Bioequivalence of Nomegestrol Acetate (NOMAC) and Estradiol (E2) in Commercial Versus Phase 3 Pivotal Clinical Batches of NOMAC-E2 Tablets (P06328)

Study Overview
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Brief Summary
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For the contraceptive application a film-coated tablet has been developed which combines nomegestrol acetate (NOMAC) with estradiol (E2). This was an open-label, randomized, single-dose, four-way, replicate, cross-over study design conducted in 2 parallel parts at two sites, one site per study part. The primary objective of Part 1 was to assess the bioequivalence of NOMAC and E2 of the drug product manufactured using the commercial process (commercial batch) versus the Phase 3 drug product (Batch A). The primary objective of Part 2 was to assess bioequivalence of NOMAC and E2 of the drug product manufactured using the commercial process (commercial batch) versus the Phase 3 drug product (Batch B).

Official Title
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A 2-part, Cross-over Trial of NOMAC-E2 to Assess Bioequivalence Between the Phase 3 Pivotal Clinical Batches and a Batch Prepared Using the Commercial Drug Manufacturing Process

Conditions
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Healthy Postmenopausal Females

Intervention / Treatment
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* Drug: Commercial NOMAC-E2
* Drug: Phase 3 NOMAC-E2 Batch A
* Drug: Phase 3 NOMAC-E2 Batch B


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Healthy postmenopausal females between the ages of 45 and 70 years, inclusive, having a Body Mass Index (BMI) between 18 and 32, inclusive; Free of any clinically significant disease that would interfere with the study evaluations. Key Exclusion Criteria: Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug; History of any infectious disease that affected the subject's ability to participate in the trial; History of alcohol or drug abuse in the past 2 years; Previously received NOMAC-E2; Current participation in another clinical study or had participated in a clinical study (eg, laboratory or clinical evaluation) within 30 days of baseline; Smoked more than 10 cigarettes or equivalent tobacco use per day; History of malignancy; Contraindications for the use of contraceptive steroids; Recent history of medication use of certain medications specified in the protocol.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Commercial NOMAC-E2, Part 1<br>Participants received a single oral dose of the NOMAC-E2 fixed-dose combination commercial tablet (2.5 mg NOMAC/1.5 mg E2), either on the first day of Period 1 and Period 3 (for participants randomized to Sequence 1) or on the first day of Period 2 and Period 4 (for participants randomized to Sequence 2). Participants in Part 1 were from Site 1. | Drug: Commercial NOMAC-E2<br>* 1 x 2.5 mg NOMAC/1.5 mg E2 fixed dose combination commercial tablet orally in the morning on Day 1 for all periods<br>* Other names: SCH 900121;|
| Active Comparator: Phase 3 NOMAC-E2, Part 1<br>Participants received a single oral dose of the NOMAC-E2 fixed-dose combination tablet (2.5 mg NOMAC/1.5 mg E2) from the Phase 3 clinical trial program (Batch A), either on the first day of Period 2 and Period 4 (for participants randomized to Sequence 1) or on the first day of Period 1 and Period 3 (for participants randomized to Sequence 2). Participants in Part 1 were from Site 1. | Drug: Phase 3 NOMAC-E2 Batch A<br>* 1 x 2.5 mg NOMAC/1.5 mg E2 fixed dose combination tablet from the Phase 3 clinical trial program (Batch A) orally in the morning on Day 1 for all periods<br>* Other names: SCH900121;|
| Experimental: Commercial NOMAC-E2, Part 2<br>Participants received a single oral dose of the NOMAC-E2 fixed-dose combination commercial tablet (2.5 mg NOMAC/1.5 mg E2), either on the first day of Period 1 and Period 3 (for participants randomized to Sequence 1) or on the first day of Period 2 and Period 4 (for participants randomized to Sequence 2). Participants in Part 2 were from Site 2. | Drug: Commercial NOMAC-E2<br>* 1 x 2.5 mg NOMAC/1.5 mg E2 fixed dose combination commercial tablet orally in the morning on Day 1 for all periods<br>* Other names: SCH 900121;|
| Active Comparator: Phase 3 NOMAC-E2, Part 2<br>Participants received a single oral dose of the NOMAC-E2 fixed-dose combination tablet (2.5 mg NOMAC/1.5 mg E2) from the Phase 3 clinical trial program (Batch B), either on the first day of Period 2 and Period 4 (for participants randomized to Sequence 1) or on the first day of Period 1 and Period 3 (for participants randomized to Sequence 2). Participants in Part 2 were from Site 2. | Drug: Phase 3 NOMAC-E2 Batch B<br>* 1 x 2.5 mg NOMAC/1.5 mg E2 fixed dose combination tablet from the Phase 3 clinical trial program (Batch B) orally in the morning on Day 1 for all periods<br>* Other names: SCH 900121;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration of NOMAC (Cmax of NOMAC) | Bioequivalence for NOMAC and E2 were tested on the primary PK parameters: Cmax, AUC(infinity), and AUClast for NOMAC; and baseline adjusted AUC72 and Cmax for E2. Blood samples for pharmacokinetic (PK) evaluation of NOMAC were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 144 hours postdose Day 1. | 0 hours to time of maximum observed plasma concentration of NOMAC (tmax of NOMAC) (blood samples were collected for NOMAC evaluation up to 144 hours postdose) | 
| Baseline Corrected Maximum Observed Serum Concentration of E2 (Cmax of E2) | Bioequivalence for NOMAC and E2 were tested on the primary PK parameters: Cmax, AUC(infinity), and AUClast for NOMAC; and baseline adjusted AUC72 and Cmax for E2. Blood samples for PK evaluation of E2 were collected predose (-1, -0.5, and 0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours postdose Day 1; multiple predose samples were needed to correct for endogenous levels. | 0 hours to time of maximum observed serum concentration of E2 (tmax of E2) (blood samples were collected for E2 evaluation up to 96 hours postdose) | 
| Area Under the Concentration-time Curve From Time 0 to the Time of the Last Measurable Sample (AUC Last) and Area Under the Concentration-time Curve From Time 0 to Infinity (AUC Infinity) for NOMAC | Bioequivalence for NOMAC and E2 were tested on the primary PK parameters: Cmax, AUC(infinity), and AUClast for NOMAC; and baseline adjusted AUC72 and Cmax for E2. AUClast is the AUC from time 0 to the time of the final quantifiable sample. AUC infinity is the AUC from time 0 to infinity. Blood samples for PK evaluation of NOMAC were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 144 hours postdose Day 1. | 0 hours to time of the last measurable sample (blood samples were collected for NOMAC evaluation up to 144 hours postdose) | 
| Baseline Corrected Area Under the Concentration-time Curve From Time 0 to 72 Hours (AUC72) for E2 | Bioequivalence for NOMAC and E2 were tested on the primary PK parameters: Cmax, AUC(infinity), and AUClast for NOMAC; and baseline adjusted AUC72 and Cmax for E2. AUC72 is the AUC from time 0 to 72 hours. Blood samples for PK evaluation of E2 were collected predose (-1, -0.5, and 0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours postdose Day 1; multiple predose samples were needed to correct for endogenous levels. | 0 hours to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax of NOMAC |  | 0 hours to tmax of NOMAC (blood samples were collected for NOMAC evaluation up to 144 hours postdose) | 
| Tmax of E2 |  | 0 hours to tmax of E2 (blood samples were collected for E2 evaluation up to 96 hours postdose) | 
| Terminal Phase Half Life (t1/2) of NOMAC |  | 0 hours to t1/2 (blood samples were collected for NOMAC evaluation up to 144 hours postdose) | 
| t1/2 of E2 |  | 0 hours to t1/2 (blood samples were collected for E2 evaluation up to 96 hours postdose) | 
| Clearance (Calculated for NOMAC Only) |  | blood samples were collected for NOMAC evaluation up to 144 hours postdose | 
| Volume of Distribution (Calculated for NOMAC Only) |  | blood samples were collected for NOMAC evaluation up to 144 hours postdose |