Trial Design
A cardiovascular safety study of LibiGel (testosterone gel) in postmenopausal women with elevated cardiovascular risk and hypoactive sexual desire disorder

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Evaluation of the safety of hormonal preparations for the treatment of female sexual dysfunction is important to assess the benefit-to-risk profile of these drugs and has been strongly encouraged by the Food and Drug Administration. LibiGel (Biosante Pharmaceuticals, Inc., Lincolnshire, IL), a low-dose testosterone gel, is under development for the treatment of hypoactive sexual desire disorder (HSDD) in oophorectomized women. To evaluate the long-term effects of LibiGel on risk for cardiovascular (CV) events, breast cancer, and general safety, a randomized, placebo-controlled clinical study using a novel adaptive design to optimize sample size and power is being conducted. The primary end point of the BioSante LibiGel Safety Study (BLISS) is a composite of CV events including death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, hospitalized unstable angina, and venous thromboembolic events. Breast cancer is a coprimary end point. Postmenopausal women (both surgically and naturally) with HSDD and increased risk for CV events will be followed up for up to 5 years postrandomization with an interim data analysis for regulatory approval after the last woman enrolled has been on therapy for at least 12 months. Determination of the number of subjects to enroll is based on an adaptive design that uses interim data to estimate the predictive probability of study success. In agreement with the Food and Drug Administration, LibiGel will be declared safe if the upper limit of the 97.2% CI of the hazard ratio is ≤2.0 or the upper bound of the 97.2% CI for the absolute difference between CV event rates per 100 person-years is ≤1% and the observed hazard ratio is ≤2.0. The BLISS study will define the CV safety profile of low-dose testosterone therapy in the formulation of LibiGel for postmenopausal women with HSDD, and the trial design may provide a paradigm for studies that aim to document long-term safety when the proposed outcome under study is an uncommon adverse event.

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.

References (26)

  • D. Shames et al.

    Regulatory perspective on clinical trials and endpoints for female sexual dysfunction, in particular, hypoactive sexual desire disorder: formulating recommendations in an environment of evolving clinical science

    Int J Impot Res

    (2007)
  • E. Barrett-Connor et al.

    Effects if raloxifene on cardiovascular events and breast cancer in postmenopausal women

    N Engl J Med

    (2006)
  • J. Hsia et al.

    Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative

    Arch Intern Med

    (2006)
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