A Three-part Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of MK-2640 in Healthy Participants (Part I) and Participants With Type 1 Diabetes Mellitus (Parts II and III) (MK-2640-001)

A Three-part Study Parts I, II and III: Rising Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of MK-2640 in Healthy Subjects (Part I) and Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of MK-2640 in Subjects With Type 1 Diabetes Mellitus (Part II and Part III).

The purpose of Part I of this study is to evaluate the safety and tolerability of intravenous (IV) doses of MK-2640 in healthy participants and to obtain preliminary plasma pharmacokinetic profiles of MK-2640. The purpose of Parts II and III of this study is to evaluate the safety and tolerability of IV doses of MK-2640 and regular human insulin (RHI), and to evaluate the pharmacokinetic and pharmacodynamic profile of MK-2640 and RHI in participants with type 1 diabetes mellitus (T1DM). Part II will be initiated only if Part I general safety, tolerability and other observed data are supportive of progression to Part II. Part III will be initiated only if Parts I and II general safety, tolerability and other observed data are supportive of progression to Part III.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: MK-2640; Drug: Dextrose; Drug: Rescue medication; Biological: Regular Human Insulin (RHI); Biological: Insulin aspart

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria (Part I):

• healthy male or healthy female of non-child bearing potential
• in good health
• is a non-smoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months

Inclusion Criteria (Parts II and III):

• male or female of non-child bearing potential
• has T1DM for at least 12 months
• on stable doses of insulin
• in good health
• is a nonsmoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months

Exclusion Criteria:

• is mentally or legally incapacitated, or has significant emotional problems at the time of screening visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder of the last 5 years
• has a history of clinically significant endocrine (except T1DM for Part II subjects), gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases
• is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV)
• has a history of cancer (malignancy), except adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix
• has a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food, had major surgery, donated or lost 1 unit of blood within 4 weeks prior to the screening visit
• has participated in another investigational trial within 4 weeks prior to the screening visit
• is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks prior to administration of the initial dose of trial drug, throughout the trial, until the posttrial visit
• consumes greater than 3 glasses of alcoholic beverages daily
• consumes greater than 6 servings of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day.
• is currently a regular or recreational user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months

Exclusion Criteria (Parts II and III):

• has a history of diabetic ketoacidosis in the last 6 months.
• has had one or more severe hypoglycemic episodes associated with hypoglycemic seizures, comas or unconsciousness within 2 weeks prior to dosing
• has used systemic (intravenous, oral, inhaled) glucocorticoids within 3 months of screening or is anticipated to require treatment with systemic glucocorticoids during study participation
• has a history of hypersensitivity to pharmacologic insulins or to any of the inactive ingredients in regular human insulin, or to any E. coli-derived drug product

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part I: MK-2640 (Panel A); Part I: Lowest dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel B); Part I: Low dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel C); Part I: Medium-low dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel D); Part I: Medium dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel E); Part I: Medium-high dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel F); Part I: High dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part I: MK-2640 (Panel G); Part 1: Highest dose of MK-2640 infusion (3 approximately three-hour infusions at escalating rates) and dextrose infusion for 9 hours.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.
EXPERIMENTAL: Part II: MK-2640 followed by RHI; Part II: MK-2640 infusion and dextrose infusion for 9 hours during Period 1 of Part II followed by a 7-day wash-out period followed by RHI infusion and dextrose infusion for 9 hours during Period 2 of Part II. Insulin aspart administered approximately 10 hours before Periods 1 and 2 of Part II.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Biological: Insulin aspart; Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.
EXPERIMENTAL: Part II: RHI followed by MK-2640; Part II: RHI infusion and dextrose infusion for 9 hours during Period 1 of Part II followed by a 7-day wash-out period followed by MK-2640 infusion and dextrose infusion for 9 hours during Period 2 of Part II. Insulin aspart administered approximately 10 hours before Periods 1 and 2 of Part II.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Biological: Insulin aspart; Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.
EXPERIMENTAL: Part III: MK-2640 followed by RHI; Part III: MK-2640 infusion and dextrose infusion for 7 hours during Period 1 of Part III followed by a 7-day wash-out period followed by RHI infusion and dextrose infusion for 7 hours during Period 2 of Part III. Insulin aspart administered approximately 10 hours before Periods 1 and 2 of Part III.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Biological: Insulin aspart; Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.
EXPERIMENTAL: Part III: RHI followed by MK-2640; Part III: RHI infusion and dextrose infusion for 7 hours during Period 1 of Part III followed by a 7-day wash-out period followed by MK-2640 infusion and dextrose infusion for 7 hours during Period 2 of Part III. Insulin aspart administered approximately 10 hours before Periods 1 and 2 of Part III.	Drug: MK-2640; MK-2640 intravenous infusion administered to participant in a fasted state; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level; Drug: Rescue medication; Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Biological: Insulin aspart; Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants who experienced an adverse event	Up to 30 days following last dose
Pharmacokinetic parameter: steady state plasma concentration (Css)	Part I: final 30 minutes of each infusion rate; Parts II and III: final 30 minutes of each interval
Pharmacokinetic parameter: area under the plasma concentration curve from time 0 to infinity (AUC [0 to infinity])	Part I: 18 time points between predose and 600 minutes (min.); Part II: 19 time points between predose and 535 min.; Part III: 18 time points between predose and 415 min. following start of infusion
Pharmacokinetic parameter: clearance (CL)	Part I: final 30 minutes of each infusion rate; Parts II and III: final 30 minutes of each interval
Pharmacokinetic parameter: volume of distribution (Vd)	Part I: final 30 minutes of each infusion rate; Parts II and III: final 30 minutes of each interval
Pharmacokinetic parameter: plasma apparent terminal half-life	Part II: following 9 hour infusion; Part III: following 7 hour infusion
Pharmacodynamic parameter: steady-state glucose infusion-rate (GIR) in Part II	Part II: during the final 60 minutes of the infusion
Number of participants who discontinued study drug due to an adverse event	Part I: 1 day; Parts II and III: 9 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with anti-drug antibody (ADA) formation	Up to 30 days following last dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Krug AW, Visser SAG, Tsai K, Kandala B, Fancourt C, Thornton B, Morrow L, Kaarsholm NC, Bernstein HS, Stoch SA, Crutchlow M, Kelley DE, Iwamoto M. Clinical Evaluation of MK-2640: An Insulin Analog With Glucose-Responsive Properties. Clin Pharmacol Ther. 2019 Feb;105(2):417-425. doi: 10.1002/cpt.1215. Epub 2018 Sep 30.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 26, 2014
• Primary Completion (ACTUAL): July 29, 2016
• Study Completion (ACTUAL): July 29, 2016

Study Registration Dates

• First Submitted: October 16, 2014
• First Submitted That Met QC Criteria: October 20, 2014
• First Posted (ESTIMATE): October 21, 2014

Study Record Updates

• Last Update Posted (ACTUAL): January 15, 2019
• Last Update Submitted That Met QC Criteria: January 11, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Aspart; MK-2640
• Other Study ID Numbers: 2640-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf