A Phase III Randomized Study of a Levonorgestrel-Releasing Intrauterine System and Mirena for Long Term Reversible Contraception

Overview

Status: Completed
Keywords: Long Term Birth Control , Birth Control , IUD
IRB Number: 00039191
Specialty: OB/Gyn, General
Sub Specialties: General Obstetrics

Brief Summary

The levonorgestrel IUS (LNG20) that Medicines360 proposes to develop consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir around the vertical stem. The steroid reservoir is covered with a polydimethylsiloxane membrane which controls the release rate of levonorgestrel from the reservoir. The LNG20 reservoir contains 52 mg levonorgestrel; providing an initial release rate of 20 mcg/day. A polypropylene monofilament blue thread is attached to the end of the vertical stem. Please refer to the Investigator’s Brochure for full details on the components of LNG20.
 
LNG20 is currently being investigated in a multi-center, single-blind randomized trial in Europe to assess the therapeutic equivalence in terms of efficacy and safety compared to Mirena in patients with menorrhagia. Enrollment of 280 subjects was completed in January, 2009 and 50% were randomized to LNG20. Serious Adverse Events collected during the reporting period did not reveal any new safety concerns and did not change the overall risk-benefit evaluation for LNG20. To date, adverse event-related removals of the IUS have occurred in five women (three LNG20, two Mirena). The three LNG20 removals were related to ovarian cysts (one of these three subjects required hospitalization). The two Mirena removals followed development of abdominal and peripheral edema in one subject, and reported nervousness, chest tension, abdominal pain, and hypertension in a second subject. Expulsion of the IUS has been reported in a total of 10 subjects (five LNG20, five Mirena). No deaths occurred in this reporting period. An interim review of all safety data reported as of December 2008 supports that LNG20 was generally well tolerated in female subjects with menorrhagia.
 

OBJECTIVES:
 
This study is being performed to evaluate the Medicines360 levonorgestrel-releasing IUS, LNG20. LNG20 is expected to provide safe and effective contraception for 5 or more years.
 
 
Primary Objective
 
The primary objective of this study is to assess the efficacy of a levonorgestrel-releasing intrauterine system (LNG20) in nulliparous and parous females of child-bearing potential who request long-term, reversible contraception.
 
Secondary Objectives
 
The secondary objectives of this study are to assess:
 
• The safety, tolerability, bleeding patterns, and continuation rates of LNG20
 
• The occurrence of menses and return to fertility after IUS discontinuation
 
• The plasma pharmacokinetics of levonorgestrel in a subset of 80 subjects (40 for each IUS) with serial sampling over the duration of use
 
• Levonorgestrel levels in a subset of approximately 60 subjects (LNG20 arm only) following IUS removal at 60 months with sampling at various timepoints up to 14 days post-IUS removal
 
• Plasma levonorgestrel levels for all subjects at each visit starting with Month 36 to support a decision for extended duration of use of LNG20 beyond Month 60
 
• Residual levonorgestrel levels and ex vivo release rates in an appropriate sampling of IUSs that are removed and, when available, expelled during the study
 
• The safety and tolerability of LNG20 in a small cohort of women between ages 36 and 45 years
 
• Endometrial thickness at 1 year and 5 years of LNG20 use
 

The Utah study site has been selected to participate in the PK Treatment substudy.
 
• Levonorgestrel PK data will be generated in a subset of 80 subjects, (approximately 40 subjects per study arm). Blood samples will be obtained at the Enrollment Visit (pre-IUS insertion), Weeks 1 and 2, and Months 1, 3, 6, 9, 12, 18, 24 and 30 after IUS insertion.
 

Principal Investigator: David Turok
Department: DFPM-Family Practice
Co Investigator:

Contact Information

Name:Vineela Maddukuri
Phone: 801-213-3796
Email: vineela.maddukuri@hsc.utah.edu

Inclusion Criteria

PRIMARY STUDY:
 

  1. Signed informed consent
  2. Healthy females 16-45 years old inclusive at the time of enrollment
  3. Sexually active and in a mutually monogamous relationship at study entry
  4. Willing to rely on the IUS as the primary method of contraception during study participation
  5. History of regular menstrual cycles defined as occurring every 21-35 days when not using hormones and with a variation of typical cycle length of no more than 5 days
  6. Willing to comply with study visit schedule and assessments, including diary completion requirements 

Treatment PK Substudy
 
In addition to meeting all entry criteria for the primary study, subjects desiring to enter the PK substudy must meet all of the following criteria:
 

  • be 16-35 years old at the time of enrollment in the primary study.
  • have signed informed consent for the PK sampling prior to collection of the blood sample on Day 1. 
  • Have venous access adequate for multiple blood draws 
  • have not received hormonal contraception within 7 days of enrollment

Exclusion Criteria

Subjects meeting any of the following criteria will be ineligible for study entry:
 

  1. Currently pregnant 
  2. Pregnant within 4 weeks prior to study entry
  3. Planning pregnancy within 24 months of study entry
  4. Currently breastfeeding
  5. History of ectopic pregnancy without a subsequent intrauterine pregnancy
  6. History of trophoblastic disease (benign or malignant gestational) without a subsequent non-trophoblastic intrauterine pregnancy
  7. Acute pelvic inflammatory disease or a history of pelvic inflammatory disease without subsequent intrauterine pregnancy
  8. Known to be HIV positive or have a partner who is known to be HIV positive
  9. History of cervical or vaginal infection (unless successfully treated and considered clinically cured for at least 7 days prior to study entry)
  10. Postpartum or post-abortion endometritis unless symptoms resolved at least 4 weeks prior to study entry
  11. Current persistent, abnormal vaginal bleeding
  12. Abnormal Pap smear based on the following criteria:

 •Pap smear in the past 18 months with ASC-US unless:


oLess than 21 years of age
 
oa repeat Pap smear at least 6 months later was normal;
 
oreflex HPV testing was performed and was negative for high-risk HPV; or
 
oreflex HPV testing was performed and was positive for high-risk HPV, and colposcopy (with or without biopsy) found no evidence of dysplasia requiring treatment or treatment was performed and follow-up at least six months after the treatment showed no evidence of the disease;
 
•Pap smear in the past 18 montsh with LSIL unless:
 
oLess than 21 years of age; or
 
oA coloposcopy (with or without biopsy) found no evidence of dysplasia requiring treatment or treatment was performed and follow-up at least six months after the treatment showed no evidence of disease;
 
•Pap smear in the past 18 months with ASC-H, atypical glandular cells, LSIL, or HSIL unless colposcopy and/or treatment was performed and follow-up at least 6 months after the colposcopy and/or treatment showed no evidence of disease;
 
•Pap smear in the past 18 months with malignant cells
 
13. History of malignancy of the genital tract (e.g. cervical cancer, ovarian cancer, endometrial cancer)
 
14. History of breast cancer, or suspicion of breast cancer until proven otherwise
 
15. History of bicornuate uterus or any other abnormality of the uterus resulting in distortion of the uterine cavity or cervical canal incompatible with insertion
 
16. Known or suspected allergy to levonorgestrel or hypersensitivity to any component of the product
 
17. Bleeding diathesis (inherited or acquired)
 
18. Use of anticoagulants within 30 days prior to study entry
 
19. Body habitus or history of lower genital tract abnormalities or prior surgeries which may prohibit proper visualization of the cervix or not allow the uterus to be appropriately instrumented [Note: any women who may meet this criteria should have a pelvic examination prior to randomization to confirm that the cervix cannot be properly visualized for IUS insertion]
 
20. Current or history of alcohol or illicit drug abuse within 12 months prior to study entry
 
21. Current use of hormonal contraception for cycle control
 
22. DMPA (Depo-Provera®/Depo-Ralovera®) injection:
 
• within the past 9 months, OR
 
• within the past 6 months, if subject has also had two spontaneous menstrual cycles (requires minimum of 3 menses) that meet criteria for normal menstrual cycles
 
23. Current use of non-contraceptive estrogen, progesterone, or testosterone
 
24. Use of an experimental medication or receipt of an experimental treatment for any condition within 30 days of study entry
 
25. Study staff or a member of the immediate family of a study staff
 
26. Any condition that, in the opinion of the investigator, would constitute contraindications to participation in the study or would compromise ability to comply with the study protocol