Clinical trial NCT05547438: Single Ascending Dose Safety and Tolerability of NTS-104 Healthy Adults
Official title: A Single-Center, Randomized, Placebo-Controlled, Single Ascending Dose Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Nts-104 Tris in Healthy Adults
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Acute Ischemic Stroke
Lead sponsor: NeuroTrauma Sciences, LLC
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2022-09-21
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Single ascending doses with review of safety, tolerability and pk prior to next dose level
Primary purpose: TREATMENT

Brief summary: NTS-104 TRIS will be administered as a single intravenous dose to healthy subjects at doses of 0.8, 4, 8 and 16 mg/kg in 4 Cohorts. Each cohort of 8 subjects will begin with dosing 2 sentinel subjects with one being given the investigational product and one the placebo. If no safety issues arise, dosing the remaining subjects in the cohort will begin. A Safety Review Committee will review the safety and pharmacokinetic data before approving escalation to the next dose level.

Detailed description: This is a randomized, , placebo-controlled, Phase 1, single-dose, dose-escalation study to assess the safety, tolerability, and PK of IV NTS-104 in healthy participants. The study is composed of a screening period, a treatment day, and a follow-up period. The study will enroll 4 cohorts with 8 participants in each cohort. Participants in each cohort will be randomized 3:1 to receive either a single IV administration of NTS-104 or placebo. Cohort 1 will be administered 0.8 mg/kg (Cohort 1) with proposed subsequent doses of 4 mg/kg (Cohort 2), 8 mg/kg (Cohort 3), and 16 mg/kg (Cohort 4). Two additional cohorts of 8 participants each, Cohorts 5 and 6, may be enrolled if the human equivalent dose to the no-observed-adverse-effect level (NOAEL) dose in rats is not reached or if exposure limits are not exceeded in the first 4 cohorts. Each cohort will start with a sentinel pair of participants, with 1 participant assigned to NTS-104 Tris (Arm 1) and 1 participant randomized to placebo (Arm 2). If there are no safety concerns identified at 48 hours, the remainder of the cohort will be dosed, with 5 participants randomized to NTS-104 Tris (Arm 1) and 1 participant assigned to placebo (Arm 2).

Eligibility criteria: Inclusion Criteria:

1. Participants who provide written informed consent to participate in the study.
2. Healthy males and females between 18 and 65 years (inclusive) of age at the time of signing informed consent.
3. Body mass index (BMI) of 18 to 32 kg/m2 (inclusive) and weighing at least 50 kg at screening.
4. Participants in general good health in the opinion of the Investigator as determined by medical history; vital signs; and physical, neurological, and suicidal ideation examinations.
5. Blood pressure and heart rate within normal limits (blood pressure: systolic 90 to 140 mmHg and diastolic 50 to 90 mmHg; heart rate: 45 to 100 beats per minute) at screening and at admission on Day -1.
6. Female participants must have a negative serum pregnancy test at screening and at admission and be willing and able to use a medically acceptable method of birth control - Acceptable methods of birth control in this study must start one complete menstrual cycle (and at least 30 days) prior to the first day of dosing and continue until 4 weeks after the final follow-up visit.

   * Acceptable methods of birth control include abstinence, tubal ligation, bilateral tubal occlusion, progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable), combined hormonal contraception (i.e., estrogen- and progestogen-containing), IUS and IUD.
   * Female participants of non-childbearing potential are defined as either postmenopausal (evidence of menopause based on a combination of amenorrhea for at least one year confirmed with pre-admission serum follicle-stimulating hormone level \[\>30 IU/L\]), or surgical sterilization (evidence of hysterectomy and/or bilateral oophorectomy).
   * Male participants with a partner who might become pregnant must use reliable forms of contraception during the trial and 4 weeks afterward. Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method (condom).
   * The participant's female partner uses oral contraceptives (combined hormonal contraception), injectable progesterone or subdermal implants, and the male partner uses a barrier method (condom)

Exclusion Criteria:

1. History of significant medical disorder that, in the opinion of the Investigator, contraindicates administration of the study medications.
2. Any active or current comorbidity with the exception of topical or allergic conditions treated with topical comedication and/or non-drowsy anti-allergic medication or acetaminophen
3. Any use of current comedication at admission or during the 30 days prior to enrollment with the exception of topical dermatological medication and/or non-drowsy anti-allergic medication or acetaminophen
4. Any acute illness (e.g., acute infection) within 72 hours of study drug administration, if considered of significance by the Investigator.
5. Any clinically significant abnormality in safety laboratory tests at screening or admission, in particular a screening TSH test
6. Positive human immunodeficiency virus, hepatitis B, or hepatitis C serology at screening.
7. Specifically, any history or current diagnosis of hepatic impairment at screening and Day - 1
8. Specifically, any history or current diagnosis of renal impairment at screening
9. Specifically, a history of type 1 diabetes mellitus or current type 2 diabetes.
10. Any abnormality on the neurological examination, at screening or enrollment
11. Positive Columbia-Suicide Severity Rating Scale (C-SSRS).
12. Participation in another clinical trial with drugs received within 3 months prior to dosing (calculated from the previous study's last dosing date).
13. Participant who is an active smoker and/or has smoked or used nicotine or nicotine- containing products (e.g., nicotine patch, gum, e-cigarettes) within the past 6 months before enrollment.
14. The use of ketogenic diets within 12 months prior to enrollment.
15. Electrocardiogram (ECG) with clinically significant findings recorded at screening or admission.

17. Positive coronavirus disease 2019 (COVID-19) test determined at screening and admission (nasal swab).

18. Known history of alcohol or drug abuse in the past 5 years. 19. Positive urinary drug or cotinine screen determined at screening and admission.

20. Positive serum alcohol screen determined during the screening period and on admission.

21. Any other condition, which in the Investigator's opinion, would not make the participant a good candidate for the study.

22. Blood donation of 500 mL (1 pint) or more: 56 days before the screening visit and until after the follow-up visit.

23. Plasma donation: 7 days before the screening visit and until after the follow-up visit.

24. Grapefruit, grapefruit juice, star fruit, pomegranate, and Seville oranges: 7 days before screening and until after the follow-up visit

Primary outcomes:
measure: Adverse Events and Serious Adverse Events
timeFrame: Day -28 to Day 8
measure: Change from Baseline in Physical Examination
timeFrame: Day -28 to Day 8
measure: Change in Baseline Vital Signs
timeFrame: Day -28 to Day 8
measure: Concomitant Medication Use
timeFrame: Day -1 to Day 8
measure: Change in QTcF Determined by Electrocardiogram
timeFrame: Day -28 to Day 8
Secondary outcomes:
measure: Cmax
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: Tmax
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: AUC(0-t)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: AUC(inf)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: Elimination rate constant (λz)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: Elimination half-life (t½)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: Total Plasma Clearance (CL)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
measure: Volume of Distribution (Vz)
timeFrame: Blood will be drawn from each patient prior to the start of the infusion, at 30, 60, 75, 90, 105, 120, 150, and 180 minutes after the infusion as well as at 4, 6, 8, 12, 24, 36, and 48 hours after the infusion.
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Parexel International EPCU Baltimore 7th floor
state: Maryland
Study officials:
affiliation: NeuroTrauma Sciences, LLC
name: Marc de Somer, MD
role: STUDY_DIRECTOR
References: