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Bioequivalence of Losartan and Hydrochlorothiazide (HCTZ) Combination Tablet and Coadministration of Its Components (0954A-306)

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ClinicalTrials.gov Identifier: NCT00953680
Recruitment Status : Completed
First Posted : August 6, 2009
Results First Posted : July 16, 2010
Last Update Posted : January 22, 2016
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hypertension
Interventions Drug: losartan potassium (+) hydrochlorothiazide (HCTZ)
Drug: losartan potassium
Drug: hydrochlorothiazide (HCTZ)
Enrollment 77
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule Losartan Tablet +HCTZ Capsule/Losartan-HCTZ Combination Tablet
Hide Arm/Group Description Single dose losartan 100 mg and hydrochlorothiazide (HCTZ) 12.5 mg combination tablet then a single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule Single dose losartan 100 mg tablet + hydrochlorothiazide (HCTZ) 12.5 mg capsule then a single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
Period Title: Period 1
Started 38 39
Completed 38 38
Not Completed 0 1
Reason Not Completed
Withdrawal by Subject             0             1
Period Title: Period 2
Started 38 38
Completed 38 38
Not Completed 0 0
Arm/Group Title All Participants
Hide Arm/Group Description All randomized patients
Overall Number of Baseline Participants 77
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 77 participants
33.87
(18 to 45)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants
Female
46
  59.7%
Male
31
  40.3%
Height  
Mean (Full Range)
Unit of measure:  Centimeters
Number Analyzed 77 participants
166.81
(152 to 191)
Weight  
Mean (Full Range)
Unit of measure:  Kilograms
Number Analyzed 77 participants
73.01
(50 to 99.1)
1.Primary Outcome
Title Area Under the Curve (AUC(0 to Infinity)) of Losartan
Hide Description [Not Specified]
Time Frame 0 to 36 Hours Post Dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) results included complete data from 75 of 77 subjects (with 1 replacement). Partial data from 1 subject were not analyzed. Plasma concentrations for another subject were undetectable following 1 treatment, with partial data excluded from analyses.
Arm/Group Title Losartan-HCTZ Combination Tablet Losartan Tablet + HCTZ Capsule
Hide Arm/Group Description:
single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Overall Number of Participants Analyzed 75 75
Least Squares Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
1018.1  (382.5) 1024.9  (354.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-HCTZ Combination Tablet, Losartan Tablet + HCTZ Capsule
Comments Least-Squares Mean Ratio (A/B); A= Single dose losartan 100 mg-HCTZ 12.5 mg combination tablet; B= Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence Bounds of (0.80, 1.25).
Method of Estimation Estimation Parameter Least-Squares Mean Ratio
Estimated Value 0.993
Confidence Interval 90%
0.950 to 1.039
Estimation Comments [Not Specified]
2.Primary Outcome
Title Peak Plasma Concentration (Cmax) for Losartan
Hide Description Peak Plasma Concentration (Cmax), or maximal concentration of drug following dosing.
Time Frame 36 Hours Post Dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) results included complete data from 75 of 77 subjects (with 1 replacement). Partial data from 1 subject were not analyzed. Plasma concentrations for another subject were undetectable following 1 treatment, with partial data excluded from analyses.
Arm/Group Title Losartan-HCTZ Combination Tablet Losartan Tablet + HCTZ Capsule
Hide Arm/Group Description:
single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Overall Number of Participants Analyzed 75 75
Least Squares Mean (Standard Deviation)
Unit of Measure: ng/mL
532.7  (334.9) 637.9  (425.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-HCTZ Combination Tablet, Losartan Tablet + HCTZ Capsule
Comments Least-Squares Mean Ratio (A/B); A= Single dose losartan 100 mg-HCTZ 12.5 mg combination tablet; B= Single dose losartan 100-mg tablet + HCTZ 12.5 mg capsule
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence Bounds of (0.80, 1.25).
Method of Estimation Estimation Parameter Least-Squares Mean Ratio
Estimated Value 0.835
Confidence Interval 90%
0.749 to 0.931
Estimation Comments [Not Specified]
3.Primary Outcome
Title Area Under the Curve (AUC(0 to Infinity)) of HCTZ
Hide Description Plasma Area Under the Curve, a measure of drug exposure following dosing
Time Frame 0 to 30 Hours Post Dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) results included complete data from 75 of 77 subjects (with 1 replacement). Partial data from 1 subject were not analyzed. Plasma concentrations for another subject were undetectable following 1 treatment, with partial data excluded from analyses.
Arm/Group Title Losartan-HCTZ Combination Tablet Losartan Tablet + HCTZ Capsule
Hide Arm/Group Description:
single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Overall Number of Participants Analyzed 20 20
Least Squares Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
462.08  (144.72) 499.90  (133.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-HCTZ Combination Tablet, Losartan Tablet + HCTZ Capsule
Comments Least-Squares Mean Ratio (A/B); A= Single dose losartan 100 mg-HCTZ 12.5 mg combination tablet; B= Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence Bounds of (0.80, 1.25).
Method of Estimation Estimation Parameter Least-Squares Mean Ratio
Estimated Value 0.924
Confidence Interval 90%
0.825 to 1.035
Estimation Comments [Not Specified]
4.Primary Outcome
Title Peak Plasma Concentration (Cmax) of HCTZ Following Single Dose Administration of Losartan/HCTZ or Losartan and HCTZ
Hide Description Peak Plasma Concentration (Cmax), or maximal concentration of drug following dosing
Time Frame 30 Hours Post Dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) results were based on data from the 20 subjects who had blood drawn for the HCTZ assay. These 20 subjects were selected as the first 10 subjects from each treatment sequence who completed both periods of the study.
Arm/Group Title Losartan-HCTZ Combination Tablet Losartan Tablet + HCTZ Capsule
Hide Arm/Group Description:
single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Overall Number of Participants Analyzed 20 20
Least Squares Mean (Standard Deviation)
Unit of Measure: ng/mL
76.15  (39.55) 81.76  (31.05)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-HCTZ Combination Tablet, Losartan Tablet + HCTZ Capsule
Comments Least-Squares Mean Ratio (A/B); A= Single dose losartan 100 mg-HCTZ 12.5 mg combination tablet; B= Single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence Bounds of (0.80, 1.25).
Method of Estimation Estimation Parameter Least-Squares Mean Ratio
Estimated Value 0.931
Confidence Interval 90%
0.836 to 1.037
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description Serious Adverse Events are reported by treatment group (Combination/Tablet+Capsule [N=38] or Tablet+Capsule/Combination [N=39]). For Other Adverse Events, the Combination/Tablet+Capsule group includes all subjects who received Combination Tablet (N=76) and the Tablet+Capsule/Combination group includes all subjects who received Tablet+Capsule (N=77)
 
Arm/Group Title Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule Losartan Tablet +HCTZ Capsule/Losartan-HCTZ Combination Tablet
Hide Arm/Group Description Single dose losartan 100 mg and hydrochlorothiazide (HCTZ) 12.5 mg combination tablet then a single dose losartan 100 mg tablet + HCTZ 12.5 mg capsule losartan 100 mg tablet + hydrochlorothiazide (HCTZ) 12.5 mg capsule then a single dose losartan 100 mg and HCTZ 12.5 mg combination tablet
All-Cause Mortality
Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule Losartan Tablet +HCTZ Capsule/Losartan-HCTZ Combination Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule Losartan Tablet +HCTZ Capsule/Losartan-HCTZ Combination Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   0/38 (0.00%)   0/39 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule Losartan Tablet +HCTZ Capsule/Losartan-HCTZ Combination Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   12/76 (15.79%)   10/77 (12.99%) 
Gastrointestinal disorders     
Nausea * 1  0/76 (0.00%)  1/77 (1.30%) 
Vomiting * 1  1/76 (1.32%)  1/77 (1.30%) 
Investigations     
Alanine Aminotransferase Increased * 1  1/76 (1.32%)  0/77 (0.00%) 
Aspartate Aminotransferase Increased * 1  1/76 (1.32%)  0/77 (0.00%) 
Nervous system disorders     
Dizziness * 1  5/76 (6.58%)  3/77 (3.90%) 
Headache * 1  8/76 (10.53%)  6/77 (7.79%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 7.0
PK analyses included complete data from 75 subjects. 3 losartan/E-3174 concentrations from 3 different subjects were excluded from analyses due to gross deviations; 75 minutes-Treatment B, 75 minutes-Treatment A, & 15 minutes-Treatment A.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
Phone: 1-800-672-6372
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00953680     History of Changes
Other Study ID Numbers: 0954A-306
2009_628
First Submitted: August 4, 2009
First Posted: August 6, 2009
Results First Submitted: May 13, 2010
Results First Posted: July 16, 2010
Last Update Posted: January 22, 2016