Comparing Bioavailability When Makena® is Administered in Healthy Post-menopausal Women
Conditions
Brief summary
To demonstrate that a single dose of Makena® delivered SQ via auto-injector has comparable bioavailability to a single IM injection of Makena®.
Interventions
Sponsors
AMAG Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Naturally or surgically postmenopausal women, with or without an intact uterus, aged 50 to 75 years of age, inclusive. FSH levels greater than 40 mIU/mL
Exclusion criteria
1. Currently taking any estrogen/progesterone hormone replacement therapy (HRT). 2. History of allergy or sensitivity to hydroxyprogesterone caproate, castor oil or any of the constituents of the study medications, or history of any drug hypersensitivity or intolerance 3. Poorly controlled diabetes. 4. History or current evidence of deep vein thrombosis, pulmonary embolism or arterial thromboembolic disease (e.g., stroke, myocardial infarction). 5. Known, suspected, or current history of carcinoma of the breast. 6. Subjects with a past history of breast cancer on aromatase inhibitors or selective estrogen receptor modulators. 7. Known, suspected, or current history of hormone dependent tumor within the last 5 years. 8. Any current or recent (within previous 12 months) genital bleeding of unknown etiology. 9. Receipt of any investigational drug within 30 days. 10. Receipt of any prescription or OTC medications that are known to alter CYP3A4 or CYP3A5 levels (e.g., carbamazepine, St. John's Wort, ketoconazole, rifampin, ritonavir, alprazolam, azithromycin, loratadine, etc.) within 14. 11. Any estrogen, progestin, or selective estrogen receptor modulator (SERM) treatment within specified time windows before the study start, ranging from 2 to 6 months. 12. High blood pressure at the screening evaluation, defined as systolic blood pressure \> 150 mm Hg or diastolic blood pressure \> 90 mm Hg. 13. History of excessive alcohol consumption (on average more than 14 units of alcohol/week) during the past 12 months. 14. Use of tobacco products within 30 days of the start of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf] | 9 weeks | Comparison of areas under the curve (AUC) to the last time with a concentration ≥ LLOQ \[AUC0-t\] and to infinity \[AUCinf\] for the Primary PK Population |
| Comparison of the Maximum Plasma Concentration (Cmax) | 9 weeks | Comparison of the maximum plasma concentration (Cmax) for the Primary PK Population |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Tmax | 9 weeks | Comparison of PK parameter Tmax for the Primary PK population |
| Comparison of AUC (0-168) | 9 weeks | Comparison of PK Parameter AUC (0-168) for the Primary PK Population |
| Comparison of t1/2 | 9 weeks | Comparison of PK parameter t1/2 for the Primary PK Population |
| Comparison of Elimination Rate Constant | 9 weeks | Comparison of the elimination rate constant for the Primary PK Population |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment A Subcutaneous (SQ) injection using an autoinjector
Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) | 59 |
| Treatment B Intramuscular injection (IM) using syringe and needle
Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) | 61 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment B | Treatment A | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 12 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 47 Participants | 100 Participants |
| Age, Continuous | 57.0 years STANDARD_DEVIATION 5.68 | 59.7 years STANDARD_DEVIATION 6.16 | 58.4 years STANDARD_DEVIATION 6.05 |
| Region of Enrollment United States | 61 participants | 59 participants | 120 participants |
| Sex: Female, Male Female | 61 Participants | 59 Participants | 120 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 59 | 23 / 61 |
| serious Total, serious adverse events | 0 / 59 | 0 / 61 |
Outcome results
Primary
Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf]
Comparison of areas under the curve (AUC) to the last time with a concentration ≥ LLOQ \[AUC0-t\] and to infinity \[AUCinf\] for the Primary PK Population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf] | AUC(0-t) | 2,313 hr x ng/mL | Geometric Coefficient of Variation 23.5 |
| Treatment A | Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf] | AUC(inf) | 2,469 hr x ng/mL | Geometric Coefficient of Variation 22.8 |
| Treatment B | Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf] | AUC(0-t) | 2,098 hr x ng/mL | Geometric Coefficient of Variation 27.7 |
| Treatment B | Comparison of Areas Under the Curve (AUC) to the Last Time With a Concentration ≥ LLOQ [AUC0-t] and to Infinity [AUCinf] | AUC(inf) | 2,175 hr x ng/mL | Geometric Coefficient of Variation 27.8 |
Primary
Comparison of the Maximum Plasma Concentration (Cmax)
Comparison of the maximum plasma concentration (Cmax) for the Primary PK Population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Comparison of the Maximum Plasma Concentration (Cmax) | 7.88 ng/mL | Geometric Coefficient of Variation 71.9 |
| Treatment B | Comparison of the Maximum Plasma Concentration (Cmax) | 6.91 ng/mL | Geometric Coefficient of Variation 62.9 |
Secondary
Comparison of AUC (0-168)
Comparison of PK Parameter AUC (0-168) for the Primary PK Population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Comparison of AUC (0-168) | 813 hr x ng/mL | Geometric Coefficient of Variation 41.5 |
| Treatment B | Comparison of AUC (0-168) | 790 hr x ng/mL | Geometric Coefficient of Variation 55.5 |
Secondary
Comparison of Elimination Rate Constant
Comparison of the elimination rate constant for the Primary PK Population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Comparison of Elimination Rate Constant | 0.0033 1/hr | Geometric Coefficient of Variation 29.1 |
| Treatment B | Comparison of Elimination Rate Constant | 0.0038 1/hr | Geometric Coefficient of Variation 25.5 |
Secondary
Comparison of t1/2
Comparison of PK parameter t1/2 for the Primary PK Population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Comparison of t1/2 | 212 hr | Geometric Coefficient of Variation 29.1 |
| Treatment B | Comparison of t1/2 | 185 hr | Geometric Coefficient of Variation 25.5 |
Secondary
Comparison of Tmax
Comparison of PK parameter Tmax for the Primary PK population
Time frame: 9 weeks
Population: The Primary PK Population consisted of 45 subjects each for both treatments for whom whole blood was analyzed. Subjects were excluded from Treatment A and Treatment B due to insufficient number of samples for planned analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Comparison of Tmax | 48.1 hr |
| Treatment B | Comparison of Tmax | 49.7 hr |