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)

Study Overview
=================
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.

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).

Conditions
-----------------
Type 1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: MK-2640
* Biological: Regular Human Insulin (RHI)
* Drug: Dextrose
* Biological: Insulin aspart
* Drug: Rescue medication


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: MK-2640 (Panel A)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel B)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel C)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel D)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel E)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel F)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part I: MK-2640 (Panel G)<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part II: MK-2640 followed by RHI<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Biological: Regular Human Insulin (RHI)<br>* RHI 100 units/mL intravenous infusion to maintain target glycemic level<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Biological: Insulin aspart<br>* Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part II: RHI followed by MK-2640<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Biological: Regular Human Insulin (RHI)<br>* RHI 100 units/mL intravenous infusion to maintain target glycemic level<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Biological: Insulin aspart<br>* Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part III: MK-2640 followed by RHI<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Biological: Regular Human Insulin (RHI)<br>* RHI 100 units/mL intravenous infusion to maintain target glycemic level<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Biological: Insulin aspart<br>* Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|
| Experimental: Part III: RHI followed by MK-2640<br>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<br>* MK-2640 intravenous infusion administered to participant in a fasted state<br>Biological: Regular Human Insulin (RHI)<br>* RHI 100 units/mL intravenous infusion to maintain target glycemic level<br>Drug: Dextrose<br>* Dextrose 20% or 50% intravenous infusion for approximately 9 or 7 hours, as appropriate to attain a target glycemic level<br>Biological: Insulin aspart<br>* Insulin aspart subcutaneous injection or intravenous infusion the evening before each period in Parts II and III to achieve/maintain glycemic target.<br>Drug: Rescue medication<br>* Rescue medication may be administered for hypotension or mild to moderate infusion reaction. Rescue medication may include epinephrine, antihistamines, steroids, or acetaminophen/paracetamol.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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