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
Overview
- Phase
- Phase 1
- Intervention
- MEB-1170
- Conditions
- Pain
- Sponsor
- Mebias Discovery, Inc
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
- Status
- Recruiting
- Last Updated
- 3 years ago
Overview
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:
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects.
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects.
- 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •To be eligible for this study, subjects must meet all of the following inclusion criteria:
- •Provides written IRB-approved informed consent prior to any study procedures.
- •Male or female between 18 and 55 years old (inclusive) at the time of screening.
- •In good general health at screening, free from clinically significant unstable medical, surgical or psychiatric illness, at the discretion of the Investigator.
- •Subjects have a BMI between ≥ 18.0 and ≤ 32.0 kg/m2 at screening.
- •Vital signs (measured in supine position after a 5-minute rest) at screening:
- •Systolic blood pressure ≥90 and ≤140 mmHg
- •Diastolic blood pressure ≥50 and ≤ 90 mmHg
- •Heart rate ≥45 and ≤100 bpm
- •Temperature ≥35.5 °C and ≤ 37.5 °C
Exclusion Criteria
- •To be eligible for this study, subjects must not meet any of the following exclusion criteria:
- •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.
- •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.
- •Clinically significant infection within 28 days of the start of dosing, or infections requiring parenteral antibiotics within the 6 months prior to screening.
- •Clinically significant surgical procedure within 3 months of screening, at the discretion of the Investigator.
- •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.
- •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.
- •History or presence at screening or baseline of a condition associated with significant immunosuppression.
- •Positive test for hepatitis C (HCV), hepatitis B (HBsAg), COVID, or human immunodeficiency virus (HIV) antibody at screening.
- •Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules.
Arms & Interventions
A2a MEB-1170
Single MEB-1170 Sentinel 60 mg Dose
Intervention: MEB-1170
A1a Placebo
Single Sentinel Placebo Comparator for 20 mg Dose of MEB-1170
Intervention: Placebo
A1a MEB-1170
Single MEB-1170 Sentinel 20 mg Dose
Intervention: MEB-1170
A1b Placebo
Single Placebo comparator for 20 mg dose cohort of MEB-1170
Intervention: Placebo
A1b MEB-1170
Single MEB-1170 20 mg dose cohort
Intervention: MEB-1170
A2a Placebo
Single Sentinel Placebo Comparator for 60 mg Dose of MEB-1170
Intervention: Placebo
A2b Placebo
Single Placebo comparator for 60 mg dose cohort of MEB-1170
Intervention: Placebo
A2b MEB-1170
Single MEB-1170 60 mg dose cohort
Intervention: MEB-1170
A3a Placebo
Single Sentinel Placebo Comparator for 120 mg Dose of MEB-1170
Intervention: Placebo
A3a MEB-1170
Single MEB-1170 Sentinel 120 mg Dose
Intervention: MEB-1170
A3b Placebo
Single Placebo comparator for 120 mg dose cohort of MEB-1170
Intervention: Placebo
A3b MEB-1170
Single MEB-1170 120 mg dose cohort
Intervention: MEB-1170
A4a Placebo
Single Sentinel Placebo Comparator for 200 mg Dose of MEB-1170
Intervention: Placebo
A4a MEB-1170
Single MEB-1170 Sentinel 200 mg Dose
Intervention: MEB-1170
A4b Placebo
Single Placebo comparator for 200 mg dose cohort of MEB-1170
Intervention: Placebo
A4b MEB-1170
Single MEB-1170 200 mg dose cohort
Intervention: MEB-1170
A5a Placebo
Single Sentinel Placebo Comparator for 400 mg Dose of MEB-1170
Intervention: Placebo
A5a MEB-1170
Single MEB-1170 Sentinel 400 mg Dose
Intervention: MEB-1170
A5b Placebo
Single Placebo comparator for 400 mg dose cohort of MEB-1170
Intervention: Placebo
A5b MEB-1170
Single MEB-1170 400 mg dose cohort
Intervention: MEB-1170
B1 Placebo
MAD Placebo 60 mg comparator cohort of MEB-1170
Intervention: Placebo
B1 MEB-1170
MAD 60 mg MEB-1170 cohort
Intervention: MEB-1170
B2 Placebo
MAD Placebo 100 mg comparator cohort of MEB-1170
Intervention: Placebo
B2 MEB-1170
MAD 100 mg MEB-1170 cohort
Intervention: MEB-1170
B3 Placebo
MAD Placebo 200 mg comparator cohort of MEB-1170
Intervention: Placebo
B3 MEB-1170
MAD 200 mg MEB-1170 cohort
Intervention: MEB-1170
B4 Placebo
MAD Placebo 400 mg comparator cohort of MEB-1170
Intervention: Placebo
B4 MEB-1170
MAD 400 mg MEB-1170 cohort
Intervention: MEB-1170
A3a Placebo Fed State
Single Sentinel Placebo Comparator for 120 mg Dose of MEB-1170 in Fed State
Intervention: Placebo
A3a MEB-1170 Fed State
Single Sentinel 120 mg Dose of MEB-1170 in Fed State
Intervention: MEB-1170
A3b Placebo Fed State
Single Placebo comparator for 120 mg dose cohort of MEB-1170 in Fed State
Intervention: Placebo
A3b MEB-1170 Fed State
Single MEB-1170 120 mg dose cohort in Fed State
Intervention: MEB-1170
Outcomes
Primary Outcomes
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
Time Frame: Through study completion, approximately 12 months
Hematology parameters to be tested are: • Leukocytes with differential (including Eosinophils (ESN), Neutrophils (NEUT), Basophils (BASO), Lymphocytes (LYM) and Reticulocytes (RETI)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess suicidality risk
Time Frame: Through study completion, approximately 12 months
Utilize C-SSRS to assess suicidality risks. Performed at screening and in both SAD and MAD
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess adverse events
Time Frame: Through study completion, approximately 12 months
Occurrence of all adverse events from first dose through end of study treatment and follow-up last visit will be monitored and treated as adverse events.
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
Time Frame: Through study completion, approximately 12 months
Biochemistry parameters to be tested - Bicarbonate (BICARB)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
Time Frame: Through study completion, approximately 12 months
Macroscopic urinalysis parameters to be tested - Leukocytes (WBC)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
Time Frame: Through study completion, approximately 12 months
Vital sign of respiratory rate will be measured at the time points specified in the study schedules with subjects resting for at least 5 minutes in a supine position. When the time of vital signs measurement coincides with a blood draw, the vital signs will be taken before the scheduled blood draw where possible while ensuring the blood draw is within the window specified in the protocol.
Safety and Tolerability of Single Ascending Doses of MEB-1170 for Fasting SAD and MAD laboratory assessments for blood chemistry
Time Frame: Through study completion, approximately 12 months
Biochemistry parameters to be tested - Glucose (GLU) (fasting labs only)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
Time Frame: Through study completion, approximately 12 months
A 12-lead ECG will be taken at the time points delineated in the study schedules. Additional ECG monitoring may be performed at other times if deemed necessary. Note that triplicate ECGs are required during SAD, while single ECGs are required during MAD. Readout QTcB
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess subjects with a physical exam
Time Frame: Through study completion, approximately 12 months
Complete physical examinations will be performed by a licensed physician, nurse practitioner or physician's assistant at the time points specified in the study schedules to ensure there are no changes compared to baseline assessment physical exams.
Secondary Outcomes
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - AUC(Through study completion, approximately 12 months)
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - Cmax(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response using capnography following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - Cmax(Through study completion, approximately 12 months)
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - AUC(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response of Pupillometry following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response using oximetry following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) effect of analgesia using a Cold Pressor Test following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)