A Bioequivalence Study Comparing A Fixed Dose Combination Formulation Of Myrin P Forte That Contains Rifampicin, Isoniazid, Ethambutol And Pyrazinamide Per Tablet To An Equivalent Dose Of Single Drug Reference Preparations Of Similar Combination Following Oral Administration In Healthy Adults

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01399788
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 35.3

Study Details

Study Description

Brief Summary

This is a bioequivalence trial to evaluate the bioequivalence of Myrin P Forte against reference drug in healthy volunteers.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Myrin P Forte; Drug: Single drug references	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open Label, Single Dose, 2-Way Cross-Over Randomized Bioequivalence Study Comparing a Fixed Dose Combination Formulation, Myrin®-p Forte, (Contains 150 Mg Rifampicin, 75 Mg Isoniazid, 275 Mg Ethambutol and 400 Mg Pyrazinamide Per Tablet) to an Equivalent Dose of Single Drug Reference Preparations of Rifampicin, Isoniazid, Ethambutol and Pyrazinamide Following Oral Administration in Healthy Adults Under Fasting Conditions
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1.0 Test Myrin P Forte Contains 150mg Rifampicin, 75mg Isoniazid, 275mg Ethambutol, 400mg Pyrazinamide	Drug: Myrin P Forte; Tablet containing Rifampicin, Isoniazid, Ethambutol and Pyrazinamide, given once daily, single dose
Active Comparator: 2.0 Reference Single drug reference preparations contain Rifampicin, Isoniazid, Ethambutol, Pyrazinamide	Drug: Single drug references; containing Rifampicin, Isoniazid, Ethambutol and Pyrazinamide as single agents

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours (hrs) post-dose]

   Area under the plasma concentration-time curve from time zero (pre-dose) to the time of last measured concentration (AUClast).

2. Maximum Observed Plasma Concentration (Cmax) [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose]

3. Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose]

   AUClast[dn] = Dose normalized area under the plasma concentration-time curve (AUC[dn]) from time zero (pre-dose) to the time of last measured concentration. It is obtained from AUClast divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.

4. Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose]

   It is obtained from Cmax divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.

Secondary Outcome Measures

1. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose]

   AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞).

2. Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose]

   AUC [0-∞][dn] = Dose normalized area under the plasma concentration versus time curve (AUC[dn]) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-∞) divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.

3. Plasma Decay Half-life (t1/2) [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide]

   Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

4. Time to Reach Maximum Observed Plasma Concentration (Tmax) [0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy, male or female, 21 to 55 years of age, body weight no less than 55 kg, Body mass index (BMI) of 17.5 to 30.5 kg/m2. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead electrocardiogram (ECG) or clinical laboratory tests.

• An informed consent document signed and dated by the subject.

• Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), positive Hepatitis B surface antigen or Human Immunodeficiency Virus (HIV) serology results.

• pregnant or nursing female,

• alcohol, drug, smoke user,

• sensitive to any study medication or related component,

• History or active gout,

• History or active tuberculosis,

• Known optic neuritis or other ophthalmological conditions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Singapore		Singapore	188770

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01399788
• Other Study ID Numbers: B3801002
• First Posted: Jul 22, 2011
• Last Update Posted: Apr 5, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Pfizer: Bioequivalence; Healthy Volunteers

Study Results

Participant Flow

Arm/Group Title	Myrin-P Forte First, Then Four Single Drug References	Four Single Drug References First, Then Myrin-P Forte
Arm/Group Description	Single oral dose of 4 fixed dose combination (FDC) tablets of Myrin-P Forte (each tablet contains 150 milligram (mg) rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide) in first intervention period; and single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in second intervention period. A washout period of at least 1 week was maintained between each period.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in first intervention period; and single oral dose of 4 FDC tablets of Myrin-P Forte (each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide) in second intervention period. A washout period of at least 1 week was maintained between each period.
Period Title: First Intervention Period
STARTED	18	18
COMPLETED	17	18
NOT COMPLETED	1	0
Period Title: First Intervention Period
STARTED	17	18
COMPLETED	17	18
NOT COMPLETED	0	0
Period Title: First Intervention Period
STARTED	17	18
COMPLETED	17	18
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes participants randomized to receive Myrin-P Forte first and four single drug references first.
Overall Participants	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.6 (8.8)
Sex: Female, Male (Count of Participants)
Female	2 5.6%
Male	34 94.4%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Description	Area under the plasma concentration-time curve from time zero (pre-dose) to the time of last measured concentration (AUClast).
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours (hrs) post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Rifampicin	79360.0 (29613.0)	77180.0 (20516.0)
Isoniazid	20550.0 (12920.0)	18800.0 (12941.0)
Ethambutol	15070.0 (3298.8)	15170.0 (3119.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Rifampicin; 32 participants (16 per sequence) provided at least 99% power that 90% confidence interval (CI) for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject coefficient of variation (CV) estimate of approximately 14.5% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	103.81
	Confidence Interval	(2-Sided) 90%; 99.20 to 108.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Isoniazid; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 12.0% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	107.28
	Confidence Interval	(2-Sided) 90%; 101.95 to 112.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Ethambutol; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 12.9% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	99.48
	Confidence Interval	(2-Sided) 90%; 94.92 to 104.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Rifampicin	12120.0 (3682.3)	11830.0 (2351.8)
Isoniazid	4418.0 (1619.0)	4237.0 (1658.9)
Ethambutol	2771.0 (825.4)	2865.0 (950.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Rifampicin: 32 participants (16 per sequence) provided at least 98% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 18.2% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	102.75
	Confidence Interval	(2-Sided) 90%; 95.36 to 110.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Isoniazid; 32 participants (16 per sequence) provided at least 98% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 18.2% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	103.85
	Confidence Interval	(2-Sided) 90%; 92.13 to 117.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Ethambutol; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 16.0% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	99.48
	Confidence Interval	(2-Sided) 90%; 94.92 to 104.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide
Description	AUClast[dn] = Dose normalized area under the plasma concentration-time curve (AUC[dn]) from time zero (pre-dose) to the time of last measured concentration. It is obtained from AUClast divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Geometric Mean (Standard Deviation) [(ng*hr/mL)/mg]	453500 (76250)	447900 (82578)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Pyrazinamide; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 5.2% for AUClast was used for this power calculation. Natural log transformed AUClast(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	101.73
	Confidence Interval	(2-Sided) 90%; 99.12 to 104.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide
Description	It is obtained from Cmax divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Geometric Mean (Standard Deviation) [(ng/mL)/mg]	33890.0 (6490.2)	35580.0 (12134.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Pyrazinamide; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 6.7% for Cmax was used for this power calculation. Natural log transformed Cmax(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	95.17
	Confidence Interval	(2-Sided) 90%; 88.60 to 102.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞])
Description	AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞).
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period. Here, 'n' is number of participants who were evaluable for this measure.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Rifampicin (n= 36, 35)	80940.0 (34613.0)	78400.0 (22226.0)
Isoniazid (n= 35, 35)	21210.0 (13562.0)	19460.0 (14171.0)
Ethambutol (n= 28, 31)	17150.0 (3362.1)	17050.0 (3378.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Rifampicin; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	104.30
	Confidence Interval	(2-Sided) 90%; 99.70 to 109.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Isoniazid; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	105.74
	Confidence Interval	(2-Sided) 90%; 100.32 to 111.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Ethambutol; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	100.97
	Confidence Interval	(2-Sided) 90%; 96.28 to 105.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide
Description	AUC [0-∞][dn] = Dose normalized area under the plasma concentration versus time curve (AUC[dn]) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-∞) divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Geometric Mean (Standard Deviation) [(ng*hr/mL)/mg]	471000 (85153)	464800 (92222)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myrin-P Forte, Four Single Drug References
	Comments	Pyrazinamide; Natural log transformed AUC (0 -∞)(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	101.80
	Confidence Interval	(2-Sided) 90%; 99.24 to 104.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Plasma Decay Half-life (t1/2)
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period. Here, 'n' is number of participants who were evaluable for this measure.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Rifampicin (n= 36, 35)	3.6630 (1.0477)	3.4290 (0.6938)
Isoniazid (n= 35, 35)	3.7340 (0.9197)	3.9470 (1.1751)
Ethambutol (n= 28, 31)	7.7430 (1.1716)	7.6390 (1.1158)
Pyrazinamide (n= 36, 35)	9.8630 (1.3333)	9.7660 (1.3671)

8. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame	0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.

Arm/Group Title	Myrin-P Forte	Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.	Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
Measure Participants	36	35
Rifampicin	2.00	1.50
Isoniazid	1.02	1.00
Ethambutol	2.77	2.48
Pyrazinamide	1.50	1.50

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Myrin-P Forte		Four Single Drug References
Arm/Group Description	Single oral dose of 4 FDC tablets of Myrin-P Forte (Test) in either first intervention period or second intervention period. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 275 mg ethambutol and 400 mg pyrazinamide.		Single oral dose of 4 reference products: 600 mg rifampicin capsules, 300 mg isoniazid, 1100 mg ethambutol and 1500 mg pyrazinamide tablets in either first intervention period or second intervention period.
All Cause Mortality
	Myrin-P Forte		Four Single Drug References
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Myrin-P Forte		Four Single Drug References
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Myrin-P Forte		Four Single Drug References
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/36 (94.4%)		31/35 (88.6%)
Gastrointestinal disorders
Abdominal pain	1/36 (2.8%)		0/35 (0%)
Diarrhoea	1/36 (2.8%)		0/35 (0%)
Nausea	1/36 (2.8%)		0/35 (0%)
General disorders
Catheter site swelling	1/36 (2.8%)		0/35 (0%)
Pyrexia	1/36 (2.8%)		0/35 (0%)
Infections and infestations
Oral herpes	1/36 (2.8%)		0/35 (0%)
Upper respiratory tract infection	1/36 (2.8%)		0/35 (0%)
Investigations
Blood glucose increased	1/36 (2.8%)		1/35 (2.9%)
Cardiac murmur functional	0/36 (0%)		1/35 (2.9%)
Nervous system disorders
Dizziness	0/36 (0%)		1/35 (2.9%)
Headache	1/36 (2.8%)		0/35 (0%)
Renal and urinary disorders
Chromaturia	32/36 (88.9%)		31/35 (88.6%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/36 (0%)		1/35 (2.9%)
Rhinorrhoea	1/36 (2.8%)		0/35 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	1/36 (2.8%)		1/35 (2.9%)
Drug eruption	1/36 (2.8%)		1/35 (2.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.