Sperm suppression and contraceptive protection provided by norethisterone enantate (NET-EN) combined with testosterone undecanoate (TU) in healthy men
| ISRCTN | ISRCTN07760234 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN07760234 |
| EudraCT/CTIS number | 2007-005315-26 |
| Secondary identifying numbers | WHO/HRP ID A25165 |
- Submission date
- 22/03/2004
- Registration date
- 01/04/2004
- Last edited
- 17/02/2021
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Pregnancy and Childbirth
Plain English Summary
Background and study aims
There are good reasons for developing a male contraceptive: women who have health-related difficulties with the currently available contraceptives will benefit, and secondly, a male option other than condoms addresses important issues regarding shared responsibilities in family planning. This study is designed to test whether the combination of norethisterone enantate (NET-EN) and testosterone undecanoate (TU) represents a safe, effective, reversible, and acceptable method of male contraception. The two main objectives are to assess the rate of suppression (reduction) of sperm production caused by NET-EN and TU taken every 8 weeks for up to 6 months, and the level of contraceptive protection provided by the continued use of NET-EN and TU every 8 weeks for up to 56 weeks.
Who can participate?
Healthy men and women
What does the study involve?
Male participants provide semen, blood and urine samples and undergo physical examinations including a prostate examination. Their female partners are tested for normal reproductive function and pregnancy. Male participants then receive an injection of NET-EN and TU every 8 weeks for up to 26 weeks. During this time, couples use alternative contraception and the male participants undergo regular semen tests. When two consecutive semen tests have demonstrated low enough levels of sperm, the male participants continue to receive injections of NET-EN and TU every 8 weeks for up to 56 weeks. During this phase, participants are asked to rely only on the injections for contraception. When this phase is complete, male participants no longer receive injections, but are regularly followed for up to 52 weeks until their sperm count rises again. Alternative contraception is resumed. Participants are asked to provide information on sexual activity and the acceptability of the injections at scheduled times throughout the study.
What are the possible benefits and risks of participating?
Participants benefit from using a long-acting, reversible male contraceptive option, which offers important gender issues of shared responsibilities for family planning decisions. This is particularly relevant for couples that wish to use a highly-effective method, but the female partner has health-related problems with currently available methods for women. The male participant in this study will also benefit from receiving regular, study-related healthcare for up to 2.5 years. The risks are expected to be the same as those experienced in other hormone-based studies of contraceptives for men.
Where is the study run from?
World Health Organization (Switzerland)
When is the study starting and how long is it expected to run for?
January 2008 to May 2012
Who is funding the study?
1. United Nations Development Programme (UNDP)/United Nations Population Fund (UNFPA)/World Health Organization (WHO)/World Bank - Special Programme of Research, Development and Research Training in Human Reproduction (HRP)
2. CONRAD (USA)
Who is the main contact?
1. Kirsten Vogelsong (vogelsongk@who.int)
2. Dr Doug Colvard (dcolvard@conrad.org)
Contact information
Scientific
Department of Reproductive Health and Research
World Health Organization
20 Avenue Appia
Geneva
CH-1211
Switzerland
| Phone | +41 (0)22 7913267 |
|---|---|
| festinma@who.int |
Scientific
CONRAD (USA)
1911 North Fort Myer Drive
Suite 900
Arlington
22209
United States of America
| dcolvard@conrad.org |
Study information
| Study design | Added 24/09/2007: Single-arm open-label trial (Phase IIb) |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Other |
| Study type | Quality of life |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Sperm suppression and contraceptive protection provided by norethisterone enantate (NET-EN) combined with testosterone undecanoate (TU) in healthy men |
| Study hypothesis | Establish the contraceptive efficacy of a combined androgen and progestogen regimen for male fertility regulation. |
| Ethics approval(s) | 1. WHO Research Ethics Review Committee, 17/08/2007 2. Institutional IRBs have granted approval |
| Condition | Male contraception |
| Intervention | Interventions as of 24/09/2007: Study participants will receive the following: Norethisterone enantate (NET-EN) 200 mg and testosterone undecanoate (TU) 1000 mg injections at eight week intervals. When a volunteer's sperm concentration is suppressed to 1 million/mL or below, he and his partner will be asked to rely on these injections as their primary method of contraception for a period of approximately one year. Men will be followed until their sperm concentrations recover to levels generally accepted as fertile. Previous intervention information: Study participants will receive the following: Norethisterone enantate (NET-EN) 200 mg and testosterone undecanoate (TU) 1000 mg injections at eight week intervals. When a volunteer's sperm concentration is suppressed to 1 million/mL, he will be randomly assigned to one of the following groups: 1. NET-EN 200 mg and TU 1000 mg injections at eight week intervals for 48 weeks (4/5 of men), or 2. Placebo and TU 1000 mg injections at 8 week intervals for 48 weeks (1/5 of men) |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II/III |
| Drug / device / biological / vaccine name(s) | Norethisterone enantate, testosterone undecanoate |
| Primary outcome measure | 1. The proportion of male participants who are rendered azoospermic and/or severely oligozoospermic (sperm concentrations less than or equal to 1 million/ml) at any point in the Suppression Phase 2. 12-month contraceptive method failure rates. |
| Secondary outcome measures | 1. Proportion of men who remain azoospermic and/or severely oligozoospermic (sperm concentrations less than or equal to 1 million/ml) throughout the Efficacy Phase 2. Average length of time that men remain azoospermic and/or severely oligozoospermic (sperm concentrations less than or equal to 1 million/ml) in the Efficacy Phase 3. Proportion of men who recover, as defined in the protocol, within 12 months after their last “missed” injection 4. Average length of time to recovery among all men who enter the Efficacy Phase 5. Changes in steroid and peptide hormone levels compared with baseline 6. Reports of adverse events, overall and product-related 7. Changes in key physical findings, endocrinology levels, serum chemistries, urinalysis, hematology tests and PSA levels at study end compared with baseline 8. Answers to key questions on acceptability questionnaires |
| Overall study start date | 01/01/2008 |
| Overall study end date | 30/05/2012 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 400 |
| Total final enrolment | 320 |
| Participant inclusion criteria | Amended 13/08/2010: Male participants: 3.1. Sperm concentration greater than or equal to 15 million sperm/ml semen or total sperm count greater than or equal to 39 million sperm per ejaculate in two semen samples, with no gross abnormalities of sperm motility and morphology, per investigator's discretion 3.2. Screening gonadotropin (LH and FSH) and testosterone levels should be within the centre's normal ranges, however gonadotropin levels may fall below the lower limit of the normal ranges assuming the overall endocrine profile and semen parameters are indicative of a normal reproductive state Female partners: 3. Age 18 to 39 years, inclusive All other inclusion criteria remain the same. Current information as of 24/09/2007: Male participants: 1. Signed written consent form 2. Male healthy volunteer 3. Normal reproductive state demonstrated by: 3.1. Sperm concentrations greater than or equal to 20 million sperm/ml semen in two semen samples with no gross abnormalities if sperm motility and morphology per investigator's discretion 3.2. Screening gonadotropin and testosterone levels within the centre's normal ranges 4. Body mass index between 20 and 32 kg/m^2 5. History and clinical examination without pathological findings relevant to the study including symptoms or signs of a sexually transmitted infection 6. Digital rectal examination of the prostate does not reveal any abnormal findings and prostate specific antigen (PSA) level is within normal range 7. Laboratory assays do not suggest the presence of any illness 8. Sexually active with female partner, with a coital frequency of twice a week, on average 9. In a stable, mutually monogamous relationship/partnership with the female partner for at least one year within first visit and intends to remain in the relationship for the course of the study 10. Willing to comply with the requirements of the protocol 11. No desire for partner pregnancy within the next two years and willing to accept a low but unknown risk of pregnancy Female partners: 1. Signed written consent form 2. Female healthy volunteer 3. Age 18 to 35 years, inclusive 4. No tubal ligation 5. Sexually active with male volunteer, with a coital frequency of twice a week, on average 6. Normal reproductive state, demonstrated by: 6.1. Regular menstrual cycles (23 - 38 days) by volunteer history for the past three months 6.2. Medical and gynaecological history without findings suggestive of impaired fertility 6.3. No contraindication to pregnancy 6.4. No signs or symptoms of a sexually transmitted infection 7. In a stable mutually monogamous relationship/partnership with the male volunteer for at least one year and intends to remain in the relationship for the course of the study 8. Willing to comply with the requirements of the study protocol 9. Not pregnant at the time of entry into the Suppression phase 10. No desire for pregnancy within the next two years and willing to accept a low but unknown risk of pregnancy Information at time of registration: Male participants: 1. General good health, aged 18 to 45 2. Normal reproductive state: 2.1. Sperm concentration 20 million/mL 2.2. Sperm motility 50% [grades a + b] or 25% or more with grade a 2.3. Sperm morphology 10% normal forms 2.4. Gonadotropin and testosterone levels within the centre's normal range 3. Body mass index between 20 and 32 kg/m^2 4. Clinical examination without pathological findings relevant to the study 5. No desire for children within the next two years Female partners: 1. Aged 18 to 35 2. Normal reproductive state: 2.1. Regular menses 2.2. Medical and gynaecologic history without findings suggestive of impaired fertility or contraindication to pregnancy) 3. History of fertility in couple |
| Participant exclusion criteria | Amended 13/08/2010: Male participants: 4. History of or current prostate or testicular pathology (including varicocele that is visible or palpable without Valsalva maneuver) or male infertility. All other exclusion criteria remain the same. Added 24/09/2007: Male participants: 1. Participation in another clinical trial within 30 days preceding the first drug administration, or simultaneous participation in another clinical trial 2. Institutionalised or imprisoned by order of the court 3. Competition in sports which use World Anti-Doping Agency (WADA) monitoring 4. History of prostate or testicular pathology or male infertility 5. Serious organic or psychiatric disease suspected from history and.or clinical examination 6. Diseases (including tumours) that may be affected by testosterone use or that may affect the outcome of the study, for example: 6.1. Prostate disease 6.2. Past or present history, or family history, of thrombotic or embolic diseases 6.3. Hypertension requiring therapy (blood pressure [BP] greater than or equal to 140/190 mmHg) 6.4. Acute or chronic hepatic diseases 6.5. Manifest renal diseases with renal dysfunction 7. Biochemical and/or haematological laboratory values outside normal ranges, unless the investigator confirms that the deviations are of no clinical revelance 8. Any indication of chronic use of illicit drugs or alcohol abuse 9. Use of any disallowed medications or of any drug known to affect absorption, distribution, metabolism or elimination (ADME) of testosterone within the 30 days preceding the first administration of the test compounds 10. Use of oral anti-coagulatory drugs (e.g. warfarin) within the 30 days preceding the first administration of the test compounds and during the study (aspirin is allowed) 11. Implantation of a sustained-action sex hormone within 8 months of screening 12. History of allergy to any component of the study drugs Female partners: 1. Participation in any other clinical trial that would affect fertility 2. Use of depot medroxyprogesterone acetate (DMPA) 12 months prior to screening 3. Any indication of chronic use of illicit drugs or alcohol abuse |
| Recruitment start date | 04/09/2008 |
| Recruitment end date | 10/11/2010 |
Locations
Countries of recruitment
- Australia
- Chile
- Germany
- India
- Indonesia
- Italy
- United Kingdom
Study participating centres
Concord Hospital and University of Sydney
Concord
-
Australia
Melbourne
-
Australia
Bologna
-
Italy
University of Indonesia
Jakarta
-
Indonesia
Münster
-
Germany
-
Chile
Munirka
New Delhi
-
India
University of Manchester, Central Manchester University Hospitals NHS Foundation Trust
Manchester
-
United Kingdom
Martin Luther University Halle-Wittenberg
Halle
-
Germany
The University of Edinburgh
Edinburgh
-
United Kingdom
Sponsor information
Research organisation
World Health Organization
20 Avenue Appia
Geneva
CH-1211
Switzerland
| Website | http://www.who.int/reproductive-health/hrp/ |
|---|
Research organisation
1911 North Fort Myer Drive
Suite 900
Arlington
22209
United States of America
| Website | http://www.conrad.org |
|---|
Funders
Funder type
Research organisation
No information available
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF
- Location
- United States of America
Government organisation / National government
- Alternative name(s)
- U.S. Agency for International Development, Agency for International Development, USAID
- Location
- United States of America
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | The first manuscript describing the primary results has been submitted to a peer-reviewed scientific journal. A second manuscript with additional study results is expected. |
| IPD sharing plan | All essential study documents including analytic datasets will be stored in the HRP e-Archive system. They are not available for public access. The researchers do not own individual-level data, so when appropriate data share agreements are in place, the data manager of the e-Archive system will be able to transfer the dataset to the recipient. If the de-identified study dataset has not been migrated to the e-Archive system yet, then the statistician or study data-manger would be sharing the dataset upon receipt of necessary data share agreements. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/12/2016 | 04/01/2021 | Yes | No |
Editorial Notes
17/02/2021: IPD sharing statement added.
04/01/2021: Publication reference and total final enrolment added.
22/12/2020: Internal review.
23/08/2016: Plain English summary added.
05/04/2011: WHO Technical review panel recommended that study drug administration be discontinued. WHO Research Ethics Review Committee and Institutional IRBs were notified of this decision.
13/08/2010: the overall trial end date was changed from 31/12/2010 to 30/04/2012.
24/09/2007 the following changes were made to the trial record:
1. The title was amended from 'NET-EN plus TU as a male contraceptive: sperm suppression and contraceptive protection provided by norethisterone enantate plus testosterone undecanoate in normal healthy men' to the above title.
2. The overall trial start date was changed from 01/07/2000 to 01/01/2008.
3. The overall trial end date was changed from 01/05/2002 to 31/12/2010.
