Hypertension, Type 2 Diabetes Mellitus
Conditions
Brief summary
The study will assess the efficacy and tolerability of MK0736 in patients with Type 2 Diabetes Mellitus and Hypertension who are on ongoing therapy with Angiotensin-Converting Enzyme or Angiotensin Receptor Blocker. After a 3 to 5 week pre-randomization phase, patients will be randomized to either MK0736 (3 doses), placebo, or hydrochlorothiazide (HCTZ). The study will also include a 3 week, posttreatment follow-up period.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Must be 18 to 75 years of age * Type 2 Diabetes Mellitus (Glycohemoglobin \[A1CHbA1c\]: 7 to 10%) * Hypertension: Diastolic blood pressure (DBP; 85 to 99 mm Hg) and systolic blood pressure (SBP; 120 to 159 mm Hg) * LDL-C \< 140 mg/dL * On stable treatment with an Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB)
Exclusion criteria
* History of Type I Diabetes mellitus or ketoacidosis * Patients taking 3 or more blood pressure lowering medications * Have severe chronic heart failure * History of certain diseases or conditions such as cardiac arrhythmias, heart attack, stroke, unstable angina, or decompensated vascular disease * History of cancer within the last 5 years * Human immunodeficiency virus (HIV) Positive * Have received treatment with any investigational drugs within the past 30 days * History of alcohol or drug abuse within the past 3 years * Body Mass Index ( BMI) \>= 41 kg/m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | Baseline and Week 12 | Participant remained in the sitting position for at least 5 minutes before any blood pressure readings were recorded. Systolic and diastolic blood pressures were determined by taking 6 replicate measurements obtained 1 to 2 minutes apart. First reading was discarded and the average of the last 5 measurement was recorded. |
| Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | Baseline and Week 12 | Participant remained in the sitting position for at least 5 minutes before any blood pressure readings were recorded. Systolic and diastolic blood pressures were determined by taking 6 replicate measurements obtained 1 to 2 minutes apart. First reading was discarded and the average the last 5 measurement was recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C calculated by the method of Friedewald equation at baseline and after 12 weeks of study drug administration |
| Change From Baseline in Body Weight at Week 24 | Baseline and Week 24 | Fasting weight was assessed at baseline and after 24 weeks of study drug administration and was measured after voiding, with shoes and socks off, wearing clinic gown to reduce variability and maintain consistency. Same standardized digital scale was used throughout the study. |
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | Baseline and Week 24 | HbA1c reported as a % and was measured at baseline and after 24 weeks of study drug administration |
Participant flow
Pre-assignment details
Study terminated after participants completed a minimum of 24 weeks of the study (i.e., Phase A) due to lack of efficacy. Phase B was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| MK-0736 0.5 mg One MK-0736 0.5 mg tablet, orally, once daily for 24 weeks (Phase A). Participant will then be switched to MK-0736 8.0 mg, once daily for an additional 52 weeks (Phase B). | 137 |
| MK-0736 2.0 mg One MK-0736 2.0 mg tablet, orally, once daily for 24 weeks (Phase A). Participant will then be switched to MK-0736 8.0 mg, once daily for 52 weeks (Phase B). | 134 |
| MK-0736 8.0 mg One MK-0736 8.0 mg tablet, orally, once daily for 24 weeks (Phase A). Participant will continue to receive MK-0736 8.0 mg, once daily for 52 weeks (Phase B). | 141 |
| HCTZ 12.5 mg → MK-0736 8.0 mg one 12.5 mg hydrochlorothiazide (HCTZ) tablet daily, orally, for 12 weeks. Participant then switched to MK-0736 8.0 mg for 12 weeks (Phase A). Participant will continue to receive MK-0736 8.0 mg, once daily for an additional 52 weeks (Phase B). | 71 |
| Placebo One placebo tablet daily, orally, for 24 weeks (Phase A). Participant will continue to receive placebo, once daily for 52 weeks (Phase B) | 137 |
| Total | 620 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 | 3 | 4 | 2 |
| Overall Study | Completion status unknown | 15 | 14 | 12 | 4 | 12 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 | 2 | 2 | 5 |
| Overall Study | Physician Decision | 0 | 2 | 3 | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 1 | 2 | 0 | 0 |
| Overall Study | Study terminated by Sponsor | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 8 | 9 | 3 | 11 |
Baseline characteristics
| Characteristic | MK-0736 0.5 mg | MK-0736 2.0 mg | MK-0736 8.0 mg | HCTZ 12.5 mg → MK-0736 8.0 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58.0 years | 60.0 years | 58.0 years | 57.0 years | 58.0 years | 58.0 years |
| Sex: Female, Male Female | 48 Participants | 55 Participants | 63 Participants | 34 Participants | 50 Participants | 250 Participants |
| Sex: Female, Male Male | 89 Participants | 79 Participants | 78 Participants | 37 Participants | 87 Participants | 370 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 46 / 137 | 54 / 134 | 54 / 141 | 25 / 71 | 43 / 137 |
| serious Total, serious adverse events | 9 / 137 | 7 / 134 | 6 / 141 | 0 / 71 | 5 / 137 |
Outcome results
Primary
Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12
Participant remained in the sitting position for at least 5 minutes before any blood pressure readings were recorded. Systolic and diastolic blood pressures were determined by taking 6 replicate measurements obtained 1 to 2 minutes apart. First reading was discarded and the average of the last 5 measurement was recorded.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) Population defined as all participants who received at least 1 dose of study drug and had endpoint data (both baseline and post-randomization)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0736 0.5 mg | Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | -5.8 mmHg | Standard Error 0.7 |
| MK-0736 2.0 mg | Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | -5.7 mmHg | Standard Error 0.7 |
| MK-0736 8.0 mg | Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | -6.7 mmHg | Standard Error 0.7 |
| HCTZ 12.5 mg → MK-0736 8.0 mg | Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | -7.7 mmHg | Standard Error 1 |
| Placebo | Change From Baseline in Sitting Diastolic Blood Pressure (SiDBP) at Week 12 | -5.6 mmHg | Standard Error 0.7 |
p-value: 0.25395% CI: [-3.1, 0.8]Constrained longitudinal data analysis
p-value: 0.91995% CI: [-2.1, 1.9]Constrained longitudinal data analysis
p-value: 0.82995% CI: [-2.2, 1.8]Constrained longitudinal data analysis
p-value: 0.07495% CI: [-4.5, 0.2]Constrained longitudinal data analysis
p-value: 0.39395% CI: [-1.3, 3.3]Constrained longitudinal data analysis
p-value: 0.08895% CI: [-0.3, 4.4]Constrained longitudinal data analysis
p-value: 0.10895% CI: [-0.4, 4.3]Constrained longitudinal data analysis
Primary
Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12
Participant remained in the sitting position for at least 5 minutes before any blood pressure readings were recorded. Systolic and diastolic blood pressures were determined by taking 6 replicate measurements obtained 1 to 2 minutes apart. First reading was discarded and the average the last 5 measurement was recorded.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) Population defined as all participants who received at least 1 dose of study drug and had endpoint data (both baseline and post-randomization)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0736 0.5 mg | Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | -5.7 mmHg | Standard Error 1.1 |
| MK-0736 2.0 mg | Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | -7.2 mmHg | Standard Error 1.1 |
| MK-0736 8.0 mg | Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | -6.3 mmHg | Standard Error 1.1 |
| HCTZ 12.5 mg → MK-0736 8.0 mg | Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | -12.4 mmHg | Standard Error 1.5 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure (SiSBP) at Week 12 | -5.4 mmHg | Standard Error 1.2 |
p-value: 0.54395% CI: [-4, 2.1]Constrained longitudinal data analysis
p-value: 0.24695% CI: [-4.9, 1.3]Constrained longitudinal data analysis
p-value: 0.82195% CI: [-3.5, 2.7]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-10.7, -3.3]Constrained longitudinal data analysis
p-value: 0.00195% CI: [2.4, 9.8]Constrained longitudinal data analysis
p-value: 0.00695% CI: [1.5, 8.9]Constrained longitudinal data analysis
p-value: <0.00195% CI: [3, 10.4]Constrained longitudinal data analysis
Secondary
Change From Baseline in Body Weight at Week 24
Fasting weight was assessed at baseline and after 24 weeks of study drug administration and was measured after voiding, with shoes and socks off, wearing clinic gown to reduce variability and maintain consistency. Same standardized digital scale was used throughout the study.
Time frame: Baseline and Week 24
Population: Full Analysis Set (FAS) Population defined as all participants who received at least 1 dose of study drug and had endpoint data (both baseline and post-randomization)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0736 0.5 mg | Change From Baseline in Body Weight at Week 24 | -0.7 kg | Standard Error 0.5 |
| MK-0736 2.0 mg | Change From Baseline in Body Weight at Week 24 | -1.4 kg | Standard Error 0.5 |
| MK-0736 8.0 mg | Change From Baseline in Body Weight at Week 24 | -1.3 kg | Standard Error 0.5 |
| HCTZ 12.5 mg → MK-0736 8.0 mg | Change From Baseline in Body Weight at Week 24 | -1.6 kg | Standard Error 0.7 |
| Placebo | Change From Baseline in Body Weight at Week 24 | 0.6 kg | Standard Error 0.5 |
p-value: 0.00695% CI: [-3.2, -0.5]Constrained longitudinal data analysis
p-value: 0.00495% CI: [-3.3, -0.6]Constrained longitudinal data analysis
p-value: 0.06695% CI: [-2.6, 0.1]Constrained longitudinal data analysis
p-value: 0.00895% CI: [-3.7, -0.6]Constrained longitudinal data analysis
Secondary
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24
HbA1c reported as a % and was measured at baseline and after 24 weeks of study drug administration
Time frame: Baseline and Week 24
Population: Full Analysis Set (FAS) Population defined as all participants who received at least 1 dose of study drug and did not lack of any endpoint data (both baseline and post-randomization)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0736 0.5 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.10 Percentage Change | Standard Error 0.09 |
| MK-0736 2.0 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.16 Percentage Change | Standard Error 0.1 |
| MK-0736 8.0 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.06 Percentage Change | Standard Error 0.09 |
| HCTZ 12.5 mg → MK-0736 8.0 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.20 Percentage Change | Standard Error 0.13 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | 0.13 Percentage Change | Standard Error 0.1 |
p-value: 0.15295% CI: [-0.44, 0.07]Constrained longitudinal data analysis
p-value: 0.03595% CI: [-0.54, -0.02]Constrained longitudinal data analysis
p-value: 0.09595% CI: [-0.48, 0.04]Constrained longitudinal data analysis
p-value: 0.04595% CI: [-0.63, -0.01]Constrained longitudinal data analysis
Secondary
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C calculated by the method of Friedewald equation at baseline and after 12 weeks of study drug administration
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) Population defined as all participants who received at least 1 dose of study drug and had endpoint data (both baseline and post-randomization)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0736 0.5 mg | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 1.1 Percentage Change | Standard Error 2.3 |
| MK-0736 2.0 mg | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 3.9 Percentage Change | Standard Error 2.5 |
| MK-0736 8.0 mg | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 0.6 Percentage Change | Standard Error 2.5 |
| HCTZ 12.5 mg → MK-0736 8.0 mg | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 2.8 Percentage Change | Standard Error 3.5 |
| Placebo | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 2.0 Percentage Change | Standard Error 2.5 |
p-value: 0.68495% CI: [-8.3, 5.5]ANCOVA
p-value: 0.59795% CI: [-5, 8.7]ANCOVA
p-value: 0.79395% CI: [-7.6, 5.8]ANCOVA
p-value: 0.85495% CI: [-7.6, 9.2]ANCOVA