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A Bioequivalence Study Comparing A Fixed Dose Combination Formulation, Rin 150 And Individual Reference Drugs In Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT02014272
Recruitment Status : Completed
First Posted : December 18, 2013
Results First Posted : July 16, 2014
Last Update Posted : July 16, 2014
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy Volunteers
Interventions Drug: RIN 150
Drug: reference drugs
Enrollment 28
Recruitment Details  
Pre-assignment Details  
Arm/Group Title RIN 150 First, Then Rifampicin and Isoniazid Rifampicin and Isoniazid First, Then RIN 150
Hide Arm/Group Description Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contained 150 milligram [mg] rifampicin and 75 mg isoniazid) on Day 1 in first intervention period, followed by single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in second intervention period. A washout period of at least 7 days was maintained between each intervention period. Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in first intervention period followed by single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in second intervention period. A washout period of at least 7 days was maintained between each intervention period.
Period Title: Intervention Period 1
Started 14 14
Completed 13 13
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             0
Adverse Event             0             1
Period Title: Washout Period 1 (7 Days)
Started 13 13
Completed 13 13
Not Completed 0 0
Period Title: Intervention Period 2
Started 13 13
Completed 13 13
Not Completed 0 0
Arm/Group Title Entire Study Population
Hide Arm/Group Description Includes all participants randomized to receive RIN 150 first and rifampicin and isoniazid first.
Overall Number of Baseline Participants 28
Hide Baseline Analysis Population Description
Analysis population included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 28 participants
31.5  (7.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants
Female
1
   3.6%
Male
27
  96.4%
1.Primary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Time Frame 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: (nanogram*hour) per milliliter (ng*h/mL)
AUClast: Rifampicin
85020
(20%)
90030
(24%)
AUClast: Isoniazid
16220
(79%)
16120
(77%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed AUClast of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 95.45
Confidence Interval (2-Sided) 90%
92.07 to 98.94
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed AUClast of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 103.45
Confidence Interval (2-Sided) 90%
99.33 to 107.75
Estimation Comments [Not Specified]
2.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax)
Hide Description Cmax was reported for rifampicin and isoniazid.
Time Frame 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cmax: Rifampicin
13670
(21%)
15000
(28%)
Cmax: Isoniazid
6080
(45%)
5577
(37%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed Cmax of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 91.63
Confidence Interval (2-Sided) 90%
83.13 to 101.01
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed Cmax of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 107.58
Confidence Interval (2-Sided) 90%
96.07 to 120.47
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)]
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞) was reported for rifampicin and isoniazid. It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time Frame 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest. Here, n=participants in the treatment group who were evaluable for this measure for specified drug of each group with reportable AUC (0 - ∞) values, respectively.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC (0 - ∞): Rifampicin (n=27, 27)
86670
(21%)
91340
(24%)
AUC (0 - ∞): Isoniazid (n=27, 26)
16680
(78%)
17390
(71%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed AUC(0 - ∞) of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 95.92
Confidence Interval (2-Sided) 90%
92.54 to 99.43
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection RIN 150, Rifampicin and Isoniazid
Comments Natural log transformed AUC(0 - ∞) of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 102.41
Confidence Interval (2-Sided) 90%
98.76 to 106.19
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Plasma Decay Half-Life (t1/2)
Hide Description Plasma decay half life (t1/2) was reported for rifampicin and isoniazid.
Time Frame 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest. Here, n=participants in the treatment group who were evaluable for this measure for specified drug of each group with reportable t½ values, respectively.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Mean (Standard Deviation)
Unit of Measure: hour
t1/2: Rifampicin (n=27, 27) 3.608  (0.89531) 3.572  (0.72948)
t1/2: Isoniazid (n=27, 26) 2.776  (1.4110) 3.000  (1.4375)
5.Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax)
Hide Description Tmax was reported for rifampicin and isoniazid.
Time Frame 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Median (Full Range)
Unit of Measure: hour
Tmax: Rifampicin
1.67
(0.750 to 3.52)
1.67
(0.750 to 3.52)
Tmax: Isoniazid
0.500
(0.250 to 2.67)
0.500
(0.250 to 3.00)
6.Other Pre-specified Outcome
Title Number of Participants With Clinically Significant Changes in Vital Signs
Hide Description Criteria for clinical significant change in vital signs: systolic blood pressure (BP) less than (<) 90 millimeters of mercury (mmHg), diastolic BP <50 mmHg, supine and sitting heart rate <40 beats per minute (bpm) or greater than (>) 120 bpm, standing and erect heart rate <40 bpm or >140 bpm. Maximum change from baseline in systolic BP >=30 mmHg, maximum change from baseline in diastolic BP >=20 mmHg. Participants who met the criteria were reported.
Time Frame Screening up to Day 2 of intervention period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set consisted of all participants who received at least 1 dose of study medication.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 27 27
Measure Type: Number
Unit of Measure: participants
0 0
7.Other Pre-specified Outcome
Title Number of Participants With Laboratory Test Abnormalities
Hide Description Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (less than [<] 0.8*lower limit of normal[LLN]); leucocytes (<0.6/ greater than [>] 1.5*limit of reference range [LRR]); platelets (<0.5/>1.75*LRR); neutrophils, lymphocytes (<0.8/>1.2*LRR); eosinophils, basophils, monocytes (>1.2*upper LN [ULN]); bilirubin (>1.5*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (>3*ULN); creatinine, urea (>1.3*ULN); fasting glucose (<0.6 />1.5*LRR); uric acid (>1.2*ULN); sodium (<0.95/>1.05*LRR); potassium, calcium, chloride, bicarbonate (<0.9/>1.1*LRR); albumin, total protein (<0.8/>1.2*LRR); creatine kinase (>2.0*ULN); urine red blood cells (RBCs), urine white blood cells (WBCs) (>=20 high-powered field). Total number of participants with any laboratory abnormalities was reported.
Time Frame Screening up to Day 2 of intervention period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set consisted of all participants who received at least 1 dose of study medication. Here ‘N’ (number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description:
Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods.
Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
Overall Number of Participants Analyzed 26 27
Measure Type: Number
Unit of Measure: participants
4 2
Time Frame [Not Specified]
Adverse Event Reporting Description Safety analysis population included all participants who received at least 1 dose of study medication.
 
Arm/Group Title RIN 150 Rifampicin and Isoniazid
Hide Arm/Group Description Single oral dose of 4 fixed dose combination (FDC) tablets of RIN 150 (each tablet contains 150 mg rifampicin and 75 mg isoniazid) on Day 1 in either of the 2 intervention periods. Single oral dose of 4 rifampicin 150 mg capsules and 3 isoniazid 100 mg tablets on Day 1 in either of the 2 intervention periods.
All-Cause Mortality
RIN 150 Rifampicin and Isoniazid
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
RIN 150 Rifampicin and Isoniazid
Affected / at Risk (%) Affected / at Risk (%)
Total   0/27 (0.00%)   0/27 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
RIN 150 Rifampicin and Isoniazid
Affected / at Risk (%) Affected / at Risk (%)
Total   27/27 (100.00%)   26/27 (96.30%) 
Gastrointestinal disorders     
Mouth ulceration * 1  1/27 (3.70%)  0/27 (0.00%) 
Nausea * 1  0/27 (0.00%)  1/27 (3.70%) 
General disorders     
Catheter site haematoma * 1  0/27 (0.00%)  2/27 (7.41%) 
Catheter site pain * 1  1/27 (3.70%)  1/27 (3.70%) 
Fatigue * 1  0/27 (0.00%)  1/27 (3.70%) 
Infections and infestations     
Upper respiratory tract infection * 1  1/27 (3.70%)  1/27 (3.70%) 
Injury, poisoning and procedural complications     
Contusion * 1  1/27 (3.70%)  1/27 (3.70%) 
Lip injury * 1  1/27 (3.70%)  1/27 (3.70%) 
Nervous system disorders     
Headache * 1  1/27 (3.70%)  1/27 (3.70%) 
Renal and urinary disorders     
Chromaturia * 1  26/27 (96.30%)  25/27 (92.59%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA v15.0
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.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02014272     History of Changes
Other Study ID Numbers: B3801003
First Submitted: December 12, 2013
First Posted: December 18, 2013
Results First Submitted: June 16, 2014
Results First Posted: July 16, 2014
Last Update Posted: July 16, 2014