Trial Outcomes & Findings for Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis (MK-0000-117)(Completed) (NCT NCT00871871)

NCT ID: NCT00871871

Last Updated: 2015-07-28

Results Overview

Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

64 participants

Primary outcome timeframe

90 -120 minutes post-dose

Results posted on

2015-07-28

Participant Flow

Enrolled participants were place into two periods. 36 Part I participants received Hydrochlorothiazide (HCTZ) first, then placebo or placebo first, then HCTZ. A new group of 28 Part II participants received Isosorbide Mononitrate (ISMN) first, then placebo or placebo first, then ISMN.

Participant milestones

Participant milestones
Measure
HCTZ First, Then HCTZ Placebo
Part I Overall: Placebo in Period 1 followed by hydrochlorothiazide (HCTZ) in Period 2 or HCTZ in Period 1, followed by placebo in Period 2
HCTZ Placebo First, Then HCTZ
Part I Overall: Placebo in Period 1 followed by hydrochlorothiazide (HCTZ) in Period 2 or HCTZ in Period 1, followed by placebo in Period 2
ISMN First, Then ISMN Placebo
Part II Overall: Placebo in Period 1, followed by isosorbide mononitrate (ISMN) in Period 2 or ISMN in Period 1, followed by placebo in Period 2
ISMN Placebo First, Then ISMN
Part II Overall: Placebo in Period 1, followed by isosorbide mononitrate (ISMN) in Period 2 or ISMN in Period 1, followed by placebo in Period 2
Part I
STARTED
18
18
0
0
Part I
COMPLETED
15
15
0
0
Part I
NOT COMPLETED
3
3
0
0
Part II
STARTED
0
0
13
15
Part II
COMPLETED
0
0
9
11
Part II
NOT COMPLETED
0
0
4
4

Reasons for withdrawal

Reasons for withdrawal
Measure
HCTZ First, Then HCTZ Placebo
Part I Overall: Placebo in Period 1 followed by hydrochlorothiazide (HCTZ) in Period 2 or HCTZ in Period 1, followed by placebo in Period 2
HCTZ Placebo First, Then HCTZ
Part I Overall: Placebo in Period 1 followed by hydrochlorothiazide (HCTZ) in Period 2 or HCTZ in Period 1, followed by placebo in Period 2
ISMN First, Then ISMN Placebo
Part II Overall: Placebo in Period 1, followed by isosorbide mononitrate (ISMN) in Period 2 or ISMN in Period 1, followed by placebo in Period 2
ISMN Placebo First, Then ISMN
Part II Overall: Placebo in Period 1, followed by isosorbide mononitrate (ISMN) in Period 2 or ISMN in Period 1, followed by placebo in Period 2
Part I
Adverse Event
0
2
0
0
Part I
Withdrawal by Subject
3
0
0
0
Part I
Laboratory abnormality
0
1
0
0
Part II
Lack of Efficacy
0
0
1
0
Part II
Withdrawal by Subject
0
0
2
1
Part II
Adverse Event
0
0
1
2
Part II
Protocol Violation
0
0
0
1

Baseline Characteristics

Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis (MK-0000-117)(Completed)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
All Part I Participants
n=36 Participants
Part I Overall: Hydrochlorothiazide (HCTZ) in Period 1 followed by Placebo in Period 2 or Placebo in Period 1, followed by HCTZ in Period 2
All Part II Participants
n=28 Participants
Part II Overall: Isosorbide mononitrate (ISMN)in Period 1, followed by placebo in Period 2 or placebo in Period 1, followed by ISMN in Period 2
Total
n=64 Participants
Total of all reporting groups
Age, Continuous
57 years
n=5 Participants
54 years
n=7 Participants
55 years
n=5 Participants
Sex: Female, Male
Female
20 Participants
n=5 Participants
13 Participants
n=7 Participants
33 Participants
n=5 Participants
Sex: Female, Male
Male
16 Participants
n=5 Participants
15 Participants
n=7 Participants
31 Participants
n=5 Participants

PRIMARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with IGT.

Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=5 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=5 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)
3.44 ng/minute
Standard Deviation 1.03
3.55 ng/minute
Standard Deviation 1.03

PRIMARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with IFG.

Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=7 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=8 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)
5.60 ng/minute
Standard Deviation 1.45
4.50 ng/minute
Standard Deviation 0.95

PRIMARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with NGT.

Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG \<100 mg/dL \& 2 hour plasma glucose (PG) \<140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=22 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=23 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)
5.54 ng/minute
Standard Deviation 2.15
5.01 ng/minute
Standard Deviation 1.63

PRIMARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants who took ISMN/placebo.

Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=20 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=23 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state
0.040 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.027
0.044 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.041

SECONDARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with IGT.

Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=5 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=5 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)
0.061 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.044
0.045 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.041

SECONDARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with IFG.

Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=7 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=8 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG)
0.038 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.019
0.037 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.109

SECONDARY outcome

Timeframe: 90 -120 minutes post-dose

Population: Number of participants with NGT.

Steady state was defined as 90-120 minutes post-dose. The ratio was the measure of the quantity of glucose disposed per unit of plasma insulin concentration (PIC). Approximate PIC was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals, time = 90, 100, 110, and 120 minutes. NGT participants (FPG \<100 mg/dL \& 2 hour PG \<140 mg/dL during a 75g OGTT at screening) were neither IGT nor IFG at screening. IGT - defined as a 2 hour PG \>= 140 and \<= 199 mg/dL during a 75g OGTT at screening. IFG - defined as FPG between 100 and 125 mg/dL at screening.

Outcome measures

Outcome measures
Measure
Hydrochlorothiazide (HCTZ)
n=22 Participants
Part I: Participants on HCTZ in either Period 1 or Period 2
Hydrochlorothiazide (HCTZ) Placebo
n=23 Participants
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT)
0.045 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.028
0.042 (mg/kg/minute)/(µIU/mL)
Standard Deviation 0.024

Adverse Events

HCTZ

Serious events: 0 serious events
Other events: 29 other events
Deaths: 0 deaths

HCTZ Placebo

Serious events: 0 serious events
Other events: 25 other events
Deaths: 0 deaths

ISMN

Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths

ISMN Placebo

Serious events: 0 serious events
Other events: 17 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure
HCTZ
n=36 participants at risk
Part I: Participants on HCTZ in either Period 1 or Period 2
HCTZ Placebo
n=36 participants at risk
Part I: Participants on HCTZ Placebo in either Period 1 or Period 2
ISMN
n=28 participants at risk
Part II: Participants on ISMN in either Period 1 or Period 2
ISMN Placebo
n=28 participants at risk
Part II: Participants on ISMN Placebo in either Period 1 or Period 2
Gastrointestinal disorders
Abdominal distension
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Abdominal pain
2.8%
1/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Gastrointestinal disorders
Abdominal pain upper
0.00%
0/36
5.6%
2/36
3.6%
1/28
0.00%
0/28
Infections and infestations
Acute sinusitis
0.00%
0/36
0.00%
0/36
3.6%
1/28
0.00%
0/28
Infections and infestations
Anal abscess
0.00%
0/36
0.00%
0/36
3.6%
1/28
0.00%
0/28
Musculoskeletal and connective tissue disorders
Arthralgia
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Musculoskeletal and connective tissue disorders
Arthritis
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Injury, poisoning and procedural complications
Arthropod bite
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Injury, poisoning and procedural complications
Back injury
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Musculoskeletal and connective tissue disorders
Back pain
8.3%
3/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Investigations
Blood glucose decreased
2.8%
1/36
5.6%
2/36
0.00%
0/28
7.1%
2/28
Investigations
Blood potassium decreased
11.1%
4/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Vascular disorders
Blood pressure inadequately controlled
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Investigations
Blood pressure increased
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Investigations
Blood uric acid increased
8.3%
3/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Reproductive system and breast disorders
Breast pain
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Eye disorders
Conjunctivitis
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Constipation
5.6%
2/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Respiratory, thoracic and mediastinal disorders
Cough
5.6%
2/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Cystitis
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Metabolism and nutrition disorders
Decreased appetite
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Diarrhoea
2.8%
1/36
0.00%
0/36
3.6%
1/28
10.7%
3/28
Nervous system disorders
Dizziness
11.1%
4/36
5.6%
2/36
10.7%
3/28
3.6%
1/28
Nervous system disorders
Dysgeusia
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Dyspepsia
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Ear and labyrinth disorders
Ear discomfort
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Eructation
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
General disorders
Fatigue
8.3%
3/36
5.6%
2/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Flatulence
5.6%
2/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Gastroenteritis
2.8%
1/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Metabolism and nutrition disorders
Gout
0.00%
0/36
2.8%
1/36
0.00%
0/28
3.6%
1/28
Nervous system disorders
Headache
30.6%
11/36
33.3%
12/36
92.9%
26/28
50.0%
14/28
Infections and infestations
Hordeolum
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Vascular disorders
Hot flush
0.00%
0/36
2.8%
1/36
0.00%
0/28
3.6%
1/28
Injury, poisoning and procedural complications
Joint injury
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Musculoskeletal and connective tissue disorders
Joint stiffness
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Laryngitis
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Injury, poisoning and procedural complications
Limb injury
0.00%
0/36
0.00%
0/36
3.6%
1/28
0.00%
0/28
General disorders
Malaise
2.8%
1/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Musculoskeletal and connective tissue disorders
Muscle spasms
11.1%
4/36
13.9%
5/36
17.9%
5/28
3.6%
1/28
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
0.00%
0/36
2.8%
1/36
14.3%
4/28
7.1%
2/28
Musculoskeletal and connective tissue disorders
Myalgia
0.00%
0/36
2.8%
1/36
3.6%
1/28
0.00%
0/28
Infections and infestations
Nasopharyngitis
13.9%
5/36
8.3%
3/36
0.00%
0/28
0.00%
0/28
Gastrointestinal disorders
Nausea
8.3%
3/36
8.3%
3/36
17.9%
5/28
0.00%
0/28
Renal and urinary disorders
Nocturia
2.8%
1/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
General disorders
Oedema peripheral
0.00%
0/36
2.8%
1/36
3.6%
1/28
3.6%
1/28
Renal and urinary disorders
Oliguria
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Oral herpes
0.00%
0/36
2.8%
1/36
3.6%
1/28
3.6%
1/28
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Musculoskeletal and connective tissue disorders
Osteoarthritis
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Otitis media
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Musculoskeletal and connective tissue disorders
Pain in extremity
0.00%
0/36
2.8%
1/36
3.6%
1/28
0.00%
0/28
Cardiac disorders
Palpitations
2.8%
1/36
0.00%
0/36
3.6%
1/28
3.6%
1/28
Infections and infestations
Pharyngitis
8.3%
3/36
2.8%
1/36
0.00%
0/28
7.1%
2/28
Renal and urinary disorders
Pollakiuria
11.1%
4/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Metabolism and nutrition disorders
Polydipsia
5.6%
2/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Respiratory, thoracic and mediastinal disorders
Productive cough
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Investigations
Protein urine present
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Skin and subcutaneous tissue disorders
Pruritis
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Respiratory, thoracic and mediastinal disorders
Rhinorrhea
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Immune system disorders
Seasonal allergy
2.8%
1/36
0.00%
0/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Sinusitis
0.00%
0/36
2.8%
1/36
3.6%
1/28
0.00%
0/28
Skin and subcutaneous tissue disorders
Skin ulcer
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Respiratory, thoracic and mediastinal disorders
Sneezing
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Cardiac disorders
Tachycardia
0.00%
0/36
2.8%
1/36
3.6%
1/28
0.00%
0/28
Injury, poisoning and procedural complications
Thermal burn
0.00%
0/36
0.00%
0/36
0.00%
0/28
3.6%
1/28
Ear and labyrinth disorders
Tinnitus
0.00%
0/36
0.00%
0/36
3.6%
1/28
0.00%
0/28
Injury, poisoning and procedural complications
Tooth fracture
0.00%
0/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Respiratory, thoracic and mediastinal disorders
Upper-airway cough syndrome
5.6%
2/36
2.8%
1/36
0.00%
0/28
0.00%
0/28
Infections and infestations
Urinary tract infection
5.6%
2/36
5.6%
2/36
0.00%
0/28
0.00%
0/28
Skin and subcutaneous tissue disorders
Urticaria
0.00%
0/36
0.00%
0/36
3.6%
1/28
0.00%
0/28
Gastrointestinal disorders
Vomiting
2.8%
1/36
2.8%
1/36
3.6%
1/28
0.00%
0/28

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Results disclosure agreements

  • Principal investigator is a sponsor employee The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication guidelines.
  • Publication restrictions are in place

Restriction type: OTHER