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)

• ClinicalTrials.gov Identifier: NCT02269735
• Recruitment Status: Completed
• First Posted: October 21, 2014
• Last Update Posted: January 15, 2019
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: MK-2640; Biological: Regular Human Insulin (RHI); Drug: Dextrose; Biological: Insulin aspart; Drug: Rescue medication	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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).
• Actual Study Start Date: November 26, 2014
• Actual Primary Completion Date: July 29, 2016
• Actual Study Completion Date: July 29, 2016

Arms and Interventions

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; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a 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.; 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: 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; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a 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.; 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 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; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a 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.; 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 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; Biological: Regular Human Insulin (RHI); RHI 100 units/mL intravenous infusion to maintain target glycemic level; Drug: Dextrose; Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a 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.; 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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Number of participants with anti-drug antibody (ADA) formation [ Time Frame: Up to 30 days following last dose ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

Publications of Results:

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.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02269735
• Other Study ID Numbers: 2640-001
• First Posted: October 21, 2014
• Last Update Posted: January 15, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

Additional relevant MeSH terms:

MK-2640; Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Insulin; Insulin, Globin Zinc; Insulin Aspart; Hypoglycemic Agents; Physiological Effects of Drugs