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)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT02269735

Collaborator

(none)

Enrollment

Arms

20.1

Actual Duration (Months)

Study Details

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

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

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 :

Nov 26, 2014

Actual Primary Completion Date :

Jul 29, 2016

Actual Study Completion Date :

Jul 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

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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