Single Ascending Dose Study of MK-1092 in Healthy Participants and in Participants With Type 1 and Type 2 Diabetes Mellitus (MK-1092-001)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus

Treatments: Drug: MK-1092, 16 nmol/kg; Drug: Lispro 1.2 nmol/kg; Drug: MK-1092, 64 nmol/kg; Drug: MK-1092, 32 nmol/kg; Drug: Placebo to glargine; Drug: MK-1092, 8.0 nmol/kg; Drug: Glargine 3.0 nmol/kg; Other: Dextrose; Drug: Placebo to MK-1092; Biological: Insulin; Drug: MK-1092, 4.0 nmol/kg

Study type: Interventional

Funder types: Industry

Identifiers

NCT03170544

1092-001

MK-1092-001 (Other Identifier)

Details and patient eligibility

About

This is an active- and placebo-controlled, single-site, four-part trial of MK-1092 in healthy adult participants, in participants with type 1 diabetes mellitus (T1DM), and in participants with type 2 diabetes mellitus (T2DM). The primary hypothesis for this study is that at a dose with sufficient safety, the mean maximal glucose infusion rate (GIRmax) after single subcutaneous (SC) administration of MK-1092 in adult participants with T1DM is within an acceptable range. (Part 3)

Full description

There will be 4 parts in this study. In Part 1, healthy adult participants will be randomized to receive blinded MK-1092 subcutaneously (SC) or glargine SC, as a single dose under the euglycemic clamp. Once a safe and tolerated dose that achieves GIRmax is identified in Part 1, Part 2 will start. In Part 2, 4 different healthy adult participants will be enrolled in a single panel and receive open-label MK-1092 SC as a single dose under the euglycemic clamp and also receive an intravenous infusion of Humalog®. In Part 3, adult participants with T1DM will be randomized to receive blinded MK-1092 SC or insulin glargine SC, as a single dose under the euglycemic clamp. Part 4 includes a 3-period (Periods 1, 2, and 3) design that will explore up to 3 single subcutaneous doses of MK-1092 or insulin glargine in participants with Type 2 diabetes mellitus.

Enrollment: 69 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Subject Inclusion Criteria

All participants

• Be a healthy male, or healthy female participant (excluding diabetes mellitus in Part 3 participants) of non-child bearing potential. A female non-child bearing potential is one who is postmenopausal without menses for at least 1 year or whose status is post hysterectomy, bilateral oophorectomy, or tubal ligation.
• Be judged to be in good health based on medical history, physical exam, vital sign measurements, electrocardiogram (ECG) and laboratory safety tests
• Have adequate venous access to support execution of trial procedures

For Parts 1 and 2 (Healthy adult participants)

• Healthy male and female participants between the ages of 18 and 50 years (inclusive)
• Have a Body Mass Index (BMI) ≥18.5 kg/m^2 and ≤28.0 kg/m^2 at screening
• Have fasting blood glucose values at screening must be <100 mg/dL
• Be a non-smoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months.

For Part 3 (Adult participants with T1DM):

• Be male, or female of non-childbearing potential between 18 to 60 years of age
• Have a diagnosis of T1DM as defined by standard diagnostic criteria for ≥12 months at time of the pretrial (screening) visit
• Have a BMI ≥18.5 kg/m^2 and ≤32 kg/m^2 at screening.
• Be on stable doses of basal insulin over the 2-week period prior to screening and over the 2 weeks prior to dosing
• Have a total daily insulin requirement (basal plus prandial) of ≤1.2 units/kg at screening
• Have a hemoglobin A1C (HbA1c) ≤10% at the screening visit.
• Be a non-smoker or smoker who uses no more than 5 cigarettes or equivalent (e.g., e-cigarettes) per day over the prior 3-month period also may be enrolled (at the discretion of the investigator).
• Have a serum C-peptide concentration ≤0.7 ng/mL with a concurrent plasma glucose >90 mg/dL at screening or anytime within 24 weeks prior to screening.

For Part 4 (Adult participants with T2DM):

• Diagnosis of T2DM as defined by standard diagnostic criteria for ≥12 months at time of pretrial screening.
• Have a BMI ≥18.5 kg/m2 and ≤35.0 kg/m^2 at screening. BMI = mass (kg)/height (m)^2.
• Have a hemoglobin A1C (HbA1c) ≥6.5% and ≤10.0%.
• T2DM participants are not required to have been on insulin. If using insulin as background therapy, subjects should have a total daily insulin requirement of ≤1.2 units/kg, and have been on stable doses of basal insulin over the 2-week period prior to screening and over the 2 weeks prior to dosing.
• Be a non-smoker or smoker who uses no greater than 5 cigarettes or equivalent (e.g., e-cigarettes) daily over the prior 3-month period.

Subject Exclusion Criteria

All participants

• Is mentally or legally incapacitated
• Has a history of clinically significant endocrine (excluding diabetes mellitus in Part 3 participants), gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases.
• Has a systolic blood pressure (SBP) ≥140 mm Hg and/or a diastolic blood pressure (DBP) ≥90 mm Hg at screening.
• Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) at screening.
• Has a history of cancer (malignancy) Exceptions: (1) Participants with adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix may participate in the trial; (2) Participants with other malignancies which have been successfully treated ≥10 years prior to the pretrial (screening) visit
• Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit.
• Has participated in another investigational trial within 4 weeks.
• Has been randomized to, and received MK-5160 in prior clinical studies.
• Has a QTcF interval >450 msec, has a history of risk factors for Torsades de Pointes (e.g., heart failure/cardiomyopathy or family history of Long QT Syndrome).
• Has uncorrected hypokalemia
• Has uncorrected hypomagnesemia
• Is taking concomitant medications that prolong the QT/QTc interval.
• 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 post-trial visit.
• Has had a vaccination within 12 weeks of the pretrial visit.
• Consumes greater than 3 glasses of alcoholic beverages per day.
• Consumes excessive amounts, defined as greater than 6 servings 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 6 months
• Has used systemic (intravenous, oral, inhaled) glucocorticoids within 3 months of screening or is anticipated to require treatment with systemic glucocorticoids during study participation.

For Part 1 and Part 2 (Healthy Adult Participants)

• Has an estimated creatinine clearance of <90 mL/min based on Cockcroft-Gault equation

For Part 3 (Adult participants with T1DM):

• Has a history of diabetic ketoacidosis in the last 6 months prior to screening.
• Has an estimated creatinine clearance of <60 mL/min based on the Cockcroft-Gault equation at screening
• Has the diagnosis of hypoglycemia unawareness, or has had one or more severe hypoglycemic episodes associated with hypoglycemic seizures, comas or unconsciousness within 6 months prior to dosing.
• Has other major medical problems requiring medication (i.e., history of myocardial infarction (MI), hypercholesterolemia).
• Has a known history of celiac disease or significant food allergy, at the discretion of the investigator and Sponsor.
• Has a history of hypersensitivity to pharmacologic insulins or to any of the inactive ingredients in recombinant human insulin, or to any E.coli-derived drug product.

For Part 4 (Adult participants with T2DM):

• Participant has an estimated creatinine clearance of <60 mL/min based on the Cockcroft-Gault equation.
• Has a history of diabetic ketoacidosis in the last 6 months prior to screening.
• Has the diagnosis of hypoglycemia unawareness, or has had one or more severe hypoglycemic episodes associated with hypoglycemic seizures, comas or unconsciousness within 6 months prior to dosing.
• Has a known history of celiac disease or significant food allergy, at the discretion of the Investigator and Sponsor.
• Has been treated with a thiazolidinedione or injectable non-insulin anti-diabetic therapy within the past three months prior to dosing.
• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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69 participants in 14 patient groups

Part 1, MK-1092, 4.0 nmol/kg

Experimental group

Description:

MK-1092, 4.0 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 4.0 nmol/kg

Part 1, MK-1092, 8.0 nmol/kg

Experimental group

Description:

MK-1092, 8.0 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 8.0 nmol/kg

Part 1, MK-1092, 16 nmol/kg

Experimental group

Description:

MK-1092, 16 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Other: Dextrose

Drug: MK-1092, 16 nmol/kg

Drug: Placebo to glargine

Part 1, MK-1092, 32 nmol/kg

Experimental group

Description:

MK-1092, 32 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 32 nmol/kg

Part 1, MK-1092, 64 nmol/kg

Experimental group

Description:

MK-1092, 64 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 64 nmol/kg

Part 1, Glargine, 3.0 nmol/kg

Active Comparator group

Description:

Glargine, 3.0 nmol/kg, SC, as a single dose under the euglycemic clamp, in healthy participants

Treatment:

Drug: Glargine 3.0 nmol/kg

Other: Dextrose

Drug: Placebo to MK-1092

Part 2, MK-1092, 8.0 nmol/kg + lispro, 1.2 nmol/kg

Experimental group

Description:

MK-1092, 8.0 nmol/kg dose selection based on Part 1 + lispro (Humalog®), 1.2 nmol/kg, as a single dose, in healthy participants

Treatment:

Other: Dextrose

Drug: Lispro 1.2 nmol/kg

Drug: MK-1092, 8.0 nmol/kg

Part 3, MK-1092, 8.0 nmol/kg

Experimental group

Description:

MK-1092, (8.0 nmol/kg based on Part 1), SC, in participants with T1DM.

Treatment:

Biological: Insulin

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 8.0 nmol/kg

Part 3, MK-1092, 32 nmol/kg

Experimental group

Description:

MK-1092, 32 nmol/kg, SC, as a single dose, in participants with T1DM

Treatment:

Biological: Insulin

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 32 nmol/kg

Part 3, Glargine, 3.0 nmol/kg

Active Comparator group

Description:

Glargine, 3.0 nmol/kg, SC, as a single dose, in participants with T1DM

Treatment:

Biological: Insulin

Drug: Glargine 3.0 nmol/kg

Other: Dextrose

Drug: Placebo to MK-1092

Part 4, MK-1092, 32 nmol/kg

Experimental group

Description:

MK-1092, 32 nmol/kg, SC, as a single dose, in participants with T2DM

Treatment:

Biological: Insulin

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 32 nmol/kg

Part 4, MK-1092, 16 nmol/kg

Experimental group

Description:

MK-1092, 16 nmol/kg, SC, as a single dose, in participants with T2DM

Treatment:

Biological: Insulin

Other: Dextrose

Drug: MK-1092, 16 nmol/kg

Drug: Placebo to glargine

Part 4, MK-1092, 64 nmol/kg

Experimental group

Description:

MK-1092, 64 nmol/kg, SC, as a single dose, in participants with T2DM

Treatment:

Biological: Insulin

Other: Dextrose

Drug: Placebo to glargine

Drug: MK-1092, 64 nmol/kg

Part 4, Glargine, 3.0 nmol/kg

Active Comparator group

Description:

Glargine, 3.0 nmol/kg, SC, as a single dose, in participants with T2DM

Treatment:

Biological: Insulin

Drug: Glargine 3.0 nmol/kg

Other: Dextrose

Drug: Placebo to MK-1092