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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)

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

Tracking Information
First Submitted Date  ICMJE October 16, 2014
First Posted Date  ICMJE October 21, 2014
Last Update Posted Date January 15, 2019
Actual Study Start Date  ICMJE November 26, 2014
Actual Primary Completion Date July 29, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 29, 2015)
  • Number of participants who experienced an adverse event [ Time Frame: Up to 30 days following last dose ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Pharmacokinetic parameter: plasma apparent terminal half-life [ Time Frame: Part II: following 9 hour infusion; Part III: following 7 hour infusion ]
  • Pharmacodynamic parameter: steady-state glucose infusion-rate (GIR) in Part II [ Time Frame: Part II: during the final 60 minutes of the infusion ]
  • Number of participants who discontinued study drug due to an adverse event [ Time Frame: Part I: 1 day; Parts II and III: 9 days ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 20, 2014)
  • Number of participants who experienced an adverse event [ Time Frame: Up to 28 days following last dose ]
  • Pharmacokinetic parameter: steady state plasma concentration (Css) [ Time Frame: Part I: final 30 minutes of each infusion rate; Part II: final 30 minutes of each interval ]
  • Pharmacokinetic parameter: area under the plasma concentration curve from time 0 to infinity (AUC [0 to infinity]) [ Time Frame: Part I: predose, 10, 30, 90, 170, 190, 210, 270, 350, 370, 390, 450, 530, 545, 550, 560, 580, and 600 minutes; Part II: predose, 140, 160, 175, 210, 240, 270, 330, 345, 355, 390, 420, 450, 510, 525, and 535 minutes following start of infusion ]
  • Pharmacokinetic parameter: clearance (CL) [ Time Frame: Part I: final 30 minutes of each infusion rate; Part II: final 30 minutes of each interval ]
  • Pharmacokinetic parameter: volume of distribution (Vd) [ Time Frame: Part I: final 30 minutes of each infusion rate; Part II: final 30 minutes of each interval ]
  • Pharmacokinetic parameter: plasma apparent terminal half-life [ Time Frame: Following 9 hour infusion ]
  • Pharmacodynamic parameter: steady-state glucose infusion-rate (GIR) in Part II [ Time Frame: during the final 60 minutes of the infusion ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2015)
Number of participants with anti-drug antibody (ADA) formation [ Time Frame: Up to 30 days following last dose ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 20, 2014)
Number of participants with anti-drug antibody (ADA) formation [ Time Frame: Up to 28 days following last dose ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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).
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes Mellitus
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Drug: Dextrose
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Biological: Regular Human Insulin (RHI)
    • Drug: Dextrose
    • Biological: Insulin aspart
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Biological: Regular Human Insulin (RHI)
    • Drug: Dextrose
    • Biological: Insulin aspart
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Biological: Regular Human Insulin (RHI)
    • Drug: Dextrose
    • Biological: Insulin aspart
    • Drug: Rescue medication
  • 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.
    Interventions:
    • Drug: MK-2640
    • Biological: Regular Human Insulin (RHI)
    • Drug: Dextrose
    • Biological: Insulin aspart
    • Drug: Rescue medication
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 29, 2015)
74
Original Estimated Enrollment  ICMJE
 (submitted: October 20, 2014)
40
Actual Study Completion Date  ICMJE July 29, 2016
Actual Primary Completion Date July 29, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT02269735
Other Study ID Numbers  ICMJE 2640-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP