Contraception

Research Grid

Contraceptive Research	Description	Status
NEW LONG-ACTING PROGESTIN – The general objective of this activity is to provide formulated levonorgestrel butanoate (LNG-B) for preclinical and clinical studies as a component of long-acting female and male contraceptives. It is expected that LNG-B may have advantages over DMPA for female contraception and may be better than norethisterone enanthate in combination with an androgen for male contraception.	CONRAD is overseeing process development and production of clinical supplies. Formulation and sterilization of LNG-B which will provide progestational activity for 4 months after a single injection is ongoing.	A pharmacokinetic (PK) study in non-human primates (NHPs) has been completed. Based on stability data of 10, 15 and 20 mg/mL formulations, the 20 mg/mL concentration will be used for the initial Phase I study(s). The first Phase I PK study in women will begin when clinical materials are available. This is a joint project of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), CONRAD and the World Health Organization (WHO).
NOVEL MALE LEADS – Research and development of new male contraceptives is needed. Recent activities have focused on synthesis of new compounds, functional evaluation and identification of viable leads, establishment of an animal model and in vivo proof of concept studies in the animal model and humans, structural refinement of viable leads and synthesis of optimized compounds, and validation of molecular pathways that underpin drug selectivity/targeting of the muscle types in human vas deferens.	Current leads are focused on inhibiting critical sperm functions including spermatogenesis (retinoic acid receptor), sperm motility (Eppin, GAPDHS and CatSper), and sperm emission (α-adrenoreceptor). These new methods would either disrupt sperm production (in the testis), sperm maturation (in the epididymis), or sperm function (after ejaculation).	Identification and screening of inhibitory compounds continues, including use of high throughput screening.
NOVEL FEMALE LEADS – The objective of this activity is to identify target molecules that have potential as leads for novel non-hormonal, non-barrier female contraceptives.	Inhibitory peptides are being developed against three targets and their half-life extended by PEGylation. THE GnRH II receptor, which predominates in reproductive tissue, is under investigation as an additional target.	Synthesis and anti-fertility testing of inhibitory peptides by vaginal application in mice has been completed. Of the three targets being investigated using PEGylated inhibitors, inhibition of one target molecule did not adequately inhibit pregnancy, but inhibition of the other two appears promising and will be further pursued within funding limitations.
BARRIER METHOD: SILCS DIAPHRAGM - Additional female-initiated methods for pregnancy prevention are needed. The Program for Appropriate Technology in Health (PATH) SILCS diaphragm was designed with extensive user input to ensure comfort, ease-of-use and acceptability.	Recruitment began in early 2008 for a Phase III contraceptive trial to assess the SILCS diaphragm, a new single-size barrier device, used in combination with either BufferGel® or nonoxynol-9. The primary objectives were 6 month pregnancy probability during typical use and safety of the SILCS diaphragm.	The Phase III study has been completed and data analysis is underway. After the analysis is complete, there are plans to submit a 510K application to the FDA in 2011. An industrial partner is being sought to manufacture and market the device.
BARRIER METHOD: WOMAN’S CONDOM - Lower cost and better designed female condoms are needed to expand the options women have for protecting themselves from unplanned pregnancy and sexually transmitted infections (STIs), including HIV. The PATH Woman’s Condom has performed well with good acceptability in initial studies and is the subject of further clinical studies.	An ongoing study of 425 couples is comparing the performance of the Woman’s Condom and the Female Condom 2 (FC2) based on self-reported clinical failure and will use vaginal detection of prostate-specific antigen (PSA) as an indicator of condom failure.	The CONRAD study began enrolling participants in July 2010. Results are expected in 2012. In parallel, CONRAD will submit an Investigational Device Exemption (IDE) for the Woman’s Condom under which the NICHD will conduct a Phase III contraceptive efficacy study of the Woman’s Condom. The IDE was submitted in August 2010, and the Phase III study should begin in early 2011.
EMERGENCY CONTRACEPTION - Emergency contraceptives can be taken after unprotected intercourse to prevent ovulation. There is a need for a non-hormonal alternative to the levonorgestrel pill presently available. Pilot studies with meloxicam, a COX-2 inhibitor available in many countries, have shown that it has the potential to be used either as a stand-alone nonsteroidal product or combined with levonorgestrel for emergency contraception.	A Phase I dose-finding study was conducted at the Chilean Institute of Reproductive Medicine (ICMER) to compare 15 mg and 30 mg of meloxicam administered orally for emergency contraception.	The Phase I dose-finding study showed 30 mg of meloxicam to be safe and effective at inhibiting ovulation when used for 5 days. The Phase I study was funded by the Hewlett Foundation. Funding partners for a follow-on Phase II study have yet to be identified.
MALE HORMONAL CONTRACEPTION – There are no male contraceptive options other than vasectomy (mostly irreversible) or condoms (not practical for long-term use). Hormonal methods of male fertility regulation are based on the fact that exogenous testosterone can suppress spermatogenesis. The primary objectives of this trial have been to assess the rate of suppression of spermatogenesis induced by a regimen of an androgen and progestagen and the level of contraceptive protection.	A global Phase IIb clinical trial has tested the combination of a long-acting androgen (testosterone undecanoate) and a long-acting progestagen (norethisterone enanthate) given by injection every 8 weeks as a male hormonal contraceptive. This multi-site study is ongoing in 7 countries.	The first trial participants were enrolled in 2008; enrollment ended in September 2010. Results for contraceptive efficacy are expected in 2012. This trial is being co-sponsored by CONRAD and WHO. Further injections were discontinued in April 2011 after a WHO panel review determined that the risks of possible side effects might outweigh the potential benefits to male participants.
FEMALE HORMONAL CONTRACEPTION - A Phase I pharmacokinetic and pharmacodynamic study of Cyclofem®, a monthly injectable hormonal contraceptive for women, will determine the levels of the hormones in the body after administration of Cyclofem® and will provide critical information to determine similarity of Cyclofem® to Lunelle in women residing in the USA.	Cyclofem® is a combination of medroxyprogesterone acetate and estradiol that is used in populations throughout the world. This initial pharmacokinetic study is the first step on the road to FDA approval with the ultimate goal to expand the access and range of methods available to women in resource poor areas. U.S. FDA approval of Cyclofem® is considered pivotal to the ultimate acceptance of the product in many countries.	The Phase I pharmacokinetic and pharmacodynamic study at CONRAD/EVMS began enrolling women in Summer 2010. Results are expected in 2011.
FEMALE NON-HORMONAL CONTRACEPTION - A Phase II trial which is determining the safety and efficacy of a COX-2 inhibitor, meloxicam, as a monthly contraceptive, is ongoing.	Non-hormonal birth control methods are needed, especially for women who cannot use hormonal methods. Two doses of meloxicam, 15 mg and 30 mg, given on cycle days 5-22, are being tested in women to determine the effectiveness of this method for suppression of ovulation.	Enrollment of women will begin by early 2011 at the ICMER in Chile.

Contraceptive Research

Description

Status

NEW LONG-ACTING PROGESTIN – The general objective of this activity is to provide formulated levonorgestrel butanoate (LNG-B) for preclinical and clinical studies as a component of long-acting female and male contraceptives. It is expected that LNG-B may have advantages over DMPA for female contraception and may be better than norethisterone enanthate in combination with an androgen for male contraception.

CONRAD is overseeing process development and production of clinical supplies. Formulation and sterilization of LNG-B which will provide progestational activity for 4 months after a single injection is ongoing.

A pharmacokinetic (PK) study in non-human primates (NHPs) has been completed. Based on stability data of 10, 15 and 20 mg/mL formulations, the 20 mg/mL concentration will be used for the initial Phase I study(s). The first Phase I PK study in women will begin when clinical materials are available. This is a joint project of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), CONRAD and the World Health Organization (WHO).

NOVEL MALE LEADS – Research and development of new male contraceptives is needed. Recent activities have focused on synthesis of new compounds, functional evaluation and identification of viable leads, establishment of an animal model and in vivo proof of concept studies in the animal model and humans, structural refinement of viable leads and synthesis of optimized compounds, and validation of molecular pathways that underpin drug selectivity/targeting of the muscle types in human vas deferens.

Current leads are focused on inhibiting critical sperm functions including spermatogenesis (retinoic acid receptor), sperm motility (Eppin, GAPDHS and CatSper), and sperm emission (α-adrenoreceptor). These new methods would either disrupt sperm production (in the testis), sperm maturation (in the epididymis), or sperm function (after ejaculation).

Identification and screening of inhibitory compounds continues, including use of high throughput screening.

NOVEL FEMALE LEADS – The objective of this activity is to identify target molecules that have potential as leads for novel non-hormonal, non-barrier female contraceptives.

Inhibitory peptides are being developed against three targets and their half-life extended by PEGylation. THE GnRH II receptor, which predominates in reproductive tissue, is under investigation as an additional target.

Synthesis and anti-fertility testing of inhibitory peptides by vaginal application in mice has been completed. Of the three targets being investigated using PEGylated inhibitors, inhibition of one target molecule did not adequately inhibit pregnancy, but inhibition of the other two appears promising and will be further pursued within funding limitations.

BARRIER METHOD: SILCS DIAPHRAGM - Additional female-initiated methods for pregnancy prevention are needed. The Program for Appropriate Technology in Health (PATH) SILCS diaphragm was designed with extensive user input to ensure comfort, ease-of-use and acceptability.

Recruitment began in early 2008 for a Phase III contraceptive trial to assess the SILCS diaphragm, a new single-size barrier device, used in combination with either BufferGel® or nonoxynol-9. The primary objectives were 6 month pregnancy probability during typical use and safety of the SILCS diaphragm.

The Phase III study has been completed and data analysis is underway. After the analysis is complete, there are plans to submit a 510K application to the FDA in 2011. An industrial partner is being sought to manufacture and market the device.

BARRIER METHOD: WOMAN’S CONDOM - Lower cost and better designed female condoms are needed to expand the options women have for protecting themselves from unplanned pregnancy and sexually transmitted infections (STIs), including HIV. The PATH Woman’s Condom has performed well with good acceptability in initial studies and is the subject of further clinical studies.

An ongoing study of 425 couples is comparing the performance of the Woman’s Condom and the Female Condom 2 (FC2) based on self-reported clinical failure and will use vaginal detection of prostate-specific antigen (PSA) as an indicator of condom failure.

The CONRAD study began enrolling participants in July 2010. Results are expected in 2012. In parallel, CONRAD will submit an Investigational Device Exemption (IDE) for the Woman’s Condom under which the NICHD will conduct a Phase III contraceptive efficacy study of the Woman’s Condom. The IDE was submitted in August 2010, and the Phase III study should begin in early 2011.

EMERGENCY CONTRACEPTION - Emergency contraceptives can be taken after unprotected intercourse to prevent ovulation. There is a need for a non-hormonal alternative to the levonorgestrel pill presently available. Pilot studies with meloxicam, a COX-2 inhibitor available in many countries, have shown that it has the potential to be used either as a stand-alone nonsteroidal product or combined with levonorgestrel for emergency contraception.

A Phase I dose-finding study was conducted at the Chilean Institute of Reproductive Medicine (ICMER) to compare 15 mg and 30 mg of meloxicam administered orally for emergency contraception.

The Phase I dose-finding study showed 30 mg of meloxicam to be safe and effective at inhibiting ovulation when used for 5 days. The Phase I study was funded by the Hewlett Foundation. Funding partners for a follow-on Phase II study have yet to be identified.

MALE HORMONAL CONTRACEPTION – There are no male contraceptive options other than vasectomy (mostly irreversible) or condoms (not practical for long-term use). Hormonal methods of male fertility regulation are based on the fact that exogenous testosterone can suppress spermatogenesis. The primary objectives of this trial have been to assess the rate of suppression of spermatogenesis induced by a regimen of an androgen and progestagen and the level of contraceptive protection.

A global Phase IIb clinical trial has tested the combination of a long-acting androgen (testosterone undecanoate) and a long-acting progestagen (norethisterone enanthate) given by injection every 8 weeks as a male hormonal contraceptive. This multi-site study is ongoing in 7 countries.

The first trial participants were enrolled in 2008; enrollment ended in September 2010. Results for contraceptive efficacy are expected in 2012. This trial is being co-sponsored by CONRAD and WHO. Further injections were discontinued in April 2011 after a WHO panel review determined that the risks of possible side effects might outweigh the potential benefits to male participants.

FEMALE HORMONAL CONTRACEPTION - A Phase I pharmacokinetic and pharmacodynamic study of Cyclofem®, a monthly injectable hormonal contraceptive for women, will determine the levels of the hormones in the body after administration of Cyclofem® and will provide critical information to determine similarity of Cyclofem® to Lunelle in women residing in the USA.

Cyclofem® is a combination of medroxyprogesterone acetate and estradiol that is used in populations throughout the world. This initial pharmacokinetic study is the first step on the road to FDA approval with the ultimate goal to expand the access and range of methods available to women in resource poor areas. U.S. FDA approval of Cyclofem® is considered pivotal to the ultimate acceptance of the product in many countries.

The Phase I pharmacokinetic and pharmacodynamic study at CONRAD/EVMS began enrolling women in Summer 2010. Results are expected in 2011.

FEMALE NON-HORMONAL CONTRACEPTION - A Phase II trial which is determining the safety and efficacy of a COX-2 inhibitor, meloxicam, as a monthly contraceptive, is ongoing.

Non-hormonal birth control methods are needed, especially for women who cannot use hormonal methods. Two doses of meloxicam, 15 mg and 30 mg, given on cycle days 5-22, are being tested in women to determine the effectiveness of this method for suppression of ovulation.

Enrollment of women will begin by early 2011 at the ICMER in Chile.