Simon, James A. MD1; Lin, Vivian H. MD2; Radovich, Cathy BS2; Bachmann, Gloria A. MD3; The Ospemifene Study Group
Vulvar and vaginal atrophy (VVA), a chronic postmenopausal health condition caused by a hypoestrogenic state, can negatively affect a woman’s life.1 It is common yet often underreported.2 Up to 59% of postmenopausal women are affected by VVA.3-7 Symptoms of VVA, which include dyspareunia, vaginal dryness, vulvar and vaginal itching and irritation, and dysuria, may become more pronounced with aging and are unlikely to resolve spontaneously.8 Without treatment, VVA is a health issue that can negatively impact urogenital health, sexual function, quality of life, psychosocial well-being, and partner relationships in many postmenopausal women.3,9
Although a much greater percentage of women experience VVA, data suggest that only about 25% of affected women seek medical attention for symptomatic relief.8 Women are often apprehensive or embarrassed about seeking medical care because of the sensitive nature of VVA. Also, the limitations of current treatment options (eg, estrogen-based systemic and/or local application) may discourage women from seeking treatment of this condition because of safety concerns about initiating long-term estrogen therapy or unwillingness to use topical treatments.8,10,11 In addition, many physicians may not address sexual health and quality of life with their patients, nor do they offer management strategies for improvement.12,13
The North American Menopause Society 2007 position statement describes vaginal atrophy as evidenced by thin, pale, dry, and sometimes inflamed vaginal walls, which become less elastic with diminished secretions. Histological examination shows the presence of parabasal cells and reduced or absent lactobacilli.8 Although lubricants and moisturizers are indicated as first-line therapy for the treatment of VVA symptoms,8 they do not address the vaginal atrophy changes underlying this condition. Local vaginal estrogen products14 such as vaginal creams, vaginal tablets, and vaginal rings are suggested and recognized by The North American Menopause Society as being effective and well-tolerated treatments of vaginal atrophy.8 Each of these intravaginal treatment options reduces exposure to estrogen from systemic administration but are still not suitable for all women, especially those who cannot or will not use either an estrogen product or a vaginal product.14 In addition, prescribing information for estrogen products state that the lowest effective dose should be used for the shortest duration of time consistent with treatment goals.15-19
Systemic estrogen is effective for vaginal atrophy symptoms but may be contraindicated in or unacceptable to women because of the potential for systemic adverse effects, especially with long-term use.8 In addition, systemic estrogen treatment is not recommended for symptoms of VVA alone that are not accompanied by bone or vasomotor symptoms.8
Ospemifene is an oral compound for the treatment of VVA. It belongs to a class of compounds called selective estrogen receptor modulators (SERMs). In a preclinical model of VVA using ovariectomized rats, ospemifene demonstrated a favorable pharmacologic profile for the treatment of VVA, with induced mucification and a beneficial shift of the maturation index in the rat vagina. Ospemifene has multiple tissue-specific actions, but it is differentiated from other marketed SERMs by its preclinical action in the vagina and its antagonistic activity on endometrial and breast tissues.20,21
In a phase 3 clinical study, ospemifene was demonstrated to be effective and well tolerated for the treatment of VVA and its associated symptoms, such as dyspareunia and vaginal dryness, for up to 12 weeks.22
In a phase 2 study, daily doses of ospemifene 30 to 90 mg during a 3-month treatment period resulted in a reduced percentage of parabasal cells and an increased percentage of intermediate and superficial cells.23 Reported here are the results of a 40-week extension of this 12-week study, which assessed the long-term safety of ospemifene 30 mg/day and ospemifene 60 mg/day compared with placebo for the treatment of VVA in postmenopausal women with a uterus.
Study design and population
This was a multicenter, randomized, double-blind, 40-week safety extension (NCT01585558; sponsor protocol no. 15-50310x) of a 12-week, phase 3, efficacy and safety study (sponsor protocol no. 15-50310) in postmenopausal women with a uterus (Fig. 1).22,24 An additional 40-week extension study (sponsor protocol no. 15-50312) of 301 postmenopausal women without a uterus who completed the initial study will be reported separately.25 Full inclusion and exclusion criteria have been previously published.22 Women aged 40 to 80 years were treated with daily oral doses of placebo, ospemifene 30 mg, or ospemifene 60 mg (Penn Pharmaceutical Services, UK) for 40 weeks according to the blinded treatment to which they were originally assigned in the 12-week initial study. For blinding, both dose levels of the active study drug and placebo were supplied as tablets that were identical in appearance, and all protocol-associated personnel and the data manager were blinded to treatment assignments for each participant. Study medication was taken orally each morning with food. All participants who entered the extension study had completed the 12-week study. The total duration of treatment was 52 weeks, followed by a 4-week posttreatment follow-up period (Fig. 1). A written informed consent form was obtained from each participant before enrollment. Treatment compliance was determined through reconciliation of drug consumed and drug remaining, with reconciliation based primarily on the returned drug. Institutional Review Boards approved the protocol for each study site before study initiation.
Participants were asked to report all adverse events (AEs) and were queried about AEs at every study visit (weeks 20, 26, 40, 52 [or discontinuation], and 56). Definitions of serious AE (SAE) included any untoward medical occurrence that—at any study drug dose—resulted in death, was life threatening, required inpatient hospitalization or prolonged an existing hospitalization, or resulted in persistent or significant disability/incapacity. Safety assessments included visual examination of the vagina, breast palpation, physical examination, centrally read electrocardiogram, clinical laboratory assessments, and vital signs. The severity of AEs was assessed by the investigator according to the following scale: mild (causes awareness of sign or symptom but is easily tolerated), moderate (causes enough discomfort to interfere with usual activity), and severe (results in incapacitation with inability to work or perform usual activity). Analyses of hormone levels and endometrial thickness (assessed by transvaginal ultrasonography [TVU]) were performed on all participants (weeks 26 and 52 or at discontinuation). Endometrial histology (assessed by endometrial biopsy) was evaluated at baseline and at 12 weeks during the initial study, and in the present study, on week 26 if indicated based on TVU and on week 52 or discontinuation. Papanicolaou test and mammography were performed on all participants on week 52 or at discontinuation. A summary of safety assessments is provided in Figure 2.
Endometrial biopsy laboratory procedures
Endometrial biopsy samples were obtained by the investigator using a suction curette and shipped to the central pathology laboratory for preparation of slides and initial evaluation by one pathologist. Biopsies were assessed according to predefined and generally accepted microscopic criteria (Blaustein’s classification).26 After the prespecified adjudication procedure, another independent pathologist performed a second evaluation of all samples. If there was disagreement between the evaluations (histological class), a third pathologist assessed the samples. If two of the three independent pathologists concurred, their evaluation was used as the final diagnosis. If there was no agreement among the three pathologists, the most severe pathologic diagnosis was used in all analyses. All pathologists were blinded to the study treatment and to one another’s histology slide assessment. A biopsy was performed on week 26 only if the TVU indicated a double-layer endometrial thickness of 4 mm or higher (as determined by either the investigator or the central reader). If the endometrial thickness by TVU was 4 mm or higher, up to three endometrial biopsy attempts were to have been made to obtain sufficient tissue for histology based on participant consent. If the investigator determined that the endometrial thickness was less than 4 mm and the central reader determined that it was 4 mm or higher, an endometrial biopsy was also requested. An endometrial biopsy was obtained from all participants on week 52 (end of the study). If the week 52 endometrial biopsy results confirmed insufficient endometrial tissue for diagnosis after a valid attempt to sample the endometrium, a TVU result of a double-wall endometrial thickness less than 4 mm was considered as not indicative of endometrial hyperplasia.
Visual examination of the vagina
Visual examination of the vagina included observations for petechiae, pallor, friability, dryness, and redness in the mucosa. Ratings were based on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe).
All analyses were performed using SAS release 8.2. Data were analyzed using descriptive statistics, unless otherwise noted. No statistical analysis of the data from the visual examination of the vagina was planned. Baseline was defined as the prestudy drug treatment assignment from the 12-week initial study.
Analyses were performed to characterize changes from baseline and to identify any clinically relevant abnormal findings in safety laboratory values (hematology, chemistry, urinalysis, coagulation parameters, serum lipid levels, and hormone levels), physical examination, gynecological examination, breast palpation, mammography, Papanicolaou test, endometrial thickness and biopsy, and vital signs. Safety analyses were conducted using data from the intent-to-treat population, defined as any participant who entered the study and received at least one dose of study medication. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA; version 9.1) and tabulated by treatment group, system organ class, preferred term (PT), causality, and severity. Significant AEs, SAEs, and discontinuations due to AEs were summarized. Additional safety summaries included clinical laboratory tests, vital signs, physical and gynecological examinations (including breast palpation, endometrial biopsy, and TVU), treatment compliance, and reasons for discontinuation.
Participant disposition and demographics
A total of 180 women were enrolled in this extension study; 140 (77.8%) completed the 40-week treatment period (Fig. 1). Participant demographics and baseline characteristics are shown in Table 1. Most participants were white (90.0%), ranging in age from 46 to 79 years, with body mass index values ranging from 15.7 to 36.8 kg/m2.
The proportion of participants who discontinued the study was greatest in the placebo group (30.6%) compared with 21.0% and 17.4% in the ospemifene 30 mg/day and ospemifene 60 mg/day groups, respectively. Withdrawal of consent was the most common reason for discontinuation (16.3%, 6.5%, and 7.2% in the placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day groups, respectively). The second most common reason for premature discontinuation was treatment-emergent AEs (TEAEs), which were reported for one participant (2.0%) in the placebo group, for three participants (4.8%) in the ospemifene 30 mg/day group, and for four participants (5.8%) in the ospemifene 60 mg/day group. No participants developed endometrial hyperplasia or endometrial carcinoma, and no participants discontinued because of any endometrial or cervical pathology.
Compliance to and duration of treatment
Mean compliance rates (ie, compliance with dosing schedule) were 93.4%, 85.5%, and 84.6% for the placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day treatment groups, respectively. The mean duration of treatment was 232 days for the placebo group, 266 days for the ospemifene 30 mg/day group, and 254 days for the ospemifene 60 mg/day group.
A summary of endometrial histological characteristics is presented in Table 2. At baseline and on week 52, more than 95% of all endometrial tissue samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. On week 52, no cases of endometrial hyperplasia or carcinoma were observed. Proliferative findings were observed only in one participant in each of the ospemifene 30 mg/day and ospemifene 60 mg/day groups and in none in the placebo group at baseline and on week 52. One participant in the ospemifene 30 mg/day group had atypical epithelial proliferation, and one participant in the ospemifene 60 mg/day group had disordered proliferation.
Changes in endometrial thickness determined with TVU during the 52-week treatment period are presented in Table 3. A slight dose-related increase in mean endothelial thickness was observed with ospemifene, an effect that continued during the course of the study. On week 26, the mean (SD) changes from baseline were −0.12 (1.16), 0.58 (1.90), and 0.82 (1.67) mm for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively. On week 52, the mean (SD) changes from baseline were −0.04 (1.15), 0.68 (2.57), and 1.14 (1.56) mm for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively.
Safety and tolerability
A summary of TEAEs is provided in Table 4. The percentages of participants experiencing at least one TEAE were 44.9% for the placebo group and 61.3% and 63.8%, respectively, for the ospemifene 30 mg/day and ospemifene 60 mg/day groups. Most TEAEs were mild to moderate in severity. Severe TEAEs were reported for 4.1% of participants who received placebo, and for 9.7% and 10.1%, respectively, of those treated with ospemifene 30 mg/day and ospemifene 60 mg/day. The TEAEs occurring most frequently (≥5% of participants in any treatment group) by PT were nasopharyngitis, sinusitis, urinary tract infection (UTI), hypercholesterolemia, pharyngolaryngeal pain, and hot flushes. The incidence of UTIs was similar in all treatment groups (8.2%, 6.5%, and 8.7% for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively) and did not lead to study discontinuation. Other frequently reported TEAEs were vaginal candidiasis and vulvar and vaginal mycotic infection (combined results of 2.0%, 8.1%, and 4.3% for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively).
The only TEAE considered by the investigator to be possibly, probably, or definitely related to the study drug (occurring in ≥5% of participants) were hot flushes (2.0%, 3.2%, and 7.2% for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively). The discontinuation rate due to hot flushes was 1.6%. There were no cases of venous thromboembolism in the current study.
Discontinuation of the study drug due to an AE occurred in 2.0%, 4.8%, and 5.8% of participants in the placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day groups, respectively. Eight participants reported 11 treatment-emergent SAEs (TESAEs; Table 4): one participant with one TESAE (2.0%; breast cancer in situ) in the placebo group, two participants with three TESAEs (3.2%; osteoarthritis, neck pain, and headache) in the ospemifene 30 mg/day group, and five participants with seven TESAEs (7.2%; breast prosthesis implantation, encephalitis herpes, noncardiac chest pain, candida meningitis, gastritis, chronic obstructive pulmonary disease, and dehydration) in the ospemifene 60 mg/day group. Five participants discontinued due to a TEAE that started during the long-term extension study: none (0.0%) in the placebo group, two (3.2%; diverticulitis in one participant; atrial fibrillation, tachycardia, shortness of breath, and hyperthyroidism in one participant) in the ospemifene 30 mg/day group, and three (4.3%; one participant each with upper abdominal pain, candida meningitis, and postprocedural complication) in the ospemifene 60 mg/day group. One participant in each group discontinued due to a TEAE that was ongoing from the initial 12-week study. Of the 12 TEAEs that led to discontinuation, seven were considered unlikely to be related or not related to the study drug. The other five TEAEs were considered to be possibly related to the study drug.
Clinical laboratory evaluations and examinations
Clinical laboratory evaluations were compared with the baseline of the 12-week initial study.22 From baseline to week 52, there were small mean percentage changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in each treatment group. On week 52, the mean (SD) percentage changes from baseline were −1.05 (9.289), −0.55 (13.910), and −2.45 (12.323) for total cholesterol; −0.42 (15.418), −0.87 (19.748), and −6.20 (18.623) for LDL cholesterol; and −4.41 (14.347), 6.07 (16.836), and 1.29 (12.787) for HDL cholesterol for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively. Triglycerides increased by 21.6% from baseline to week 52 in the placebo group versus a 3.1% decrease in the ospemifene 30 mg/day group and a 15.2% increase in the ospemifene 60 mg/day group. The maximal triglyceride level seen in the ospemifene group was 1.4 mmol/L.
Overall, no major changes in the mean values for the coagulation parameters were observed between study groups, except for fibrinogen, which decreased in both ospemifene groups compared with placebo. On week 52, the mean (SD) changes in fibrinogen from baseline were 0.22 (2.84), −0.71 (1.82), and −1.06 (1.99) μmol/L for placebo, ospemifene 30 mg/day, and ospemifene 60 mg/day, respectively. In the measured serum hormone levels, numerically greater changes in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone–binding globulin (SHBG) from baseline were seen in both ospemifene groups compared with placebo, although the mean FSH and LH levels remained well within the postmenopausal range in all groups. Ospemifene decreased LH and FSH levels and increased SHBG and total testosterone levels in a dose-dependent manner; the mean free testosterone and estradiol levels remained largely unaffected (Table 5).
One participant in each ospemifene group experienced vaginal bleeding (corresponding to the MedDRA PT “vaginal hemorrhage”). The participant in the ospemifene 30 mg/day group had two different TEAEs of vaginal hemorrhage. Vaginal spotting (which also maps to the MedDRA PT “vaginal hemorrhage”) occurred in one participant in the ospemifene 60 mg/day group. All cases of vaginal bleeding and spotting were self-limiting, lasting from 1 to 3 days.
Sustained improvements in severity scores for all visual examination characteristics of the gynecological examination (petechiae, pallor, friability, vaginal dryness in mucosa, and redness in mucosa) were observed from baseline to both week 26 and week 52 for the ospemifene 30 mg/day group and the ospemifene 60 mg/day group compared with placebo.27 Visual examination findings are depicted in Figure 3.
Breast palpations performed on week 52 were normal in all but one participant in the ospemifene 60 mg/day group. Mammography performed on week 52 yielded normal results for most participants in all treatment groups; one participant in the ospemifene 60 mg/day group had an abnormal mammography finding, which resolved by the end of the study. Two participants experienced a breast-related TESAE: one (2.0%; breast cancer in situ) in the placebo group and one (1.4%; breast prosthesis implantation) in the ospemifene 60 mg/day group. Six participants experienced nonserious breast-related TEAEs (breast cyst: one [2.0%] in the placebo group; breast mass: two [3.2%] in the ospemifene 30 mg/day group; breast mass, breast microcalcification, and abnormal mammography finding: one participant each [total, 4.3%] in the ospemifene 60 mg/day group). Breast-related TEAEs were mild in severity. Reproductive system–related TEAEs (adnexa uteri pain, cervical dysplasia, cervical polyp, genital discharge, genital pruritus, ovarian cyst, pelvic pain, vaginal discharge, and vaginal erythema) were not considered clinically significant. No AEs of pelvic organ prolapse and no clinically significant adverse changes in gynecological examination or Papanicolaou test results were observed.
In this 52-week study of postmenopausal women with VVA, ospemifene 30 mg/day and ospemifene 60 mg/day were generally safe and well tolerated. All current prescription treatments of VVA in postmenopausal women are estrogen-based. Therefore, there is a need for alternative treatment options for this condition because of concerns regarding the potential stimulatory effects of estrogens on breast and endometrial tissues.28-31 The risk of endometrial cancer is 4.5 to 9.3 times greater among women with a uterus on unopposed oral systemic estrogen therapy.29,31,32 In addition, a meta-analysis conducted by the Cochrane group indicated that treatment with unopposed systemic estrogen, which is dose dependent, was associated with an odds ratio for endometrial hyperplasia of 5.4 for 6 months, 9.6 for 24 months, and 16.0 for 36 months.30 Therefore, in our study, it was important to determine whether ospemifene had any negative effect on the endometrium. In the present study, no cases of endometrial hyperplasia or cancer were reported, and only three ospemifene participants reported vaginal bleeding or spotting. In this study of 180 participants during 1 year of treatment, a minimal dose-related increase in endometrial thickness of 0.48 mm from baseline was observed with TVU on week 52 (0.68 and 1.14 mm in the ospemifene 30 mg/day and ospemifene 60 mg/day groups, respectively), and only two proliferative findings were observed in endometrial biopsies on week 52.
In the present study, visual evaluations of the vagina suggested continued clinical improvement from baseline, consistent with the statistically significant efficacy observed during the first 12 weeks of ospemifene treatment.22 These clinical observations suggest that the positive effect of ospemifene on the vaginal epithelium is sustained for up to 52 weeks.
Hot flushes were the most common treatment-related TEAE, occurring in 7.2% of participants treated with ospemifene 60 mg/day, in 3.2% of participants treated with ospemifene 30 mg/day, and in 2.0% of participants treated with placebo. However, only one participant (1.6%; ospemifene 30 mg/day group) discontinued from the study due to hot flushes.
In the present study, the incidence of UTIs was similar across the treatment groups. The incidence in the ospemifene groups was less than that seen in the 12-week initial study, in which ospemifene treatment resulted in a numerically greater incidence of UTIs versus placebo. This suggests that ospemifene treatment may not increase the incidence of UTIs in the long term. Over time, it is expected that, as the vaginal pH becomes more acidic with ospemifene treatment,22 there will be fewer coliforms and more lactobacilli; thus, fewer UTIs will occur.33 Vulvar and vaginal mycotic infections were observed with ospemifene in both the 12-week initial study and the long-term study, suggesting an increased incidence associated with ospemifene. Similar findings have been observed with hormone therapy.33 No TEAEs were observed for gynecological examinations, breast palpations, or Papanicolaou tests, suggesting that long-term treatment with ospemifene is not associated with clinically significant adverse effects on the reproductive system. Similar results were observed in the 12-week initial study. No clinically significant adverse changes were observed in physical examinations or evaluation of vital signs.
No clinically significant adverse changes in laboratory values, including lipids and coagulation parameters, were observed in the ospemifene groups. Improvement in the LDL-to-HDL ratio was observed with ospemifene when compared with placebo on week 52, consistent with the findings of the 12-week study.22 A greater mean increase in triglycerides from baseline to week 52 was observed in the placebo group versus the ospemifene 60 mg/day group. Given triglyceride variability, however, these changes are unlikely to represent any true differences between groups. In addition, ospemifene, given orally, was not observed to cause a substantial increase in triglycerides in any participant at the doses used in this study.34 The decrease in fibrinogen was consistent with the 12-week initial study results. Other coagulation changes were not regarded as clinically significant, and no cases of venous thromboembolism were observed. Although these limited results must be interpreted with caution because of the small number of participants in this study, it is worth noting that estrogens and SERMs (ie, raloxifene, bazedoxifene, and lasofoxifene) are known to alter the plasma contents of various coagulation factors via mechanisms that are not fully understood, which may alter hemostatic balance and increase the risk for thrombosis.35,36
The dose-related decreases in LH and FSH levels, dose-related increases in SHBG and total testosterone levels, and negligible changes in free testosterone and estradiol levels that were observed with ospemifene were similar to the results observed in the 12-week initial study.
This study was well conducted; however, limitations include the small number of participants and the treatment duration of only 1 year. Of the 310 women with a uterus who completed the initial 12-week study, 180 (58%) enrolled in the long-term study, and 130 did not. The conclusions listed here are based on a sample size of 180, making extrapolation of these results to rare treatment-emergent events impossible. No sensitivity analyses were undertaken to determine the likelihood that our conclusions can be generalized to the population at large. Such analyses await studies with substantially increased sample sizes.
Once-daily doses of ospemifene 30 mg and ospemifene 60 mg were generally safe. There were no significant estrogenic or clinically important adverse effects on the endometrial tissue. At the doses tested, ospemifene was well tolerated, compared with placebo, for up to 1 year for the treatment of VVA in postmenopausal women with a uterus. Ospemifene has the potential to be the first oral alternative to estrogen prescription therapy for the treatment of the highly prevalent and chronic condition of VVA.
We thank the Ospemifene Study Group, the study staff at each site, and all of the women who participated in this study.
We gratefully acknowledge Mary Phelps, MPH, for suggestions and review of the manuscript. Technical and editorial assistance for this manuscript was provided by Diane Kwiatkoski, PhD, and Carol Berry, MSc (Quintiles, Parsippany, NJ).
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© 2013 by The North American Menopause Society.