Contraception
Conditions
Keywords
pharmacokinetics, pilot study
Brief summary
0.35mg norethindrone, also known as progesterone only pills, are routinely prescribed as immediate postpartum oral contraception. Norethindrone acetate is prescribed for gynecologic indications, but has never been studied as an efficacious form of contraception. This is a pilot crossover study examining the pharmacokinetics of norethindrone, the metabolically active component of both drugs, in participants taking 5mg norethindrone and 0.35mg norethindrone acetate.
Detailed description
Progesterone only pills are utilized as immediate postpartum contraception. Though it is demonstrated to be safe as contraception, it is known to be less efficacious than other forms of progestin-only contraception, such as DMPA injections, etonogestrel implant insertion, or progestin-containing intrauterine devices. This is largely secondary to its short half-life. Norethindrone acetate is known to have a longer half-life than norethindrone. Though it is widely used in various gynecologic settings, it has never been studied as a contraceptive option. The metabolically active component of norethindrone is norethindrone itself. This study aims to confirm that amounts of norethindrone are comparable or greater in participants taking 5mg of norethindrone acetate vs taking 0.35mg norethindrone, thereby demonstrating the ability to prescribe 5mg norethindrone acetate as a safe and efficacious form of contraception. This is a pilot crossover study that will study the pharmacokinetics of norethindrone vs norethindrone acetate. 6 subjects will be a part of this study. Three will be assigned to 0.35mg norethindrone as the initial drug and three will be assigned to 5 mg norethindrone acetate as the initial drug. Starting on day 1-3 of the menstrual cycle, participants will start taking Drug 1 at 7:30am every morning for Days 1-7. At 8am Day 1-7 participants will present to the the Clinical Research Laboratory at Milton S. Hershey Medical Center for an 8am blood draw to examine serum norethindrone levels. On Day 8 participants will stop taking the medication. On Day 8 subjects will present to the Clinical Research Lab and will have an IV placed. Participants will get a pregnancy test to rule-out pregnancy and then hourly blood draws from 8am to 4pm to examine serum norethindrone levels. Participants will also fill out a Symptom Diary detailing side effects and overall satisfaction with the drug. Additionally, on Days 1 and 21, participants will have serum levels drawn to evaluate levels of luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone levels. Participants will undergo a one month washout. For Cycle 2, the alternate drug will be administered and monitored in the process as detailed above. The serum samples will be collected in batches, will be spun down and stored in a -4 degree freezer. Levels of norethindrone in serum samples will be measured.
Interventions
DRUGNorethindrone Acetate 5 MG
As specified in arm design
As specified in arm design
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Women aged 18-55yo 2. Menstrual length cycles 24-34 days 3. Previously on non-hormonal forms of contraception 4. Ability to follow-up routinely
Exclusion criteria
1. Current pregnancy 2. History of anovulatory cycles 3. Irregular cycles (PCOS) 4. On hormonal-based contraception or HRT in past 3 months 5. Infertility or active hormonal treatment of infertility in past 3 months 6. Hx of hysterectomy 7. Postpartum \<3 months 8. H/o liver disease, kidney disease, breast cancer, venous thromboembolism 9. Unwilling to use barrier contraception or abstinence 10. Inability to follow-up routinely
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentration of Norethindrone | Day 1-7 | The change in serum concentration of norethindrone in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate will be assessed daily over one week of medication use. Norethindrone levels are then averaged across all subjects teaching each medication in each sequence for days 1-7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Day 8 Norethindrone Levels | Hourly for eight hours on Day 8 | The change in serum concentration of norethindrone in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate will be assessed hourly for 8 hours in the absence of exposure to either medication. This is represented as a rate of decline. |
| Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Day 1 and Day 21 | The serum levels of estradiol, LH, FSH, and progesterone will be compared in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate at study start and on Day 21 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Sequence 1: 0.35mg norethindrone first, then 5mg norethindrone acetate | 3 |
| Sequence 2 Sequence 2: 5mg norethindrone acetate first, then 0.35mg norethindrone | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | Sequence 1 | Sequence 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Continuous | 28 years STANDARD_DEVIATION 2 | 32 years STANDARD_DEVIATION 2 | 30 years STANDARD_DEVIATION 4 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants |
| Regular menstrual cycles, not on hormonal contraception | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 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 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Serum Concentration of Norethindrone
The change in serum concentration of norethindrone in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate will be assessed daily over one week of medication use. Norethindrone levels are then averaged across all subjects teaching each medication in each sequence for days 1-7.
Time frame: Day 1-7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 2 | 13.56 ng/ml | Standard Deviation 8.695089814 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 5 | 11.82 ng/ml | Standard Deviation 9.173183846 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 1 | 15.69 ng/ml | Standard Deviation 8.6 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 6 | 18.92 ng/ml | Standard Deviation 8.652213867 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 4 | 16.56 ng/ml | Standard Deviation 9.173183846 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 7 | 11.30 ng/ml | Standard Deviation 6.505930925 |
| 5mg Norethindrone Acetate | Serum Concentration of Norethindrone | Day 3 | 13.96 ng/ml | Standard Deviation 9.767023293 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 7 | 2.22 ng/ml | Standard Deviation 1.3 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 3 | 2.28 ng/ml | Standard Deviation 1.28 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 1 | 2.28 ng/ml | Standard Deviation 1.878562984 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 2 | 2.50 ng/ml | Standard Deviation 2.02 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 4 | 2.42 ng/ml | Standard Deviation 1.08 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 5 | 2.22 ng/ml | Standard Deviation 1.65 |
| 0.35mg Norethindrone | Serum Concentration of Norethindrone | Day 6 | 2.82 ng/ml | Standard Deviation 1.65 |
Secondary
Day 8 Norethindrone Levels
The change in serum concentration of norethindrone in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate will be assessed hourly for 8 hours in the absence of exposure to either medication. This is represented as a rate of decline.
Time frame: Hourly for eight hours on Day 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 7 | 1.0 ng/mL | Standard Deviation 0.433300735 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 1 | 1.17 ng/mL | Standard Deviation 0.389190923 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 6 | 0.99 ng/mL | Standard Deviation 0.38615963 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 8 | 1.03 ng/mL | Standard Deviation 0.463022482 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 0 | 1.54 ng/mL | Standard Deviation 0.583608153 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 2 | 1.31 ng/mL | Standard Deviation 0.451133779 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 3 | 1.29 ng/mL | Standard Deviation 0.535815038 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 4 | 1.13 ng/mL | Standard Deviation 0.480888744 |
| 5mg Norethindrone Acetate | Day 8 Norethindrone Levels | Hour 5 | 1.04 ng/mL | Standard Deviation 0.367513739 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 4 | 0.11 ng/mL | Standard Deviation 0.084 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 2 | 0.149843333 ng/mL | Standard Deviation 0.071421545 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 1 | 0.129893333 ng/mL | Standard Deviation 0.079030195 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 0 | 0.14729 ng/mL | Standard Deviation 0.07215209 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 6 | 0.096743333 ng/mL | Standard Deviation 0.067140596 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 7 | 0.090736667 ng/mL | Standard Deviation 0.0645776 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 3 | 0.112873333 ng/mL | Standard Deviation 0.076 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 8 | 0.089563333 ng/mL | Standard Deviation 0.063464118 |
| 0.35mg Norethindrone | Day 8 Norethindrone Levels | Hour 5 | 0.11041 ng/mL | Standard Deviation 0.11041 |
Secondary
Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone
The serum levels of estradiol, LH, FSH, and progesterone will be compared in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate at study start and on Day 21
Time frame: Day 1 and Day 21
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Estradiol Day 1 | 34.7 ng/mL | Standard Deviation 9.44 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Progesterone Day 1 | 0.45 ng/mL | Standard Deviation 0.19 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Progesterone Day 21 | 0.95 ng/mL | Standard Deviation 0.97 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Estradiol Day 21 | 147 ng/mL | Standard Deviation 176 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | LH Day 1 | 6.73 ng/mL | Standard Deviation 1.56 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | LH Day 21 | 11.8 ng/mL | Standard Deviation 9.7 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | FSH Day 1 | 8.73 ng/mL | Standard Deviation 3.5 |
| 5mg Norethindrone Acetate | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | FSH Day 21 | 6.7 ng/mL | Standard Deviation 3.1 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | FSH Day 21 | 2.75 ng/mL | Standard Deviation 0.3 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | LH Day 1 | 7.4 ng/mL | Standard Deviation 1.4 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Progesterone Day 1 | 0.44 ng/mL | Standard Deviation 0.16 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | FSH Day 1 | 8.53 ng/mL | Standard Deviation 3.2 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Progesterone Day 21 | 11.6 ng/mL | Standard Deviation 3.72 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Estradiol Day 1 | 33.5 ng/mL | Standard Deviation 7.8 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | LH Day 21 | 6.65 ng/mL | Standard Deviation 5.37 |
| 0.35mg Norethindrone | Differences of Serum Levels of Estradiol, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), and Progesterone | Estradiol Day 21 | 139 ng/mL | Standard Deviation 56.45 |