Clinical trial NCT05748119: A Study to Assess the Safety of MEB-1170 in Healthy Subjects
Official title: A Phase I, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEB-1170 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Pain
Lead sponsor: Mebias Discovery, Inc
Sponsor class: INDUSTRY
First posted: 2023-02-28
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Primary Objective: To determine the safety and tolerability of single and multiple ascending oral doses of MEB-1170 in healthy subjects.

Secondary Objectives:

1. To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects.
2. To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects.
3. To assess the pharmacodynamic (PD) response following single and multiple oral doses of MEB-1170

Detailed description: Study Design: This will be a double-blind, placebo-controlled, single and multiple oral dose study conducted in two parts:

Part A: SAD+FE:

Part A will comprise a single ascending dose (SAD), sequential cohort study, incorporating a food effect (FE) evaluation. Up to 40 subjects will be studied in 5 cohorts (Cohorts A1 to A5), each cohort consisting of 8 subjects (6 treated with MEB-1170, 2 treated with placebo).

Subjects in Cohorts A1, A2, A4 and A5 will participate in 1 treatment period only, residing at the CRU from Day -1 (the day before dosing) to Day 3 (48 hours postdose). Subjects in Cohort A3 will participate in 2 treatment periods (once in fasted state, once in fed state) separated by a minimum of 6 days. All subjects will return for a poststudy visit approximately 5 to 7 days after their final dose.

Each Cohort will include sentinel dosing such that two subjects (one active and one placebo) will be dosed at least 48 hours before the remaining subjects in the cohort. Continuation to dose the remaining subjects will be at the Investigator's discretion, in consultation with the Sponsor.

All doses will be administered in accordance with a randomization schedule in the fasted state in the morning of Day 1, except for Cohort A3 Treatment Period 2 where MEB-1170 will be given 30 minutes after start of a high fat breakfast (see below). Each subject in Cohorts A1, A2, A4 and A5 will receive only a single dose of MEB-1170 or placebo during the study.

Subjects in Cohort A3 will participate in a 2-period treatment design in which they will be assessed for both the single-dose of MEB-1170 in a Fed and in a Fasted condition. Subjects will receive the same treatment (ie, either MEB-1170 or placebo) in both Period 1 and Period 2, and thus subjects will receive either two single doses of MEB-1170 or two single doses of placebo during the study. Fasting state assessments will occur in Period 1 and Fed state assessments in Period 2.

SAD Assessments:

* Safety/tolerability throughout study
* Physical examination, vital signs, clinical laboratory findings, and ECG
* PK concentrations
* PD assessments (pupillometry, capnography, oximetry, cold pressor testing)

Following the completion of each cohort, a safety and tolerability review will be conducted by the Safety Review Committee (SRC; see below) prior to proceeding to the next cohort. Based on this review, a decision may be made to continue the study as planned, repeat the same dose in another Cohort, assess a lower dose, add an intermediate dose, or terminate the study. Additionally, if no dose limiting toxicities are seen, further cohorts at higher doses may be added.

Part B: MAD:

Part B will comprise a multiple ascending dose (MAD), sequential cohort study. This part will be initiated after the first three SAD cohorts have been fully evaluated for safety and tolerability and the SRC has concluded that the MAD portion may commence. Up to 32 subjects will be studied in 4 cohorts (Cohorts B1 to B4), each cohort consisting of 8 subjects.

In each of Cohorts B1 to B4, 6 subjects will receive MEB-1170 and 2 will receive placebo. Once-daily dosing will occur on Days 1 to 7, inclusive, for all subjects. Each subject will participate in 1 treatment period only, residing at the CRU from the evening of Day -1 (the day before dosing) until the morning of Day 9 (48 hours after the final dose on Day 7).

All subjects will return for a poststudy visit 6 to 8 days after their final dose for a final safety assessment.

Dose levels to be studied will be determined following review of data from Part A. Following completion of each cohort in Part B, a safety and tolerability review will be conducted by the SRC prior to proceeding to the next cohort (see below). Based on this review, a decision may be made to continue the study as planned, repeat the same dose in another Cohort, assess a lower dose, add an intermediate dose or terminate the study. Additionally, if no dose limiting toxicities are seen, further cohorts at higher doses may be added.

MAD Assessments:

* Safety/tolerability throughout study
* Physical examinations, vital signs, clinical laboratory findings, and ECG
* PK concentration (see Schedule of Assessments for details)
* PD assessments (pupillometry, capnography, cold pressor testing, oximetry)

Reference Therapy, Dose and Mode of Administration:

Matching placebo capsule administered orally.

Eligibility criteria: Inclusion Criteria:

To be eligible for this study, subjects must meet all of the following inclusion criteria:

1. Provides written IRB-approved informed consent prior to any study procedures.
2. Male or female between 18 and 55 years old (inclusive) at the time of screening.
3. In good general health at screening, free from clinically significant unstable medical, surgical or psychiatric illness, at the discretion of the Investigator.
4. Subjects have a BMI between ≥ 18.0 and ≤ 32.0 kg/m2 at screening.
5. Vital signs (measured in supine position after a 5-minute rest) at screening:

   1. Systolic blood pressure ≥90 and ≤140 mmHg
   2. Diastolic blood pressure ≥50 and ≤ 90 mmHg
   3. Heart rate ≥45 and ≤100 bpm
   4. Temperature ≥35.5 °C and ≤ 37.5 °C
   5. Vital signs may be repeated once, within a minimum of 10 minutes of the completion of the last set of vital signs (while maintaining supine position until the repeated set of vital signs are collected), if it is suspected that falsely high or low levels have been obtained.
6. Adequate venous access to allow collection of multiple blood samples.
7. Negative Covid PCR test upon admission to the CRU.

   a. Subjects in Cohort A3 will need a second COVID test prior to admission the CRU for Period 2.
8. No relevant dietary restrictions and willingness to consume standard meals and snacks.
9. Willing to comply with all study procedures and requirements
10. Ability to tolerate the cold pressor test (determined at screening)
11. Women of childbearing potential (WOCBP) must be non-pregnant and non-lactating, and must use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period (please see Section 9.4.2 for acceptable methods of contraception). Abstinence as a lifestyle choice is also acceptable. WOCBP must have a negative serum pregnancy test at Screening and negative urine pregnancy test at Day -1 and be willing to have additional pregnancy tests as required throughout the study. WOCBP must also use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period and for 30 days after the last dose (please see Section 10.4.2 for acceptable methods of contraception). Women not of childbearing potential must be post menopausal for ≥12 months or be surgically sterile. Hysterectomy with retention of ovary function is permitted. Post-menopausal status will be confirmed through testing of FSH levels ≥ 40 IU/mL at screening for amenorrhoeic female subjects.
12. Male subjects must be surgically sterile (\> 30 days since vasectomy per medical history or verbal confirmation), or, if engaged in sexual relations with a WOCBP, the subject and his partner must use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period and 30 days after the last dose (please see Section 9.4.2 for acceptable methods of contraception). Abstinence as a lifestyle choice is also acceptable.

Exclusion Criteria:

To be eligible for this study, subjects must not meet any of the following exclusion criteria:

1. Pregnant or lactating at screening or baseline or planning to become pregnant (self or partner) at any time during the study, including the specified follow-up period.
2. History or presence of malignancy at screening or baseline, with the exception of adequately treated localised skin cancer (basal cell or squamous cell carcinoma) or carcinoma in-situ of the cervix.
3. Clinically significant infection within 28 days of the start of dosing, or infections requiring parenteral antibiotics within the 6 months prior to screening.
4. Clinically significant surgical procedure within 3 months of screening, at the discretion of the Investigator.
5. Currently suffering from clinically significant systemic allergic disease at screening or baseline or has a history of significant drug allergies including a history of anaphylactic reaction; allergic reaction due to any drug which led to significant morbidity.
6. Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs within 3 months prior to study treatment administration; corticosteroids are permitted at the discretion of the Investigator), or exposure to any significantly immune suppressing drug within 30 days prior to screening or 5 half lives, whichever is longer.
7. History or presence at screening or baseline of a condition associated with significant immunosuppression.
8. Positive test for hepatitis C (HCV), hepatitis B (HBsAg), COVID, or human immunodeficiency virus (HIV) antibody at screening.
9. Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules.
10. Any condition at screening or baseline (eg, chronic diarrhea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism or excretion, at the discretion of the Investigator.
11. History or presence at screening or baseline of clinically significant cardiac arrhythmia or congenital long QT syndrome.
12. QT interval corrected using Fridericia's formula (QTcF) \> 450 msec for males or \>470 msec for females.
13. Use of tobacco or nicotine containing products in the previous month prior to dosing or a positive urine cotinine test at Screening or Baseline.
14. Lack of willingness to abstain from the consumption of tobacco or nicotine-containing products throughout the duration of the study and until completion of the final Follow-up visit.
15. Regular alcohol consumption defined as \> 21 alcohol units per week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine) or the subject is unwilling to abstain from alcohol for 48 h prior to admission and 48 h prior to Follow-up study visit.
16. Positive toxicology screening panel \[urine test, including qualitative identification of barbiturates, tetrahydrocannabinol (THC), amphetamines, benzodiazepines, opiates and cocaine\] or alcohol test (breath or urine) during Screening or at any time during the Study.
17. History of substance abuse or dependency or history of recreational IV drug use, over the last 5 years.
18. Use of any prescription drugs (other than permitted contraception) within 14 days prior to dosing or throughout the duration of the study, without prior approval of the Investigator and written approval of the CRO Medical Monitor.
19. Use of OTC medication including nonsteroidal anti-inflammatory drugs (NSAIDs), herbal remedies, supplements, or vitamins within 7 days prior to dosing. An exception to this is use of acetaminophen up to 4g/day to treat mild discomfort.
20. Use of any investigational drug or device within 30 days or 5 half-lives, whichever is longer, prior to screening.
21. Clinically significant blood loss, or blood or blood product donation \>250 mL within 28 days of screening.
22. Subject is unwilling to refrain from strenuous exercise from 7 days prior to admission to the clinical trial unit until completion of the final onsite follow-up visit, where strenuous exercise is defined as a significant increase in the Subject's usual level of physical activity.
23. Any other reason that, in the opinion of the Investigator, might interfere with the evaluation required by the study.

Primary outcomes:
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single Ascending Doses of MEB-1170 for Fasting SAD and MAD laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess adverse events
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess suicidality risk
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
timeFrame: Through study completion, approximately 12 months
measure: Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess subjects with a physical exam
timeFrame: Through study completion, approximately 12 months
Secondary outcomes:
measure: To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - AUC
timeFrame: Through study completion, approximately 12 months
measure: To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - Cmax
timeFrame: Through study completion, approximately 12 months
measure: To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - AUC
timeFrame: Through study completion, approximately 12 months
measure: To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - Cmax
timeFrame: Through study completion, approximately 12 months
measure: To assess the pharmacodynamic (PD) response of Pupillometry following single and multiple oral doses of MEB-1170
timeFrame: Through study completion, approximately 12 months
measure: To assess the pharmacodynamic (PD) response using capnography following single and multiple oral doses of MEB-1170
timeFrame: Through study completion, approximately 12 months
measure: To assess the pharmacodynamic (PD) response using oximetry following single and multiple oral doses of MEB-1170
timeFrame: Through study completion, approximately 12 months
measure: To assess the pharmacodynamic (PD) effect of analgesia using a Cold Pressor Test following single and multiple oral doses of MEB-1170
timeFrame: Through study completion, approximately 12 months
Other outcomes:
Locations:
city: Daytona Beach
country: United States
facility: Labcorp Clinical Research Unit, Inc
state: Florida
Study officials:
References: