A Single and Multiple-Dose Study of MK-8521 in Healthy and Obese Males (MK-8521-002)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: MK-8521 200μg; Drug: MK-8521 50/72μg; Drug: MK-8521 100μg; Drug: MK-8521 100/150μg; Drug: MK-8521 300μg; Drug: Placebo; Drug: MK-8521 72/125μg; Drug: MK-8521 175μg; Drug: MK-8521 150μg; Drug: MK-8521 125μg; Drug: MK-8521 125/150μg; Drug: MK-8521 35μg

Study type: Interventional

Funder types: Industry

Identifiers

NCT02055547

2013-000083-28 (EudraCT Number)

MK-8521-002 (Other Identifier)

8521-002

Details and patient eligibility

About

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.

Full 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.

Enrollment: 61 patients

Sex: Male

Ages: 18 to 70 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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61 participants in 19 patient groups, including a placebo group

Part 1 - Panel A - MK-8521 100μg > PBO

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and matching placebo (PBO) in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 100μg

Part 1 - Panel A - PBO > MK-8521 300μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 300μg

Part 1 - Panel A - MK-8521 100μg > MK-8521 300μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: MK-8521 300μg

Drug: MK-8521 100μg

Part 1 - Panel B - MK-8521 150μg > PBO > MK-8521 175μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, PBO in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: MK-8521 150μg

Drug: Placebo

Drug: MK-8521 175μg

Part 1- Panel B- MK-8521 150μg > MK-8521 200μg > MK-8521 175μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: MK-8521 200μg

Drug: MK-8521 150μg

Drug: MK-8521 175μg

Part 1 - Panel B - MK-8521 150μg > MK-8521 200μg > PBO

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: MK-8521 200μg

Drug: MK-8521 150μg

Drug: Placebo

Part 1 - Panel B - PBO > MK-8521 200μg > MK-8521 175μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received PBO in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: MK-8521 200μg

Drug: Placebo

Drug: MK-8521 175μg

Part 2 - Panel C - MK-8521 50μg > MK-8521 72μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 50μg Days 1 to 5 and MK-8521 72μg Days 6 to 10 in a single treatment period.

Treatment:

Drug: MK-8521 50/72μg

Part 2 - Panel D - MK-8521 100μg > MK-8521 150μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.

Treatment:

Drug: MK-8521 100/150μg

Drug: MK-8521 100μg

Part 2 - Panel E - MK-8521 125μg > MK-8521 150μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.

Treatment:

Drug: MK-8521 125/150μg

Drug: MK-8521 125μg

Part 2 - Panel F - MK-8521 72μg > MK-8521 125μg

Experimental group

Description:

Obese male participants of 45 to 65 years of age received a single dose of MK-8521 72μg Days 1 to 7 and MK-8521 125μg Days 8 to 14 in a single treatment period.

Treatment:

Drug: MK-8521 72/125μg

Drug: MK-8521 125μg

Part 2 - Panels C+D+E - Pooled Placebo

Placebo Comparator group

Description:

Healthy male participants of 18 to 45 years of age received PBO once daily for 10 days.

Treatment:

Drug: Placebo

Part 2 - Panel F - Placebo

Placebo Comparator group

Description:

Obese male participants of 45 to 65 years of age received a single dose of PBO Days 1 to 14.

Treatment:

Drug: Placebo

Part 3 - Panel H - MK-8521 125μg > MK-8521 35μg > PBO

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, MK-8521 35μg (low dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg

Part 3 - Panel H - MK-8521 35μg > PBO > MK-8521 125μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, PBO MK-8521 in the second treatment period, and 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg

Part 3 - Panel H - PBO > MK- 8521 125μg > MK-8521 35μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 125μg (high dose) in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg

Part 3 - Panel H - PBO > MK- 8521 35μg > MK-8521 125μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 35μg (low dose) in the second treatment period, and MK-8521 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg

Part 3 - Panel H - MK-8521 125μg > PBO > MK-8521 35μg

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, PBO in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg

Part 3 - Panel H - MK-8521 35μg > MK-8521 125μg > PBO

Experimental group

Description:

Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, MK-8521 125μg (high dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.

Treatment:

Drug: Placebo

Drug: MK-8521 35μg

Drug: MK-8521 125μg