A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

A pooled analysis of the effect of condoms in preventing HSV-2 acquisition.

BACKGROUND: The degree of effectiveness of condom use in preventing the transmission of herpes simplex virus 2 (HSV-2) is uncertain. To address this issue, we performed a large pooled analysis. METHODS: We identified prospective studies with individual-level condom use data and laboratory-defined HSV-2 acquisition. Six studies were identified through a review of publications through 2007: 3 candidate HSV-2 vaccine studies, an HSV-2 drug study, an observational sexually transmitted infection (STI) incidence study, and a behavioral STI intervention study. Study investigators provided us individual-level data to perform a pooled analysis. Effect of condom use was modeled using a continuous percentage of sex acts during which a condom was used and, alternatively, using absolute numbers of unprotected sex acts. RESULTS: A total of 5384 HSV-2-negative people at baseline contributed 2 040 894 follow-up days; 415 persons acquired laboratory-documented HSV-2 during follow-up. Consistent condom users (used 100% of the time) had a 30% lower risk of HSV-2 acquisition compared with those who never used condoms (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.40-0.94) (P = .01). Risk for HSV-2 acquisition increased steadily and significantly with each unprotected sex act (HR, 1.16; 95% CI, 1.08-1.25) (P < .001). Condom effectiveness did not vary by gender. CONCLUSIONS: To our knowledge, this is the largest analysis using prospective data to assess the effect of condom use in preventing HSV-2 acquisition. Although the magnitude of protection was not as large as has been observed with other STIs, we found that condoms offer moderate protection against HSV-2 acquisition in men and women.

Proteasome inhibitors stimulate both bone formation and hair growth by similar mechanisms.

We propose that the remodeling process that occurs in localized areas on endosteal bone surfaces and in Haversian canals shares many features in common with the mammalian hair cycle. In both, there are phases of resorption or regeneration, a transition phase, and then a phase of growth, termed anagen in the hair follicle, and formation in the bone remodeling cycle. Furthermore, we suggest that these processes both use the same molecular mechanisms, and specifically the Hedgehog-BMP-Wnt signal transduction cascades. We have found that proteasome inhibitors, which enhance bone formation by effects on these cascades, also stimulate anagen induction and hair growth in the murine and human hair follicle, and propose they do so by effects on similar or identical molecular targets.

The relationship between condom use and herpes simplex virus acquisition.

BACKGROUND: Few studies have evaluated the relationship between condom use and herpes simplex virus type 2 (HSV-2) and HSV type 1 (HSV-1) acquisition. OBJECTIVE: To assess the relationship between condom use and acquisition of HSV-2 and HSV-1 among men and women. DESIGN: Analysis of data collected as part of a clinical trial of an ineffective candidate vaccine for HSV-2. SETTING: Sexually transmitted disease clinics. PARTICIPANTS: Men and women at risk for HSV-2 acquisition, defined as having 4 or more sexual partners or having a sexually transmitted disease in the past year. MEASUREMENT: Acquisition of HSV-2 and HSV-1 as measured by viral culture or change to positive HSV serostatus. RESULTS: Of 1843 participants, 118 (6.4%) became infected with HSV-2. In multivariate analyses, participants reporting more frequent use of condoms were at lower risk for acquiring HSV-2 than participants who used condoms less frequently (hazard ratio, 0.74 [95% CI, 0.59 to 0.95]); categories of increasing condom use were 0% to 25%, 25% to 75%, and greater than 75% of sexual acts. Nineteen (2.9%) of 659 participants at risk for infection with HSV-1 became infected. No statistically significant association between condom use and infection with HSV-1 was found (hazard ratio, 0.79 [CI, 0.48 to 1.31]). LIMITATIONS: Use of condoms was measured by self-report, and persons who used condoms may have differed from those who did not. CONCLUSIONS: Consistent use of condoms is associated with lower rates of infection with HSV-2 and should be routinely recommended.

Interrupting herpes simplex virus type 2 transmission: the role of condoms and microbicides.

Condoms act as mechanical barriers to genital infection. In vitro models demonstrate that condoms are almost impermeable to viruses. A small amount of virus may cross the condom, but the condom can still reduce the level of virus exposure by several orders of magnitude. However, in vivo factors, such as condom failure during intercourse, can potentially limit their effectiveness. The weight of available evidence suggests that consistent and correct use of the male condom protects against herpes simplex virus (HSV) infection, as well as other sexually transmitted infections. Female condoms should theoretically protect against HSV infection as they cover a large surface area of potentially infected or susceptible tissues, but research is needed to confirm this. The lack of acceptance, or lack of consistent use, of condoms is the biggest barrier to their effectiveness. There is a need for effective counselling of individuals whose sexual behaviour increases their risk of HSV acquisition, such as young adults. Pregnant women are likely to be receptive to counselling due to the risk of neonatal herpes. No commercially available microbicides specifically inhibit HSV, although many inactivate the virus. More potent and specific microbicides are in development, but may be more expensive than those currently available. Although the effectiveness of condom and microbicide use is not completely proven, there is sufficient evidence to support the promotion of their use by healthcare professionals as an important part of safe sex counselling.