New Treatments for Troublesome Bleeding in Implanon Users

Phase 4 Study Comparison of Two Combined Oral Contraceptive Regimens and an Intravaginal Hormonal Ring Against Placebo for Management of Bleeding Problems in Women Using Implanon, the Sub-dermal Contraceptive Implant

Most Implanon users experience a reduction in the frequency and volume of menstrual bleeding, but a substantial minority experience unpredictable and frequent and/or prolonged episodes of bleeding. This is a double blind, placebo controlled, randomised study with an additional randomised non-blinded arm. Two hundred women between the ages of 18-45 years, who are Implanon users with prolonged or frequent breakthrough bleeding (WHO definition) will be recruited and randomised into 4 equal-sized treatment groups of 50 women assigned to Marvelon 7 days or 21 days, NuvaRing 21 days or placebo. Recruited subjects will maintain a daily menstrual diary chart for a minimum of 90 days prior to randomisation, and will be enrolled into the treatment phase provided that they have met one of the World Health Organization criteria for prolonged or frequent bleeding Following the initial 90 day record, eligible women will begin designated treatment on day 1 of the next episode of bleeding or spotting. Analysis of the subsequent menstrual pattern will begin from day 1 of that bleeding/spotting episode and will continue through 90 days.

Study Overview

• Status: Unknown
• Conditions: Menstrual Problem
• Intervention / Treatment: Drug: Marvelon

Detailed Description

This is a double blind, placebo controlled, randomised study with an additional randomised non-blinded arm. Two hundred women between the ages of 18-45 years, who are Implanon users with prolonged or frequent breakthrough bleeding (WHO definition) will be recruited and randomised into 4 equal-sized treatment groups of 50 women assigned to Marvelon 7 days or 21 days, NuvaRing 21 days or placebo. Recruited subjects will maintain a daily menstrual diary chart for a minimum of 90 days prior to randomisation, and will be enrolled into the treatment phase provided that they have met one of the World Health Organization criteria for prolonged or frequent bleeding (in the 90 day reference period one episode of bleeding and/or spotting lasting > 10 days, or more than 4 bleeding/spotting episodes). Randomisation will be performed by computer generation of a random number table in blocks of ten, with equal numbers in each of the four groups. The medications will be packed in sequentially numbered and sealed opaque envelopes (independent of the investigators).

Following the initial 90 day record, eligible women will begin designated treatment on day 1 of the next episode of bleeding or spotting. Analysis of the subsequent menstrual pattern will begin from day 1 of that bleeding/spotting episode and will continue through 90 days. Analysis of the pre-treatment menstrual pattern will include the 90 days immediately preceding the bleeding episode in which treatment starts.

Women will participate in the study for approximately seven months depending on their bleeding pattern.

Data analysis:

Data will be analysed on an intention to treat basis, entered on SPSS and analysed prior to breaking the randomisation code. Frequency analyses will be undertaken for demographic data and means (SD) compared to check effectiveness of the randomisation scheme. Total number of days of spotting, bleeding, bleeding and spotting and number of episodes during the pre and post 90 days reference period will be entered.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Edith Weisberg, MB BS MM FRANZCOG; Phone Number: +61 2 8752 4342; Email: edithw@fpnsw.org.au
• Study Contact Backup: Name: Lorraine Edney, RN; Phone Number: +61 2 8752 4381; Email: lorrainee@fpnsw.org.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2131
      • Sydney centre for Reproductive Health Research, FPNSW
      • Principal Investigator: Edith Weisberg, MB BS MM

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Healthy women aged 18-45 using the subdermal progestogen-only contraceptive implant and experiencing frequent or prolonged vaginal bleeding Willing to keep a menstrual diary for 6 months

Exclusion Criteria:

Women who have currently or previously had

• Heart attack or stroke
• Blood clot in a vein
• High blood pressure
• Severe liver or kidney disease
• Blood pressure > 135 mm systolic or >85 mm diastolic
• Migraine with aura
• Breast cancer or any genital cancer
• Severe chronic liver or kidney disease
• Women with known sensitivity to ethinyl oestradiol, progestogens
• Women taking phenytoin, carbamazepine or phenobarbitol
• Women who are pregnant
• Women who are lactating
• Women who are unwilling to keep a daily menstrual diary or otherwise unwilling to follow the study criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1 Marvelon ,placebo; 7 days daily intake of oral capsule containing "Marvelon" ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms followed by 14 days oral placebo capsules containing starch for 21 day treatment Cycle	Drug: Marvelon; 7 days daily intake of oral capsule containing containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms followed by 14 days oral placebo capsules; 21 days daily intake of oral capsules containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms; 21 days NuvaRing contraceptive vaginal ring releasing ethinyl oestradiol 15micrograms plus etonorgestrel 120 micrograms dailyleft in situ for 21 days; 21 days daily oral placebo capsules Treatment will be for one cycle of 21 days; Other Names: NuvaRing
Active Comparator: Marvelon; 21 days daily intake of oral capsules containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms; for one cycle of 21 days	Drug: Marvelon; 7 days daily intake of oral capsule containing containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms followed by 14 days oral placebo capsules; 21 days daily intake of oral capsules containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms; 21 days NuvaRing contraceptive vaginal ring releasing ethinyl oestradiol 15micrograms plus etonorgestrel 120 micrograms dailyleft in situ for 21 days; 21 days daily oral placebo capsules Treatment will be for one cycle of 21 days; Other Names: NuvaRing
Active Comparator: NuvaRing; 21 days NuvaRing contraceptive vaginal ring releasing ethinyl oestradiol 15micrograms plus etonorgestrel 120 micrograms dailyleft in situ for 21 days Treatment will be for 21 days	Drug: Marvelon; 7 days daily intake of oral capsule containing containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms followed by 14 days oral placebo capsules; 21 days daily intake of oral capsules containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms; 21 days NuvaRing contraceptive vaginal ring releasing ethinyl oestradiol 15micrograms plus etonorgestrel 120 micrograms dailyleft in situ for 21 days; 21 days daily oral placebo capsules Treatment will be for one cycle of 21 days; Other Names: NuvaRing
Placebo Comparator: Starch capsule; 21 days daily oral placebo capsules Treatment will be for one 21 day cycle	Drug: Marvelon; 7 days daily intake of oral capsule containing containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms followed by 14 days oral placebo capsules; 21 days daily intake of oral capsules containing ethinyl oestradiol 30micrograms plus desogestrel 150 micrograms; 21 days NuvaRing contraceptive vaginal ring releasing ethinyl oestradiol 15micrograms plus etonorgestrel 120 micrograms dailyleft in situ for 21 days; 21 days daily oral placebo capsules Treatment will be for one cycle of 21 days; Other Names: NuvaRing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of days to stop bleeding after initiation of each treatment group and placebo	The number of days to stop bleeding after initiation of each treatment group and placebo determined from menstrual diaries completed by subjects	Within 3 weeks of starting therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The mean total number of bleeding and spotting days during the 90 day "treatment" reference period	The mean total number of bleeding and spotting days during the 90 day "treatment" reference period compared with the pre-treatment reference period (calculated as percentage reduction) for each group and a comparison between treatment groups and placebo and compared to the other treatment groups determined from menstrual diaries kept for 90 days prior to starting treatment and for 90 days from initiation of treatment.	Six months after entering study

Collaborators and Investigators

• Sponsor: Family Planning Association New South Wales
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Edith Weisberg, MB BS MM, Family Planning NSW; Principal Investigator: Ian S FRASER, BSC MD, University of Sydney

Publications and helpful links

General Publications

• Weisberg E, Hickey M, Palmer D, O'Connor V, Salamonsen LA, Findlay JK, Fraser IS. A randomized controlled trial of treatment options for troublesome uterine bleeding in Implanon users. Hum Reprod. 2009 Aug;24(8):1852-61. doi: 10.1093/humrep/dep081. Epub 2009 Apr 15.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Anticipated): December 1, 2012
• Study Completion (Anticipated): April 1, 2013

Study Registration Dates

• First Submitted: June 27, 2011
• First Submitted That Met QC Criteria: June 28, 2011
• First Posted (Estimate): June 29, 2011

Study Record Updates

• Last Update Posted (Estimate): June 29, 2011
• Last Update Submitted That Met QC Criteria: June 28, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: Placebo controlled; Implanon users; Frequent bleeding; Prolonged bleeding; Comparison of treatments; Randomly allocated tretment
• Additional Relevant MeSH Terms: Pathologic Processes; Menstruation Disturbances; Hemorrhage; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Progestins; Desogestrel; NuvaRing
• Other Study ID Numbers: R2011-01; ACTRN12611000617965 (Registry Identifier: ANZCTR)