Clinical trial NCT02834741: Safety, Tolerability, PK of Oral NYX-2925 in Healthy Volunteers
Official title: A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Daily Oral NYX2925 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: Aptinyx
Sponsor class: INDUSTRY
Collaborators: name: Spaulding Clinical Research LLC
First posted: 2016-07-15
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a first in human study of NYX-2925. It will evaluate single and multiple ascending doses of NYX-2925 in healthy volunteers.

Detailed description: This is a first in human study of NYX-2925. This is a randomized, double-blind, sponsor-open, placebo-controlled, single and multiple ascending dose, parallel safety, tolerability, and PK study of oral NYX-2925 in healthy volunteers. The single ascending dose phase will comprise up to five dose groups. There will be up to 3 dose groups in the multiple ascending dose phase. One open-label dose group will be repeated in the multiple ascending dose phase to collect cerebrospinal fluid (CSF) samples, in order to explore central nervous system penetration. One elderly cohort (single dose) will be completed after all single and multiple dose escalation groups have completed. One open-label dose group will be repeated in the single ascending dose phase to collect CSF samples, in order to establish a more complete cerebral spinal fluid pharmacokinetic profile.

The influence of food ("food effect") on the bioavailability and pharmacokinetics of NYX-2925 will be explored in one dose group in the single ascending dose phase.

A data review committee will review safety and tolerability (adverse events and other relevant data), plus preliminary pharmacokinetic data, prior to proceeding to the next higher dose group, cohort, and/or phase of the study, as well as administration of the fed dose in the food effect group.

Stopping rules for individual study participants and dose groups or cohorts are established in order to evaluate the dose escalation scheme, the need to stop or terminate dosing, or to establish the maximum tolerated dose. If a cohort is stopped due to safety or tolerability concerns, the previous cohort may be repeated to determine the highest tolerated dose.

Eligibility criteria: Inclusion Criteria:

1. Male and female subjects.
2. 18 to 55 years of age, inclusive, at the time of signing the informed consent form (ICF). 55 to 80 years of age for elderly cohort.
3. Female subjects with a negative serum pregnancy test prior to entry into the study and who are practicing an adequate method of birth control (e.g., oral or parenteral contraceptives, intrauterine device, barrier, abstinence) and who do not plan to become pregnant during the course of the study.
4. Male subjects and their female sexual partner should use an acceptable method of birth control during the study. Male subjects must agree to use barrier contraception (condom with spermicide), and refrain from sperm donation, from the first dose of study drug until 90 days after the last dose of study drug.
5. Clinical laboratory values within normal limits or deemed not clinically significant by the investigator and/or the sponsor.
6. Ability to understand the requirements of the study, provide written informed consent, abide by the study restrictions, and agree to return for the required assessments.
7. Subject is judged to be in good health as determined by the investigator based on the results of a medical history, physical examination (PE), clinical laboratory profile, and electrocardiogram (ECG) performed during the screening period and confirmed prior to dosing.
8. Body mass index (BMI) between 18 and 30 kg/m2 (inclusive).
9. Normal renal and hepatic function, with calculated creatinine clearance ≥ 90 mL/minute (Cockcroft-Gault Formula) at Screening or ≥ 60 mL/minute only in the case of the elderly cohort.

Exclusion Criteria:

1. Clinically significant alcohol or other substance abuse within the last 24 months, in the opinion of the investigator; or, unable to abstain from alcoholic beverages during the course of the study.
2. Positive screen for alcohol or drugs of abuse (with the exception of a positive result considered by the investigator to be directly attributable to prescription medication approved for subject use): including benzodiazepines, opiates, cocaine, cannabinoids, and amphetamines.
3. History of smoking or tobacco use within 30 days of Screening.
4. Women who are pregnant, breast feeding, or planning to become pregnant during the course of the study.
5. History of allergy, sensitivity, or intolerance to NMDAR ligands including ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, or ketobemidone, as well as current use of such agents.
6. Received an investigational drug or device within 30 days (or 5 half-lives, whichever is longer) of dosing.
7. Previously assigned to treatment during this study (except those who did not take study medication).
8. Screening QT interval corrected for heart rate by Fridericia's formula (QTcF) \> 450 (males) or 470 (females) millisecond (msec) or an ECG that is not suitable for QT measurements (e.g., poorly defined termination of T-wave in the investigator's opinion).
9. Type I or Type II diabetes.
10. History of severe renal or hepatic impairment, in the opinion of the investigator or the sponsor-designated medical monitor.
11. History of excessive bleeding, blood thinners within 6 months, antibiotics or infection within 3 months (CSF cohort only), lumbar spine abnormality, history of elevated intracranial pressure, normal pressure hydrocephalus or other neurological conditions considered clinically significant by the investigator.
12. Human immunodeficiency virus infection, hepatitis, or other ongoing infectious disease that the investigator considers clinically significant.
13. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) in the last 5 years, with the exception of successfully treated non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
14. History of seizures.
15. History of gastrointestinal disease or surgery (except simple appendectomy or hernia repair), which can influence the absorption of the study drug.
16. History of any type of psychosis (including but not limited to bipolar disease or schizophrenia).
17. Medical history or conditions that, in the opinion of the investigator, would preclude safe study participation, or interfere with study procedures/assessments.
18. Evidence of an infection at the time of clinic admission, in the opinion of the investigator.
19. Poor venous access.
20. Use of prescription or over-the-counter medications, including herbal therapies within 7 days prior to dosing, or during the treatment and follow-up periods. Use of St. John's wort within 14 days prior to dosing, or during the treatment and follow-up periods. Occasional aspirin may be used at the investigator's discretion.
21. Unable to eat a standardized meal offered by the study center.
22. Donated or had a loss of blood or plasma within 8 weeks prior to dosing.
23. Grapefruit juice or Seville oranges within 14 days prior to dosing or during the dosing period.
24. Heart rate ≤ 45 beats per minutes.

Primary outcomes:
measure: Number of subjects with adverse events
timeFrame: Subjects will be followed for up to 30 days post-dose
Secondary outcomes:
measure: Cmax of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Tmax of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: AUC of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Half-life of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Clearance of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Volume of distribution of NYX-2925
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Renal elimination of NYX-2925
timeFrame: 0-4, 4-8, 8-12, 12-16, and 16-24 hours post dose.
measure: Food effect of NYX-2925 following consumption of a high-fat, high-caloric meal
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: CSF penetration of NYX-2925 in CSF cohort
timeFrame: 1, 2, 2.5, and 8 hours post-dose
Other outcomes:
Locations:
city: West Bend
country: United States
facility: Spaulding Clinical
state: Wisconsin
Study officials:
affiliation: Spaulding Clinical Research LLC
name: Carlos Sanabria, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aptinyx Inc.
name: Laurel Sindelar
role: STUDY_DIRECTOR
References: