Clinical trial NCT02055547: A Single and Multiple-Dose Study of MK-8521 in Healthy and Obese Males (MK-8521-002)
Official title: A Single and Multiple-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8521 in Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-02-05
Enrollment: 61
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parts 1 and 2 were parallel in design and Part 3 was crossover in design.
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-8521.

Part 1 primary hypothesis: Administration of single subcutaneous (SC) doses of MK-8521 is sufficiently safe and well- tolerated in healthy participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.

Part 2: Administration of multiple once daily SC doses of MK-8521 is sufficiently safe and well-tolerated in healthy lean and obese participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.

Detailed description: This was a 3 part, randomized, single and multiple ascending-dose trial that evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MK-8521 in healthy non-obese male (Part 1-Panels A and B, Panels C, D, and E of Part 2, and Part 3 Panel H) participants between the ages of 18 and 45 years and obese male participants (Part 2, Panel F) 45 to 65 years of age. An optional Panel G in Part 2 per protocol did not occur.

Part 1 was a single rising dose study to assess the safety and pharmacokinetics of single subcutaneous (SC) doses of MK-8521. Two panels of 8 healthy young non-obese male participants were dosed in up to 3 alternating dosing periods of MK-8521 or placebo (in a 6:2 ratio). Participants had a minimum 7 day washout between dosing periods.

Part 2 was a multiple-rising dose study to assess the safety and pharmacokinetics of multiple SC doses of MK-8521. Three panels (C-E) of 8 healthy young non-obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 10 consecutive days. One panel (Panel F) of 8 older obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 14 consecutive days.

Part 3 was a single dose, 3-period crossover study in 12 healthy lean male participants. Participants were randomized into 6 treatment groups and received a sequence of 3 treatments (MK-8521 at 35μg, 125μg and placebo). All participants in Part 3 received MK-8521 (high dose of 125μg and low dose of 35 μg) and placebo. There was a minimum 7 day washout between each dosing period for each individual participant.

Eligibility criteria: Inclusion Criteria:

* Males of either 18 to 45 or 45 to 70 years of age depending on the component of the study
* Body Mass Index between either 18-25 or 30-40 kg/m\^2 depending on the component of the study
* Is in good health
* Is a non-smoker and/or has not used nicotine for at least 3 months

Exclusion Criteria:

* Is mentally or legally incapacitated, has significant emotional problems or has a history of psychiatric disorders in the past 5 years
* Has a history of the following abnormalities or diseases: endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological.
* History of cancer
* History of significant multiple or severe allergies or has had an anaphylactic reaction or significant intolerability to drugs or food
* Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV)
* Had major surgery, donated or lost 1 unit (500 mL) of blood or participated in another study within prior 4 weeks
* Has irritable bowel disease or recurrent nausea, vomiting, diarrhea or abdominal pain
* History of acute or chronic pancreatitis
* Uses 2 weeks prior to trial, or anticipates using during trial, medications, drugs or herbal remedies such as St. John's Wort
* Consumes greater than 3 glasses of alcohol per day
* Consumes greater than 6 servings of caffeinated beverages per day
* Regularly uses illicit drugs or has a history of drug (including alcohol) abuse within prior 3 months
* Has known hypersensitivity to glucagon or any glucagon like peptide 1 (GLP-1) receptor agonist
* Is unwilling/unable to consume standardized meals and/or is on a carbohydrate restricted diet
* Has history of hypersensitivity to pharmacologic insulins

Primary outcomes:
measure: Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)
timeFrame: From Day 1 through post-trial visit (Up to 8 weeks)
measure: Number of Participants Who Discontinued Treatment Due to an AE (Part 1)
timeFrame: Up to 8 weeks (Part 1)
measure: Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
measure: Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
measure: Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
measure: Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
measure: Number of Participants With an Adverse Event (AE) (Part 2)
timeFrame: From Day 1 through post-trial visit (Up to 7 weeks)
measure: Number of Participants Who Discontinued Treatment Due to an AE (Part 2)
timeFrame: Up to 7 weeks (Part 2)
measure: AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
timeFrame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
measure: AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Days 1, 7 and 14 (Part 2) (Panel F)
measure: Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
timeFrame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
measure: Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Days 1, 7 and 14 (Part 2) (Panel F)
measure: Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
timeFrame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
measure: Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Days 1, 7 and 14 (Part 2) (Panel F)
measure: Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
timeFrame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
measure: Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Days 1, 7 and 14 (Part 2) (Panel F)
measure: Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)
timeFrame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
measure: Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)
timeFrame: Days 1, 7 and 14 (Part 2) (Panel F)
measure: Number of Participants With an Adverse Event (AE) (Part 3)
timeFrame: Up to 6 weeks (Part 3)
measure: Number of Participants Who Discontinued Treatment Due to an AE (Part 3)
timeFrame: Up to 6 weeks (Part 3)
measure: Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)
timeFrame: From -10 to 160 minutes after GGI on Day 1 (Part 3)
Secondary outcomes:
measure: Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)
timeFrame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)
timeFrame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)
timeFrame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)
measure: Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10
measure: Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), up to 16 hrs on Day -1, predose & up to 24 hours postdose on Days 1, 8, and 14
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10
measure: Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
timeFrame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14
measure: Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)
timeFrame: From -10 to 160 minutes after GGI on Day 1
measure: Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)
timeFrame: From -10 to 160 minutes after GGI on Day 1
measure: Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)
timeFrame: From -10 to 160 minutes after GGI on Day 1
measure: Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)
timeFrame: From -10 to 160 minutes after GGI on Day 1
measure: Area Under the Curve (AUC) 0-∞ for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)
timeFrame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)
measure: Area Under the Curve (AUC) 0-24hr. for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)
timeFrame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)
measure: Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)
timeFrame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)
measure: Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)
timeFrame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)
measure: Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)
timeFrame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI(Part 3)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Study Director
role: STUDY_DIRECTOR
References: