Prevention of Ovulation Achieved by Single Intra-vaginal Administration of Levogel as Compared to Oral LNG

A Randomized, Cross-over, Clinical Trial to Assess the Prevention of Ovulation Achieved by Single Intra-vaginal Administration of 0.75 mg Levonorgestrel (LNG) Gel (Levogel) as Compared to 1.5 mg Oral LNG

It has been proposed that levonorgestrel (LNG) in a vaginal gel could be used as an 'on demand' contraceptive when used before coitus. Levonorgestrel was selected as it is a component of many approved oral contraceptive pills and also it is the active agent in Plan B, an FDA-approved regimen for emergency contraception (EC). In previous studies it was demonstrated that an LNG vaginal gel was absorbed and was effective in preventing follicular rupture. The overall proportion of cycles with lack of follicular rupture within 5 days of LNG administration or with ovulatory dysfunction (follicle rupture preceded by an inadequate LH surge) was 96% for LNG gel and 39% in the inert gel cycles (control group).

Study Overview

• Status: Completed
• Conditions: Female Contraception
• Intervention / Treatment: Drug: Levonorgestrel (LNG) gel (Levogel) and oral LNG (Plan B)

Detailed Description

A dose of 0.75mg of LNG in a vaginal gel was shown to prevent ovulation in a higher percentage than what has been observed with oral LNG at the approved doses for EC of 1.5mg. Results from a study with a1.5 mg LNG oral dose or a single 0 ,75mg dose demonstrated that the proportion of cycles without follicle rupture or ovulatory dysfunction within 5 days was 86% and 79% respectively (Croxatto et al, 2004) , whereas lack of follicular rupture or the presencr of ovulatory dsyfunction was 96% with administration of a LNG gel formulation. In the group of women with follicle size ≥18mm the gel induced 50% ovulation suppression while oral LNG in previous studies blocked only 16% of ovulation in the same follicle size group . These encouraging results could be explained by higher bioavailability of LNG when administered vaginally. This comparison was made using historical data from another study; therefore this study will compare vaginal administration of LNG to oral in a direct cross-over comparative study.

LNG is known to affect the cervical mucus by making it hostile to sperm penetration and its effect may appear after only a few hours following oral administration (Kesseru, 1984; Brache, unpublished observations). Application of LNG gel in the vagina close to the cervical os may exert a direct effect on the cervical mucus. The potential local action of LNG on the cervical mucus may be another important mechanism by which protection is conferred to women who do not experience ovulation suppression.

An "on demand" precoital contraceptive is an attractive alternative to the post-coital emergency contraception currently available, especially due to the higher efficacy of this route of administration on ovulation suppression as compared with oral tablets of LNG. Should the present study confirm the superiority of vaginal administration of half the dose of the oral dose of LNG approved for emergency contraception, further development of that formulation and method would be warranted.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Chile
  • Santiago
    • José Victorino Lastarria 29, Santiago, Chile
      • Instituto Chileno de Medicina Reproductiva
• Dominican Republic
  • Santo Domingo
    • Socorro Sanchez No. 160, Santo Domingo, Dominican Republic, Apartado Postal 1053
      • Profamilia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 39 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Healthy women aged 21-39 years with regular menstrual cycles (25-35 days) and not at risk of pregnancy.

Exclusion Criteria:

• All contraindications to the use of progestins

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Levonorgestrel (LNG) gel (Levogel); This is a randomized study with a cross-over design comparing two single dose treatment sequences of either Levogel (LNG vaginal gel 0.750 mg/4g) or oral LNG (1.5mg). All women with a leading follicle diameter of ≥18 mm will be randomized to treatment with a single intra-vaginal application of LNG gel or oral LNG. After a washout cycle, the women will be crossed over to receive the other treatment and the study procedures will be repeated.	Drug: Levonorgestrel (LNG) gel (Levogel) and oral LNG (Plan B); This is a randomized study with a cross-over design comparing two single dose treatment sequences of either Levogel (LNG vaginal gel 0.750 mg/4g) or oral LNG (1.5mg). All women with a leading follicle diameter of ≥18 mm will be randomized to treatment with a single intra-vaginal application of LNG gel or oral LNG. After a washout cycle, the women will be crossed over to receive the other treatment and the study procedures will be repeated.
Active Comparator: oral LNG (1.5mg); This is a randomized study with a cross-over design comparing two single dose treatment sequences of either Levogel (LNG vaginal gel 0.750 mg/4g) or oral LNG (1.5mg). All women with a leading follicle diameter of ≥18 mm will be randomized to treatment with a single intra-vaginal application of LNG gel or oral LNG. After a washout cycle, the women will be crossed over to receive the other treatment and the study procedures will be repeated.	Drug: Levonorgestrel (LNG) gel (Levogel) and oral LNG (Plan B); This is a randomized study with a cross-over design comparing two single dose treatment sequences of either Levogel (LNG vaginal gel 0.750 mg/4g) or oral LNG (1.5mg). All women with a leading follicle diameter of ≥18 mm will be randomized to treatment with a single intra-vaginal application of LNG gel or oral LNG. After a washout cycle, the women will be crossed over to receive the other treatment and the study procedures will be repeated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of LNG gel and oral LNG on follicle rupture	The main objective of the study is to compare the effect of LNG gel and oral LNG on follicle rupture as assessed by ultrasound.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate effect of single intra-vaginal administration	The secondary objectives are to evaluate the effect of single intra-vaginal administration of LNG gel or oral LNG on the: growth of the leading follicle; suppression of the preovulatory peak of serum luteinizing hormone (LH); characteristics of the cervical mucus; serum levels of estradiol (E2) and progesterone (P)	1 year

Collaborators and Investigators

• Sponsor: Population Council
• Investigators: Principal Investigator: Vivian Brache, Lic., Profamilia; Principal Investigator: Regine Sitruk-Ware, PhD., Population Council; Principal Investigator: María José Miranda Gaete, MD, Instituto Chileno de Medicina Reproductiva

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: January 28, 2011
• First Submitted That Met QC Criteria: January 28, 2011
• First Posted (Estimate): January 31, 2011

Study Record Updates

• Last Update Posted (Actual): August 15, 2017
• Last Update Submitted That Met QC Criteria: August 11, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: LNG gel; oral LNG; follicle rupture; intra-vaginal administration; growth of the leading follicle; preovulatory peak of serum luteinizing hormone; characteristics of the cervical mucus; serum levels of estradiol (E2) and progesterone (P)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Levonorgestrel
• Other Study ID Numbers: Protocol # 441