Metabolism of 0.35mg Norethindrone vs 5mg Norethindrone Acetate

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

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.

Study Overview

• Status: Completed
• Conditions: Contraception
• Intervention / Treatment: Drug: Norethindrone Acetate 5 MG; Drug: Norethindrone 0.35 MG

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Drug 1; 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; As specified in arm design; Drug: Norethindrone 0.35 MG; As specified in arm design
Active Comparator: Drug 2; 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; As specified in arm design; Drug: Norethindrone 0.35 MG; As specified in arm design

What is the study measuring?

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. Norethindrone levels are then averaged across all subjects teaching each medication in each sequence for days 1-7.	Day 1-7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2022
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: March 1, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 24, 2022

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 11, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: pharmacokinetics; pilot study
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Norethindrone; Norethindrone Acetate
• Other Study ID Numbers: 19587

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No