the pharmacokinetics, pharmacodynamics, efficacy, or safety of DNL104.
NeuroCart tests:
Saccadic eye movements:
saccadic reaction time (msec),
saccadic peak velocity (deg/sec), and
saccadic inaccuracy (%);
Smooth pursuit eye movements:
percentage of time the eyes of the subjects are in smooth pursuit of the target (%);
Body sway:
antero-posterior sway (mm);
Adaptive tracking:
o average performance (%);
- Timepoints• Medical screening (1x), training day, 13 full day visits with multiple measurements, and 2 return visits.
- Trial web site
- status[default]
- CONTACT FOR PUBLIC QUERIES G.H. Groeneveld
- CONTACT for SCIENTIFIC QUERIES Jules Heuberger
- Sponsor/Initiator Denali Therapeutics
- Funding
(Source(s) of Monetary or Material Support)
Denali Therapeutics
- Publications
- Brief summary• Receptor-interacting protein kinase 1 (RIP1) is a serine/threonine kinase involved in the regulation of inflammation and cell death. In response to tumor necrosis factor (TNF)-alpha signaling, RIP1 is activated, and in turn regulates activation of downstream targets, including RIPK3, mixed-lineage kinase domain-like (MLKL) and NF-kB. This complex signaling cascade initiates a number of cellular processes, including cytokine release, microglial activation, and necroptosis, a regulated form of cell death. Inhibition of RIP1 kinase activity has been shown to protect against necroptotic cell death in vitro across a range of cell death models, including a model of motor neuron cell death related to Amyotrophic Lateral Sclerosis. DNL104 is a novel, potent and selective RIP1 kinase inhibitor that has favorable pharmacokinetic properties and good penetration across the blood brain barrier, allowing target inhibition in the central nervous system. As such, it is a potential therapeutic candidate for neurodegenerative diseases where histopathology and / or genetics implicates cell death and inflammation, including amyotrophic lateral sclerosis (ALS), Alzheimer Disease (AD) and Parkinson Disease (PD). All subjects are recruited in The Netherlands.
- Main changes (audit trail)
- RECORD21-mrt-2017 - 29-apr-2017


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