Trial DesignA cardiovascular safety study of LibiGel (testosterone gel) in postmenopausal women with elevated cardiovascular risk and hypoactive sexual desire disorder
Section snippets
Background and study rationale
Female sexual dysfunction is a common clinical problem. The most common form of female sexual dysfunction is hypoactive sexual desire disorder (HSDD), a syndrome of low sexual desire causing personal distress. It is estimated that >40% of women report some type of sexual dysfunction and the prevalence of HSDD is approximately 10% to 12%.1, 2, 3 Currently, there are no pharmaceutical treatments for HSDD that are approved by the US Food and Drug Administration (FDA).
Low-dose testosterone has been
Study design and conduct
BLISS is a randomized, double-blind, placebo-controlled, parallel group study comparing LibiGel (0.22 g/d of testosterone) and identical placebo gel in postmenopausal women with HSDD and increased CV risk. The primary objective is to demonstrate that the CV risk associated with LibiGel is not higher than placebo. The primary outcome of the study is a composite of adjudicated CV events including CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, hospitalized
Treatment
Participants are randomized in a 1:1 ratio to receive either 1% testosterone gel 0.22 g/d (LibiGel) or an equivalent weight of identical placebo gel daily. Randomization is stratified by use of postmenopausal hormone therapy (none, estrogen, or estrogen + progestogen).
Study procedures
There are 9 clinical visits and 14 telephone contacts during the course of the study (Figure 1). Office visits will occur at screening and randomization and at 3, 6, and 12 months postrandomization and yearly thereafter. Telephone
Statistical considerations
The primary safety outcome is time to the first occurrence of a CV event. The coprimary safety outcome is time to first incident of invasive breast cancer. In addition, each component of the composite CV outcome, all-cause mortality, as well as breast carcinoma in situ will be evaluated as secondary end points.
The primary analysis is Bayesian and will use the posterior distribution for the hazard ratio (HR) and its associated CI and the posterior distribution for the absolute risk difference to
Study progress and baseline characteristics
The BLISS study was initiated in early 2008, and >150 research sites experienced in women's health studies in the United States and Canada have been enrolling patients. All investigative personnel were trained at formal 2-day investigator meetings, site initiation visits, and continuous education on study conduct via clinical monitoring visits, monthly newsletters, and sponsor letters. Patients have been recruited from databases of the investigative sites, referrals, local advertising
Discussion
The BLISS study is the first large, long-term study of the safety of testosterone in postmenopausal women with HSDD. The dose of testosterone chosen for the study, 0.22 g/d, is approximately equal to the ovarian production rate in younger women with normal menstrual cycles.12 Although the tolerability and short-term safety of physiologic doses of testosterone in women have been acceptable for clinical use,5, 11 long-term safety has not been established. The primary safety outcome of BLISS will
Conclusions
The BLISS study is an important and novel study for establishing the safety of LibiGel testosterone therapy in postmenopausal women with HSDD. The operational principals of this study may be applicable to conducting safety studies for other drugs in other populations with low event rates. The study has been ongoing since 2008 and has been actively enrolling and randomizing participants. The BLISS study is designed to document the efficacy and safety of LibiGel for treatment of HSDD, a common
Disclosures
Funding source—The sponsor of this study is BioSante Pharmaceuticals, Inc, Lincolnshire, IL.
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Cited by (53)
Use of Testosterone in Postmenopausal Women
2021, Endocrinology and Metabolism Clinics of North AmericaCitation Excerpt :The large published studies of testosterone for HSDD excluded women with chronic disease; therefore, the safety data generated by these studies cannot be generalized to women with chronic significant health issues. A large, randomized trial of transdermal testosterone versus placebo recruited 3656 postmenopausal women at high risk of cardiometabolic disease.68 At 4 years, with more than 7000 women-years accrued, the safety monitoring committee had completed 6 unblinded reviews of the data and recommended the study continue.
Determining a Bayesian predictive power stopping rule for futility in a non-inferiority trial with binary outcomes
2020, Contemporary Clinical Trials CommunicationsThe Saga of Testosterone for Menopausal Women at the Food and Drug Administration (FDA)
2020, Journal of Sexual MedicineMethodological Challenges in Studying Testosterone Therapies for Hypoactive Sexual Desire Disorder in Women
2020, Journal of Sexual MedicineCitation Excerpt :This safety record has been further supported by an event-driven cardiovascular and breast cancer safety trial on another testosterone product for women (Libigel) which was proceeding without safety signals into year 4 of 5 when the sponsor ran out of money. While the results of this trial remain unpublished, the fact that the data safety and monitoring board was allowing the trial to continue despite enrolling women at high risk of cardiovascular disease is very reassuring.61 The passage of time has slightly improved the regulatory environment for women's sexual health as well.
Follicle-stimulating hormone promotes the transformation of cholesterol to estrogen in mouse adipose tissue
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Estrogen is a critical ovarian steroid hormone that stimulates the development of reproductive function. The marked reduction in estrogen during menopause can induce cardiovascular disease, metabolic syndrome, osteoporosis, and other syndromes [1–4]. Follicle-stimulating hormone (FSH) combines with its specific membrane receptor, follicle-stimulating hormone receptor (FSHR) to control the progesterone synthesis from granulosa cells via G protein/adenylate cyclase (cAMP)/protein kinase A (PKA)/MAPK pathway [5], and then progesterone transforms to estrogen under the regulation of enzymes in the steroid hormone metabolism pathway [6].
Clinical trials identifier: clinicaltrials.gov no. NCT00612742.