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Clinical Protocol: CCN017 (Version 05.00)
Protocol Version 05.00 Summary of Changes
Protocol Title: Clinical Evaluation of Daily Application of Nestorone® (NES) and Testosterone (T) Combination Gel for Male Contraception Protocol Number: CCN017
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Version 04.00 (Previous):
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Sponsor/IND Holder:
Co-Sponsor
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Population Council, Center for Biomedical Research
1230 York Avenue
New York, NY 10065 USA
National Institutes of Health
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Contraceptive Clinical Trial Network (Male) 6710B Rockledge Drive
Bethesda, MD 20814 USA
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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Minor typographical errors or formatting adjustments that did not affect substantive content were made.
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Inserted or updated references for publications.
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Frederick Wu, MD, PhD was listed as co-investigator for University of Manchester, UK site.
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Abbreviations and Definitions of Terms
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Added definition of IDI (In-Depth Interview)
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Synopsis: Rationale, Background, Risks and Benefits
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To achieve azoospermia by exogenously administered hormones, endogenous T production is suppressed; therefore, part of the purpose of T supplementation in the male hormonal contraceptive is to restore serum T levels to the normal range.
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Synopsis: Rationale, Background, Risks and Benefits
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NES is a synthetic progestin structurally related to progesterone that does not have any androgenic, estrogenic or glucocorticoid activity at therapeutic doses (Sitruk-Ware, 2006) and is therefore not expected to have some of the undesirable side effects of levonorgestrel or desogestrel, such as weight gain or mood changes.
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NES is a synthetic progestin structurally related to progesterone that does not have any androgenic, estrogenic or glucocorticoid activity at therapeutic doses (Sitruk-Ware, 2006) and does not interact with GABA-Receptors (Kumar et al, 2017). It is therefore not expected to have some of the undesirable side effects of levonorgestrel or DMPA, such as weight gain or mood changes.
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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This is a prospective, phase IIb, open label, single arm, multicenter study. The study protocol consists of a screening phase lasting 4 to 8 weeks, a suppression phase estimated up to 20 weeks, a 52-week maintenance/efficacy phase, and a 24- week (estimated) recovery phase. Detailed procedures about each of the study phases are listed in protocol Section 14.
The study will involve approximately 420 couples recruited throughout the CCTN that meet eligibility criteria. The nine sites propose to enroll up to 420 couples (about 30 to 60 couples per site) with a goal of obtaining 200 couples completing the contraceptive efficacy phase of the study. The study has four phases (screening phase, suppression phase, efficacy phase and recovery phase) with monthly visits to provide the male participants with the NES-8/T-62 gel, to encourage adherence, to monitor for possible side effects, and to quantify semen parameters. The female will be contacted monthly and come in for a visit every three months.
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This is a prospective, phase IIb, open label, single arm, multicenter study. The study protocol consists of a screening phase lasting 4 to 8 weeks, a suppression phase estimated up to 20 weeks, a 52-week maintenance/efficacy phase, and a 24- week (estimated) recovery phase. Detailed procedures about each of the study phases are listed in protocol Section 14.
The study will involve approximately 420 couples recruited throughout the CCTN that meet eligibility criteria. The nine sites propose to enroll up to 420 couples (about 30 to 60 couples per site) with a goal of obtaining 200 couples completing the contraceptive efficacy phase of the study. The study has four phases (screening phase, suppression phase, efficacy phase and recovery phase) with monthly visits to provide the male participants with the NES-8/T-62 gel, to encourage adherence, to monitor for possible side effects, and to quantify semen parameters. The female partner will be contacted monthly and come in for a visit every three months. Male subjects will be treated and followed as outpatients, along with their participating female partner.
Based on results from earlier studies, this fixed dose combination of T and NES is estimated to be the optimal fixed dose for men to achieve azoospermia with adequate replacement of T. It is possible that the T dose in this hormonal contraceptive gel could be too much for some men or too little for other men. Male subjects’ T level will be followed in the first 12 weeks of the study to confirm this as the optimal fixed dose for most participants.
Male subjects who have a Visit 3A/Week 2 and Visit 4/Week 4
serum T value <200 ng/dL (6.9 nmol/L), with reported gel application adherence, will be offered the choice to take part in a Supplemental Testosterone Substudy. Male subjects who elect to take part in the Supplemental Testosterone Substudy will receive supplemental T gel (20 mg with Androgel 1.62% or 25 mg of Androgel 1% or equivalent Testogel) in order to maintain serum T within the normal range. The supplemental T gel will be applied to either the right or left upper back and arms. Subjects who meet the criteria of low T to participate in the Supplemental Testosterone Substudy and decline to do so will be considered no longer eligible and discontinued unless a waiver is approved in specific cases with borderline serum T and without specific symptoms.
Male subjects who have a serum T level ≥200 ng/dL (6.9 nmol/L) and <250 ng/dL (8.68 nmol/L) with reported gel application adherence and low T symptom (refer to Appendix 14 for
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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Synopsis: Statistical Analysis
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The statistical analyses of the primary and secondary endpoints will be done for the group of subjects that do not enter the Supplemental Testosterone Sub-study, but the sub-study subjects will be summarized in a similar manner as supporting analyses.
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The statistical analyses of the primary and secondary endpoints will be done for the group of subjects that do not enter the Supplemental Testosterone Sub-study, but the sub-study subjects will be summarized in a similar manner as supporting analyses.
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To achieve azoospermia by exogenously administered hormones, endogenous T production is suppressed; therefore, part of the purpose of the T supplementation in the male hormonal contraceptive is to restore serum T levels to the normal range.
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The female will be contacted monthly and come in for a visit every three months.
Couples who meet the eligibility requirements will begin the suppression phase estimated to last up to 20 weeks during which study treatment will be administered in order to obtain suppression of sperm concentration to ≤1 million/mL (potentially longer if sperm is trending toward required suppression). If sperm suppression is successful, couples will move into the 52- week efficacy phase where study treatment is continued.
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The female partner will be contacted monthly and come in for a visit every three months.
Couples who meet the eligibility requirements will begin the suppression phase estimated to last up to 20 weeks during which study treatment will be administered in order to obtain suppression of sperm concentration to ≤1 million/mL (potentially longer if sperm is trending toward required suppression). If sperm suppression is successful, couples will move into the 52- week efficacy phase where study treatment is continued. Male subjects will be treated and followed as outpatients, along with their participating female partner.
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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Based on results from earlier studies, this fixed dose combination of T and NES is estimated to be the optimal fixed dose for men to achieve azoospermia with adequate replacement of T. It is possible that the T dose in this hormonal contraceptive gel could be too much for some men or too little for other men. Male subjects’ T level will be followed in the first 12 weeks of the study to confirm this as the optimal fixed dose for most participants.
Male subjects who have a Visit 3A/Week 2 and Visit 4/Week 4 serum T value <200 ng/dL (6.9 nmol/L), with reported gel application adherence, will be offered the choice to take part in a Supplemental Testosterone Substudy. Male subjects who elect to take part in the Supplemental Testosterone Substudy will receive supplemental T gel (20 mg with Androgel 1.62% or 25 mg of Androgel 1% or equivalent Testogel) in order to maintain serum T within the normal range. The supplemental T gel will be applied to either the right or left upper back and arms. Subjects who meet the criteria of low T to participate in the Supplemental Testosterone Substudy and decline to do so will be considered no longer eligible and discontinued unless a waiver is approved in specific cases with borderline serum T and without specific symptoms.
Male subjects who have a serum T level ≥200 ng/dL (6.9 nmol/L) and <250 ng/dL (8.68 nmol/L) with reported gel application adherence and a low T symptom (refer to Appendix 14 for definition) at both Visit 3A/Week 2 and Visit 4/Week 4 will have the option to take part in the Supplemental Testosterone Substudy or be discontinued.
If a male subject presents with a low T symptom (refer toAppendix 14 for definition) after Visit4/Week 4 through Visit 7/ Week 12, with reported gel application adherence, serum T levels will be obtained and tested locally. If levels are <250 ng/dL (8.68 nmol/L), they will be repeated. If a second consecutive level is <250 ng/dL (8.68 nmol/L), male subjects will have the option to take part in the Supplemental Testosterone Substudy or be discontinued. No subjects may enter the Substudy after Visit 7/Week 12.
Following Visit 7/Week 12, should a male subject present with a low T symptom (refer to Appendix 14 for definition), the study team will review and discuss with the subject the importance of applying the gel every day, the washing instructions, and review the area of application. If protocol compliance and gel application adherence is confirmed, the subject will be evaluated for the low T symptom per standard of care and Investigator
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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Male subjects will be treated and followed as outpatients, along with their participating female partner.
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Subject recruitment is expected to begin Q2 2018 and is planned to continue through Q2 2019. However, if the enrollment rate declines, the enrollment period may be extended beyond this date. If this enrollment timeline is met, all male subjects should finish suppression treatment by approximately the beginning of Q3 2019, efficacy phase by Q4 2020 and recovery phase by Q3 2021. Therefore, the total duration of the study, including study initiation, will be approximately 4.25 years for each study site. The end of the study will occur when the last male subject to be enrolled has completed his Exit Visit and all data is entered on the appropriate CRF pages.
Results of the study are expected to be available Q1 2022.
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Subject recruitment began Q4 2018 and is planned to continue through Q4 2020. However, if the enrollment rate declines, the enrollment period may be extended beyond this date. If this enrollment timeline is met, all male subjects should finish suppression treatment by approximately the beginning of Q2 2021, efficacy phase by Q2 2021 and recovery phase by Q2 2022. Therefore, the total duration of the study, including study initiation, will be approximately 4.25 years for each study site. The end of the study will occur when the last male subject to be enrolled has completed his Exit Visit and all data is entered on the appropriate CRF pages.
Results of the study are expected to be available Q1 2023.
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11.1 Exclusionary Medications
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Use of sex hormones/steroids (i.e. testosterone, ketoconazole, finasteride, oral corticosteroids, dutasteride and statins)
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Use of sex hormones/steroids (e.g. testosterone), unless the subject is participating in the Supplemental Testosterone Substudy; Other exclusions: ketoconazole, finasteride, oral corticosteroids, dutasteride and statins)
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After initial application at the first visit, the gel should be applied daily at a consistent time convenient to each subject’s schedule.
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NES is inactive when taken orally but very potent when given parenterally (Sitruk-Ware et al., 2003) and has shown no androgenic effects in animals, unlike 19-nortestosterone derived progestins such as norethisterone and levonorgestrel.
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NES is inactive when taken orally but very potent when given parenterally (Sitruk-Ware et al., 2003) and has shown no androgenic effects in animals, unlike 19-nortestosterone derived progestins such as norethisterone and levonorgestrel, and no transactivation of the androgen receptors (Kumar et a, 2017).
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13.2.2 CBC, Clinical Chemistries, Lipids and PSA
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Additionally, every four weeks after starting IP, non-fasting hemoglobin and hematocrit will be measured at the local laboratories.
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13.2.3.1 Hormone Measurements
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All hormone measurements (LH, FSH, Free T, T, DHT and Estradiol) will be measured centrally at the Endocrine and Metabolic Research Laboratory at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed/ Harbor-UCLA) (located at 1124 West Carson St, Liu Research Center – Rm 231, Torrance, CA 90502, USA) with the exception of the screening T samples and confirmatory recovery T samples which will be done locally with a separate sample also sent to the central laboratory.
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All hormone measurements (LH, FSH, Free T, T, DHT and Estradiol) will be measured centrally at the Endocrine and Metabolic Research Laboratory at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed/ Harbor-UCLA) (located at 1124 West Carson St, Liu Research Center – Rm 231, Torrance, CA 90502, USA) with the exception of the screening T samples, confirmatory recovery T samples and all samples assessed for the Supplemental Testosterone Substudy (described below in Section 14.2.1.1), which will be done locally with a separate sample also sent to the central laboratory.
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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13.2.3.1 Hormone Measurements
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The screening and confirmatory recovery T samples will be analyzed at the local certified laboratories at each study center and values will be recorded on case report forms (eCRFs). As mentioned above, a separate aliquot of serum will also be sent to the central laboratory where the data will be used for publication purposes,
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The screening and confirmatory recovery T samples, as well as the T samples assessed for the Supplemental Testosterone Study will be analyzed at the local certified laboratories at each study center and local values will be recorded on case report forms (eCRFs). As mentioned above, a separate aliquot of serum will also be sent to the central laboratory where the data will be used for consistency for publication and Clinical Study Report purposes.
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Serum T samples from all sites will be measured centrally by validated methods using Liquid Chromatography Tandem Mass Spectrometry developed at the LA Biomed at Harbor – UCLA and Endocrine Research Laboratory (Shiraishi et al., 2008; Wang et al., 2008), except screening T samples and confirmatory recovery T samples measured by the local lab as mentioned above. The lower limit of quantification is 2 ng/dL. Free T will be calculated using one of the standard formulae (Ly et al., 2010).
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Serum T samples from all sites will be measured centrally by validated methods using Liquid Chromatography Tandem Mass Spectrometry developed at the LA Biomed at Harbor – UCLA and Endocrine Research Laboratory (Shiraishi et al., 2008; Wang et al., 2008), except screening T samples, confirmatory recovery T samples and samples assessed for the Supplemental Testosterone Substudy (described below in Section 14.2.1.1) measured by the local lab as mentioned above with an aliquot of serum sent to the Central Lab. The lower limit of quantification is 2 ng/dL. Free T will be calculated using one of the standard formulae (Ly et al., 2010).
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13.2.5 Semen Collection and Analysis
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A normal semen concentration is defined as ≥ 15 million sperm per milliliter of ejaculate accordingly to the WHO semen manual and at least one sample with normal % progressive motility and morphology. If the initial sperm concentration is normal, the male subject qualifies for the study. If the initial sperm concentration is borderline normal (e.g. >12 million and <15 million sperm per millimeter of ejaculate), two additional concentrations should be obtained.
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A normal semen concentration is defined as ≥ 15 million sperm per milliliter of ejaculate accordingly to the WHO semen manual and at least one sample with normal % progressive motility and morphology. If the initial sperm concentration is normal, the male subject qualifies for the study. If the initial sperm concentration is borderline normal, two additional concentrations should be obtained.
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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13.2.9 In-Depth Interview
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All participants will be invited to complete an in-depth interview (IDI) before exiting from the study. Depending on participant availability and visit length, it may be necessary to conduct this assessment as a separate visit or call. The interview process will interview each male and female participant individually and then together. The IDI will address experience with study product use and acceptability during the trial. In-depth interview data on gel application instructions, sperm and T level testing requirements as well as other components of acceptability and factors affecting adherence will be collected during the IDI. These IDIs will be conducted by a trained qualitative interviewer and will follow a semi-structured questionnaire guide and are anticipated to last approximately 30 minutes for each individual interview and then 30 minutes together for a total of 1.5 hours per couple. These IDIs may be conducted over the phone. The audio from the IDI will be recorded, summarized and transcribed for analysis. The interview notes, audio recordings and transcripts will be considered as source documentation.
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Clinical Protocol: CCN017 (Version 05.00) Summary of Changes
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Protocol Version 04.00 (29 January 2019)
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Protocol Version 05.00 (07 July 2019)
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During the suppression phase, the following assessments will be performed for the male partner:
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Safe and Effective Contraception is a universal right for all men and women. Many women of reproductive age are unable to use the current contraception methods available to them and rely on their male partners to protect them from unplanned pregnancy. A majority of men surveyed internationally reported interest and willingness to use contraceptive methods; unfortunately no safe, highly effective reversible method is available to men interested in sharing the responsibility of family planning.The primary objective of the study is to determine contraceptive efficacy for a couple provided by daily application by the male partner of a gel containing testosterone (T) and Nestorone (NES) for a period of 52 weeks (about 12 months).
The secondary objectives of the study are to assess the safety and acceptability of the NES 8 mg/day + T 62 mg/day (NES-8/T-62) gel and the NES 8 mg/day + T 74 mg/day (NES-8/T-74) gel for a period of 52 weeks.
Methodology
This is a prospective, phase IIb, open label, single arm, multicenter study. The study consists of a screening phase lasting 4 to 8 weeks, a suppression phase estimated to last up to 20 weeks, a 52- week maintenance/efficacy phase, and a 24-week (estimated) recovery phase. The study population will comprise healthy men ages 18 – 50 years, involved in a stable, monogamous, relationship with an 18 – 34 year-old female partner (at the time of enrolment) with regular cycles per patient report from her previous non-hormonal contraceptive gynecology history. Across all sites, the study will enrol 420 couples into the suppression phase. The Couples Counselling Clinic will aim to enrol 60 couples into the suppression phase.Questionnaires will be administered during the study in the Couples Counselling Clinic, with the exception of the 7-Day Validated Psychosexual Daily Questionnaire that will be completed by the participant at home. Blood samples for laboratory analyses will be collected at visits throughout each phase of the study for processing at both the central laboratory and at Pathology Lancet Kenya.
Informed Consent
The principles of informed consent will be implemented according to the Declaration of Helsinki in its currently acknowledged version, ICH Consolidated Good Clinical Practice, KNH/UON Ethics Review committee. Participants male and female, that agree to voluntarily participate in the study must sign the informed consent form (ICF) prior to study-specific procedures.
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