Metabolism of 0.35mg Norethindrone vs 5mg Norethindrone Acetate

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pilot Study Examining the Pharmacokinetics of 0.35mg Norethindrone vs 5mg Norethindrone Acetate

Conditions
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Contraception

Intervention / Treatment
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* Drug: Norethindrone Acetate 5 MG
* Drug: Norethindrone 0.35 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18-55yo Menstrual length cycles 24-34 days Previously on non-hormonal forms of contraception Ability to follow-up routinely Exclusion Criteria: Current pregnancy History of anovulatory cycles Irregular cycles (PCOS) On hormonal-based contraception or HRT in past 3 months Infertility or active hormonal treatment of infertility in past 3 months Hx of hysterectomy Postpartum <3 months H/o liver disease, kidney disease, breast cancer, venous thromboembolism Unwilling to use barrier contraception or abstinence Inability to follow-up routinely

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Drug 1<br>Half of the subjects will be assigned 0.35mg norethindrone pills daily for 7 days. The other half of the subjects will be 5mg norethindrone acetate pills daily for 7 days. | Drug: Norethindrone Acetate 5 MG<br>* As specified in arm design<br>Drug: Norethindrone 0.35 MG<br>* As specified in arm design<br>|
| Active Comparator: Drug 2<br>Half of the subjects will be assigned 5mg norethindrone acetate pills daily for 7 days. The other half of the subjects will be 0.35mg norethindrone pills daily for 7 days. | Drug: Norethindrone Acetate 5 MG<br>* As specified in arm design<br>Drug: Norethindrone 0.35 MG<br>* As specified in arm design<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 1-7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The elimination rate of norethindrone | The rate of change in serum concentration of norethindrone in individuals taking 0.35mg norethindrone and 5mg norethindrone acetate will be assessed hourly beginning 24 hours after halting medication ingestion | Hourly for eight hours on Day 8 | 
| 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 | Day 1 and Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, pilot study