Clinical trial NCT03170544: Single Ascending Dose Study of MK-1092 in Healthy Participants and in Participants With Type 1 and Type 2 Diabetes Mellitus (MK-1092-001)
Official title: A Single Ascending Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Healthy Subjects, Subjects With Type 1 Diabetes Mellitus, and Subjects With Type 2 Diabetes Mellitus.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-05-31
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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)

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 112 days
measure: Number of Participants Who Discontinued the Study Due to an AE
timeFrame: Up to 58 days
measure: GIRmax After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Adult Participants With Type 1 Diabetes Mellitus (T1DM) (Part 3)
timeFrame: Up to approximately 24 hours post-dose
Secondary outcomes:
measure: GIRmax After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Healthy Adult Participants (Part 1)
timeFrame: Up to approximately 24 hours post-dose
measure: GIRmax After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Adult Participants With Type 2 Diabetes Mellitus (T2DM) (Part 4)
timeFrame: Up to approximately 24 hours post-dose
measure: Time-Weighted Average GIR (TWA[GIR]) After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Healthy Adult Participants (Part 1)
timeFrame: Up to approximately 24 hours post-dose
measure: Time-Weighted Average GIR (TWA[GIR]) After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Adult Participants With T1DM (Part 3)
timeFrame: Up to approximately 24 hours post-dose
measure: Time-Weighted Average GIR (TWA[GIR]) After a Single Dose Administration of Subcutaneous MK-1092 or Glargine to Adult Participants With T2DM (Part 4)
timeFrame: Up to approximately 24 hours post-dose
measure: Maximal Plasma MK-1092 Concentration (Cmax) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Area Under the Plasma Drug Curve From 0 to Infinity (AUC0-inf) MK-1092 Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Rate of Plasma Drug Removal (CL/F) MK-1092 Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach Maximum Plasma MK-1092 Concentration (Tmax) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach a 50% Decrease In Plasma MK-1092 Concentration (t1/2) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Maximal Plasma MK-1092 Concentration (Cmax) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Area Under the Plasma Drug Curve From 0 to Infinity (AUC0-inf) MK-1092 Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Rate of Plasma Drug Removal (CL/F) MK-1092 Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach Maximum Plasma MK-1092 Concentration (Tmax) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach a 50% Decrease In Plasma MK-1092 Concentration (t1/2) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Maximal Plasma Insulin Glargine Concentration (Cmax) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Area Under the Plasma Drug Curve From 0 to Infinity (AUC0-inf) Insulin Glargine Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach Maximum Plasma Insulin Glargine Concentration (Tmax) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach a 50% Decrease In Plasma Insulin Glargine Concentration (t1/2) Parts 1 and 3
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Maximal Plasma Insulin Glargine Concentration (Cmax) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Area Under the Plasma Drug Curve From 0 to Infinity (AUC0-inf) Insulin Glargine Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28)
measure: Time to Reach Maximum Plasma Insulin Glargine Concentration (Tmax) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28) ]
measure: Time to Reach a 50% Decrease In Plasma Insulin Glargine Concentration (t1/2) Part 4
timeFrame: -15 min (predose), 10 min, 30 min, 1.0 hr, 1.5 hr, 2.0 hr, 3.0 hr, 4.0 hr, 6.0 hr, 9.0 hr, 12 hr, 18 hr, 24 hr, an additional sample will be collected and at the end of the clamp, 2d, 3d, 4d, 5d and 7d after SC dose and at post-trial (Day 14 and Day 28) ]
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: ProSciento Inc. ( Site 0001)
state: California
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Walford GA, Duncan KE, Hernandez M, Vaddady P, Hompesch M, Morrow L, Stoch SA. A Randomized, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Insulin Dimer. Clin Pharmacol Ther. 2022 Jul;112(1):125-132. doi: 10.1002/cpt.2607. Epub 2022 May 3.