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02 September 2010
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| Sperm suppression and contraceptive protection provided by norethisterone enantate (NET-EN) combined with testosterone undecanoate (TU) in healthy men |
| ISRCTN | ISRCTN07760234 |
| ClinicalTrials.gov identifier | |
| Public title | Sperm suppression and contraceptive protection provided by norethisterone enantate (NET-EN) combined with testosterone undecanoate (TU) in healthy men |
| Scientific title | |
| Acronym | N/A |
| Serial number at source | WHO/HRP ID A25165 |
| Study hypothesis |
Establish the contraceptive efficacy of a combined androgen and progestogen regimen for male fertility regulation.
Please note that as of 24/09/07 this trial record was updated significantly by the World Health Organization (WHO) Technical Officer. 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, and any other changes to this record will be mentioned under the date 24/09/2007. Please also note that due to the revisions to this record mentioned above, the anticipated start and end dates have been amended. The previous start and end dates of this trial were: Anticipated start date: 01/07/2000 Anticipated end date: 01/05/2002 Please note that as of 13/08/10 this trial has been updated to include revisions in the inclusion and exclusion criteria. All updates can be found in the relevant field with the above update date. Please also note that the anticipated end date for this trial has been revised, the previous end date was 31/12/10. |
| Ethics approval |
Added 24/09/2007:
1. WHO Research Ethics Review Committee approval granted on the 17th of August 2007. Amended 13/08/10: 2. Institutional IRB approval have granted approval. |
| Study design | Added 24/09/2007: Single-arm, open-label trial (Phase IIb) |
| Countries of recruitment | Australia, Chile, Germany, India, Indonesia, Italy, United Kingdom |
| Disease/condition/study domain | Male contraception |
| Participants - inclusion criteria |
Amended 13/08/10:
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 |
| Participants - exclusion criteria |
Amended 13/08/10:
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 |
| Anticipated start date | 01/01/2008 |
| Anticipated end date | 30/04/2013 |
| Status of trial | Ongoing |
| Patient information material | |
| Target number of participants | 400 |
| Interventions |
As of 13/08/10, the end of the clinical intervention is expected in April 2013, study results are expected to be available in April 2014.
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) Co-sponsor of this trial: CONRAD (USA) 1911 North Fort Myer Drive Suite 900 Arlington, Virginia 22209 United States of America website: http://www.conrad.org Co-contact for this trial: Dr Doug Colvard CONRAD (USA) 1911 North Fort Myer Drive Suite 900 Arlington, Virginia 22209 United States of America email: dcolvard@conrad.org |
| Primary outcome measure(s) |
Current primary outcome measures as of 24/09/2007:
1. The proportion of male volunteers who are rendered azoospermic and/or severely oligozoospermic (sperm concentrations less than 1 million/mL) by 24 weeks of exposure 2. 12-month contraceptive method failure rates Previous primary outcome measures: Sperm suppression and contraceptive efficacy at 48 weeks; additional follow-up for reversibility of effect. |
| Secondary outcome measure(s) |
Added 24/09/2007:
1. Proportion of men who remain azoospermic and/or severely oligozoospermic throughout the period of exposure 2. Average length of time that men remain azoospermic and/or severely oligozoospermic 3. Proportion of men whose sperm counts return to fertile levels within 12 months after the drug withdrawal 4. Average length of time to recovery among all men who use the study compounds for contraception 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, haematology tests and PSA levels at study end compared with baseline 8. Acceptabilty |
| Sources of funding |
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) |
| Trial website | |
| Publications | |
| Contact name | Dr Kirsten Vogelsong |
| Address |
World Health Organization
20 Avenue Appia |
| City/town | Geneva |
| Zip/Postcode | CH-1211 |
| Country | Switzerland |
| vogelsongk@who.int | |
| Sponsor | UNDP/UNFPA/WHO/World Bank - Special Programme of Research, Development and Research Training in Human Reproduction (HRP) |
| Address |
World Health Organization
20 Avenue Appia |
| City/town | Geneva |
| Zip/Postcode | CH-1211 |
| Country | Switzerland |
| Sponsor website: | http://www.who.int/reproductive-health/hrp/ |
| Date applied | 22/03/2004 |
| Last edited | 13/08/2010 |
| Date ISRCTN assigned | 01/04/2004 |
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