Trial by "Firsts": Clinical Trial Design and Regulatory Considerations in the Development and Approval of the First AAV Gene Therapy Product in the United States.

Given the therapeutic potential of supplying a normal copy of a mutant gene to the correct target tissue, gene therapy holds extraordinary promise for the treatment of genetic disease. Like other novel classes of therapeutics however, gene therapies must overcome a range of clinical, regulatory, and manufacturing hurdles to reach regulatory approval. This paper reviews key aspects of clinical trial design, development, and evaluation of a novel primary end point, and regulatory interactions that resulted in the first approval by the U.S. Food and Drug Administration (FDA) of an adeno-associated virus (AAV) gene therapy product.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 and 4 Years.

PURPOSE: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; Luxturna [Spark Therapeutics, Inc]) administration in patients with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3 to 4 years and to review safety outcomes. DESIGN: Open-label, randomized, controlled phase 3 trial. PARTICIPANTS: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n = 21) or control (n = 10). One participant from each group withdrew before, or at, randomization. METHODS: Patients in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) patients served as control participants for 1 year then received VN. MAIN OUTCOME MEASURES: Change from injection baseline in bilateral performance on the multiluminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold white light, visual field (VF), and visual acuity (VA). RESULTS: Mean bilateral MLMT change scores at year 4 for OI patients and year 3 for DI patients were 1.7 and 2.4, respectively, with 71% of patients with a year 3 visit able to pass MLMT at the lowest light level. Mean change in full-field light sensitivity threshold white light, averaged over both eyes at year 4 for OI patients and year 3 for DI patients, was -1.90 log10(cd.s/m2) and -2.91 log10(cd.s/m2), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at year 4 for OI patients and 157.9 at year 3 for DI patients. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logarithm of the minimum angle of resolution (logMAR) at year 4 for OI patients and -0.06 logMAR at year 3 for DI patients. One OI patient experienced retinal detachment at approximately year 4 that impacted VA for the OI group. No product-related serious adverse events (AEs) occurred, nor did any deleterious immune responses. CONCLUSIONS: Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3 to 4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure and was similar between intervention groups, with no product-related serious AEs reported.

The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene.

PURPOSE: To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses. DESIGN: Global, multicenter, retrospective chart review. METHODS: Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD. PROCEDURES: Data were extracted from patient charts. MEASUREMENTS: Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available). RESULTS: VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships. CONCLUSIONS: The number of clinical diagnoses and lack of a consistent RPE65 mutation-to-phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations.

Body weight does not impact pregnancy rates during use of a low-dose extended-regimen 91-day oral contraceptive.

BACKGROUND: This study evaluated the impact of weight on efficacy during use of an extended oral contraceptive (OC). STUDY DESIGN: Data were from a Phase 3 clinical trial evaluating the efficacy of a low-dose 91-day extended regimen of 100 mcg levonorgestrel/20 mcg ethinyl estradiol (LNG/EE; 84 days)+10 mcg EE (7 days) for the prevention of pregnancy. Crude pregnancy rates were calculated for weight and body mass index (BMI) deciles. RESULTS: Of the 1736 women in this analysis, 878 (50.6%) had a BMI greater than 25 kg/m2, and 770 (44.4%) were heavier than 70 kg. Pregnancies occurred in 36 women. Crude pregnancy rates were similar across weight and BMI deciles, with no discernable differences observed between deciles using either classification criterion. CONCLUSIONS: No evidence of any reduction in the level of contraceptive efficacy was observed with this low-dose extended OC regimen in overweight and obese women.

Synthetic conjugated estrogens-B and postmenopausal nocturnal vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To evaluate two doses of oral synthetic conjugated estrogens-B tablets compared with placebo on the frequency of awakenings resulting from nocturnal vasomotor symptoms in postmenopausal women over a 12-week treatment period. METHODS: A double-blind, randomized, placebo-controlled multicenter study enrolled a total of 157 women who were experiencing daytime vasomotor symptoms and a minimum of at least three nocturnal awakenings per night as a result of hot flushes. Participants were evenly randomized to one of three treatment groups (0.3 mg, 0.625 mg, or matching placebo) and treated for up to 12 weeks. Subjective sleep quality also was assessed. RESULTS: Significantly greater reductions from baseline in the weekly mean frequency of awakenings resulting from hot flushes occurred for participants randomized to either synthetic conjugated estrogens-B dose relative to placebo (mean reductions, 3.55, P=.004, and 4.65, P<.001 for 0.3 mg and 0.625 mg, respectively). In addition, a significantly greater proportion of participants at either estrogen dose had complete elimination of nocturnal awakenings (36.5% for 0.3 mg, 34% for 0.625 mg compared with 9.8% for placebo; P ≤.002) with a general finding of improved sleep based on actigraphy data. No differences were observed in measures of sleep quality or daytime sleepiness. CONCLUSION: In this symptomatic postmenopausal population of women experiencing sleep disruption resulting from nocturnal vasomotor symptoms, a daily dose of synthetic conjugated estrogens-B as low as 0.3 mg appears to be effective in treating nocturnal hot flushes that lead to unwanted awakenings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00592839.

A look at the long-term safety of an extended-regimen OC.

BACKGROUND: Oral contraceptives (OCs) are the most widely used method of reversible contraception. Recent alterations of the standard 28-day regimen have included shortening the traditional hormone-free interval (HFI), supplementing the HFI with low-dose estrogen, or increasing the number of active pills administered, thus extending the time between withdrawal bleeding episodes by a variable number of months. In light of these changes in regimens, clinicians may be seeking evidence that the new regimens are safe and will not result in unexpected adverse events. METHODS: We initiated a long-term extension trial to evaluate the safety of a 91-day extended-regimen OC containing 150 mcg levonorgestrel/30 mcg ethinyl estradiol (EE) for 84 days, followed by 7 days of 10 mcg EE. After participation in a 1-year, open-label, phase 3 contraceptive program, 320 women qualified for enrollment in a multicenter, nonrandomized study of 91-day extended-regimen OCs for up to 3 additional consecutive years; 116 completed the study. We evaluated incidence of reported adverse events (AEs), rates of study discontinuation, and reported bleeding patterns. RESULTS: Total exposure was equivalent to 8292 28-day cycles. Participants reported no thromboembolic events. Thirty-one (9.7%) women discontinued treatment due to AEs. Unscheduled bleeding and spotting diminished during the course of the trial. Overall rates of study discontinuation and incidence of AEs were consistent with those observed in the phase 3 clinical program. CONCLUSION: This study demonstrated that the AE profile of the 91-day extended-regimen OC over 4 years was similar to that seen in the 1-year clinical trials, with no unexpected adverse events.

The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol.

BACKGROUND: This clinical trial was conducted to demonstrate the efficacy and safety of a 91-day extended-regimen, low-dose combination oral contraceptive (OC) consisting of 84 days of ethinyl estradiol (EE) 20 mcg/levonorgestrel (LNG) 100 mcg, followed by 7 days of 10 mcg EE in place of placebo. STUDY DESIGN: A multicenter open-label, single-treatment, Phase 3 study evaluated women aged 18 through 40 years over a treatment period of up to 1 year (four 91-day extended cycles). All subjects completed daily paper diaries to monitor compliance, bleeding and additional forms of contraception used during the course of the study. RESULTS: A total of 1249 subjects completed the study. The Pearl Index was 2.74 (95% confidence interval, 1.92-3.78), based on 36 pregnancies that occurred after the onset of treatment and within 14 days after the last combination tablet in women aged 18-35 years. Among compliant-use subjects 18-35 years old, the Pearl Index was 1.73 based on 22 on-treatment pregnancies. The life table pregnancy rate for subjects 18-35 years of age was 2.39%. Cycle control and adverse events reported with this regimen were similar to those reported with other low-dose OCs. CONCLUSIONS: This study demonstrated effective prevention of pregnancy with a 20-mcg EE, 91-day extended-regimen OC. In addition, the regimen was well tolerated and incidence of adverse events were consistent with what has been reported with other low-dose OCs.

Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive.

BACKGROUND: A cross-study analysis of contraceptive clinical trials for two different 91-day oral contraceptive (OC) regimens was performed to examine the impact on bleeding patterns when supplementing the 7-day hormone-free interval with 10 mcg ethinyl estradiol (EE) daily. STUDY DESIGN: Two separate 1-year Phase 3 clinical programs were conducted using similar study designs. The percentages of subjects reporting bleeding and spotting using electronic diaries for each 91-day cycle were compared. RESULTS: Scheduled bleeding with the EE regimen was less than that reported with the regimen utilizing placebo during Days 85-91, with significant differences noted for all four 91-day cycles. Unscheduled bleeding decreased more quickly with the 91-day regimen containing low-dose EE in place of placebo, with significant differences noted during the third cycle. CONCLUSIONS: This cross-study comparison suggests that the administration of low-dose estrogen in place of placebo in a 91-day extended regimen OC improves the bleeding profile.

Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy.

OBJECTIVE: The aim of this study was to evaluate low-dose synthetic conjugated estrogens A (SCE-A) cream administered twice weekly for the treatment of moderate to severe vulvovaginal atrophy (VVA) in a symptomatic postmenopausal population. METHODS: In a multicenter, double-blind, randomized, placebo-controlled study, 305 women with symptoms of VVA were treated with either 1 g SCE-A cream (n = 150) or matching placebo (n = 155) for a period of up to 12 weeks. Participants had to have a vaginal pH of greater than 5, less than or equal to 5% superficial cells on a vaginal smear, and at least one of five symptoms of VVA (dryness, soreness, irritation, pain with intercourse, and bleeding after intercourse) that was moderate or severe in intensity. Women had to select one moderate or severe symptom as the most bothersome. RESULTS: Efficacy was assessed at 2, 3, 4, 8, and 12 weeks and included the change from baseline in the severity of the most bothersome symptom (MBS), maturation index, and pH. Most women identified vaginal dryness as the MBS (48%) followed by pain with intercourse (31.3%). A statistically significant increase in the maturation index and significant decreases in pH and severity of the MBS were observed for those treated with SCE-A vaginal cream compared with placebo. CONCLUSIONS: A low dose (1 g = 0.625 mg) of SCE-A vaginal cream administered twice weekly was shown to be effective compared with placebo in treating VVA in postmenopausal women for the three coprimary efficacy measures of maturation index, pH, and severity of the MBS.

Effectiveness of a novel home-based testing device for the detection of rupture of membranes.

We evaluated the ability of a testing panty liner (TPL) embedded with a pH/ammonia indicator polymer to differentiate amniotic fluid leakage from urine. A multicenter, open-label study in which 339 pregnant women (age 18 to 45 years, minimum 16 weeks' gestation, presenting with unexplained vaginal wetness) were enrolled. The TPL was worn and the results read by the subject and a health care provider (HCP) who was blinded to the subject's reading. Results were compared with the standard clinical diagnosis, as determined by direct visualization of vaginal pooling, crystallization (ferning), and nitrazine tests, performed by a second blinded HCP. Subject experience with the test was assessed with a brief questionnaire. The TPL accurately detected 154 of the 161 subjects found to have amniotic fluid leakage by the standard diagnosis; thus, the sensitivity of the TPL was 95.65%. The specificity was 84.46% (% true negative readings), as the TPL demonstrated a negative result for 125 of the 148 subjects whose clinical diagnosis was negative for amniotic fluid leakage. The overall agreement between the TPL readings of the clinician and that of the subject was 97.40%. The TPL is a reliable test to determine the presence of amniotic fluid leakage.

Understanding the menopausal experiences of professional women.

OBJECTIVE: To assess how menopause affects the lives of busy female executives by evaluating how they view their overall health and how specific symptoms affect their lives and to gain insight into their knowledge and general perspective of hormone therapy as treatment for menopause-related symptoms. DESIGN: In this survey, 961 members of the National Association of Female Executives aged 35 years and older completed an Internet survey about the impact of menopausal symptoms and general knowledge and understanding of hormone therapy. Subgroups within this survey included women who were premenopausal (n = 118), perimenopausal (n = 239), menopausal (n = 297), and postmenopausal (n = 307). RESULTS: A majority of women surveyed (88%) had personal experience with menopause, 95% reported physical symptoms, and 79% reported emotional symptoms. Among women reporting symptoms, 40% found symptoms to be problematic in at least one area of their lives. Of the 41% of respondents who had used hormone therapy to treat their menopausal symptoms, 57% reported continued use at the time of the survey. Among those who discontinued hormone therapy, 39% cited the Women's Health Initiative results as one of the reasons. The survey also found substantial gaps in the knowledge and understanding of hormone therapy by the survey responders. CONCLUSIONS: The majority of menopausal women surveyed experience physical and/or emotional symptoms. For many women, symptoms related to menopause significantly affect their daily personal, professional, and social lives. Educating patients about scientific findings, current treatment options, and the associated risks and benefits is critical to providing effective, individualized care to improve quality of life.

Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach.

OBJECTIVE: To assess the importance and usefulness of self-reported symptom data, especially the most bothersome symptom, in the evaluation of treatment for vulvovaginal atrophy. DESIGN: This was a double-blind, placebo-controlled multicenter study. Women rated symptoms associated with vaginal atrophy (vaginal dryness, vaginal/vulvar irritation/itching, vaginal/vulvar soreness, and dyspareunia) before and during treatment and selected one moderate to severe symptom as the most bothersome. RESULTS: Among 310 women (n = 156 placebo), vaginal dryness and dyspareunia were most commonly classified as moderate to severe and as most bothersome (44.4% and 30.2%, respectively). For both symptoms, the effect size favoring active treatment consistently increased as the cohort was more narrowly defined (all treated women, women who classified the symptom as moderate or severe, and those who classified the symptom as most bothersome). Compared with the standardized effect sizes for all women, those calculated from the most bothersome symptom were 49% and 62% greater for dyspareunia and dryness, respectively. CONCLUSION: : The most bothersome symptom approach represents a meaningful new standard for measurement of self-assessed vulvovaginal atrophy symptom change, but evaluation of change in individual symptoms remains an important, unbiased primary analysis of efficacy in vulvovaginal atrophy studies.

Efficacy and safety of a 28-day oral contraceptive with 7 days of low-dose estrogen in place of placebo.

BACKGROUND: The study was conducted to evaluate the efficacy and safety for the prevention of pregnancy of a 28-day oral contraceptive (OC) containing 150 mcg desogestrel (DSG)/20 mcg ethinyl estradiol (EE) for 21 days followed by 7 days of 10 mcg EE (Cette-28). STUDY DESIGN: A 6-month, prospective, multicenter, single-arm study was conducted in 1302 women aged 18-45 years. RESULTS: Over six cycles of treatment, the cumulative risk of pregnancy among all treated subjects (n=1262) was 0.9%. The Pearl Index for women 18-35 years of age (n=1042) was 2.20, including 9 pregnancies with estimated conception dates during active drug ingestion or up to 7 days after the last combination tablet. The rate of unscheduled bleeding was low and the duration of scheduled bleeding was approximately 2 days during each of the six treatment cycles. The safety profile was similar to what has been reported for other OCs. CONCLUSION: This low-dose, 28-day OC incorporating 7 days of 10 mcg EE during the hormone free interval is effective and safe for the prevention of pregnancy and is well-tolerated by women.

Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens.

BACKGROUND: The study was conducted to evaluate follicular development and hormone patterns with three oral contraceptive (OC) regimens before, during and after the 7-day hormone-free interval (HFI) or 7-day ethinyl estradiol (EE)-supplemented interval. STUDY DESIGN: The study is a single-center, open-label, prospective, randomized trial to evaluate pituitary-ovarian suppression with three OC regimens containing identical hormones: 30 mcg of EE and 150 mcg of levonorgestrel (LNG). METHODS: After a standard 21/7 OC baseline cycle, subjects were randomized to one of three treatment groups: (1) three 21/7-day cycles of 150 mcg LNG/30 mcg EE for 21 days followed by 7 days of placebo (n=10); (2) one 84/7-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of placebo (n=12) and (3) one 84/7EE-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of 10 mcg EE (n=11). Estradiol; follicle-stimulating hormone (FSH); luteinizing hormone and inhibin-B levels, ovarian follicles and daily symptom diaries were collected. RESULTS: Compared to subjects receiving placebo during the 7-day HFI, those receiving EE demonstrated reductions (p<.05) in both FSH and estradiol. Number of developing follicles was less after the 7-day EE interval compared to that after 7-day HFI. Subjects on the 84/7 and 84/7EE regimens reported less (p=.03) daily menstrual flow than those on the 21/7-day regimen. A trend (p=.06) toward reduced headaches during the 7-day EE-supplemented interval was noted. CONCLUSIONS: Supplementation of the standard 7-day HFI with 10 mcg EE after 84 days of an extended OC decreased FSH levels and decreased the number of developing follicles.

Endometrial effects of a 91-day extended-regimen oral contraceptive with low-dose estrogen in place of placebo.

BACKGROUND: The study was conducted to evaluate the effects of a 91-day extended-regimen oral contraceptive (OC) containing levonorgestrel (LNG) with low-dose ethinyl estradiol (EE) in place of placebo on endometrial histology. STUDY DESIGN: Endometrial biopsies were obtained prior to initiation and posttreatment, between cycle Days 60 and 84 (during combination EE/LNG tablets), between cycle Days 85 and 91 (during low-dose EE tablets) or after completion of therapy. RESULTS: Paired endometrial biopsy samples obtained before and after treatment were available for 63 subjects. Biopsy results demonstrated that this OC regimen did not promote unexpected changes in the endometrium, either during the course of active treatment with EE/LNG or during the 7-day low-dose EE interval. Endometrial hyperplasia or malignancy was not observed in any endometrial biopsy sample. CONCLUSION: Use of a 91-day extended-regimen OC with low-dose EE in place of placebo was not associated with any untoward effects on the endometrium.

Effects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive.

BACKGROUND: The study was conducted to evaluate the effects of low-dose estrogen compared to placebo on ovarian activity during the traditional 7-day hormone-free interval (HFI) of an oral contraceptive (OC). STUDY DESIGN: Women were randomized to placebo or low-dose estrogen for 7 days during the HFI. Serum levels of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone and inhibin B were obtained before, during and after treatment. RESULTS: Mean hormone levels remained constant or only increased slightly for the low-dose estrogen group compared to greater more sustained increases observed for the placebo group. Estradiol, FSH and inhibin B levels were substantially higher for those on placebo. Differences were most noticeable by the end of the HFI and persisted into the subsequent cycle. CONCLUSION: Subjects receiving low-dose estrogen for 7 days during the HFI demonstrated more pronounced ovarian suppression compared to placebo as evidenced by attenuation of increases in serum inhibin B, FSH and estradiol levels.

Randomized, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healthy postmenopausal women.

OBJECTIVE: To evaluate the safety and efficacy of synthetic conjugated estrogens B (SCE-B; 0.3 mg/d) for 12 weeks in the treatment of vulvovaginal atrophy in symptomatic, postmenopausal women. DESIGN: Prospective, randomized, multicenter, double-blind, placebo-controlled trial. SETTING: Forty-two participating sites in the United States. PATIENT(S): Postmenopausal women with at least one moderate to severe symptom of vaginal atrophy. INTERVENTION(S): Daily oral administration, in a randomized, placebo-controlled setting, of SCE-B (0.3 mg) or of placebo for 12 weeks. MAIN OUTCOME MEASURE(S): Mean changes in vaginal maturation index, percentage of parabasal and superficial cells, vaginal pH, and severity of the most bothersome symptom (MBS) between baseline and predetermined time points were assessed. Safety and tolerability were evaluated. RESULT(S): A total of 310 women (mean age, 58.6 y) were enrolled. Synthetic conjugated estrogens B yielded statistically significantly greater differences in vaginal maturation index and vaginal pH from baseline to the end of treatment. Vaginal dryness (44.4%) and pain during intercourse (30.2%) were the symptoms most commonly identified as the MBS. A statistically significant mean reduction in the severity of the MBS was noted for SCE-B. There were no clinically significant differences observed between the two groups for findings related to safety. CONCLUSION(S): Synthetic conjugated estrogens B (0.3 mg/d) was effective in treating vulvovaginal atrophy in symptomatic postmenopausal women. Significant improvement was seen in vaginal maturation index, vaginal pH, and severity of MBS from baseline to the end of treatment.

Effects of synthetic conjugated estrogens A on sleep quality in postmenopausal women with nocturnal diaphoresis and/or hot flushes: a pilot study.

In a single-center, double-blind, placebo-controlled pilot study, patients who received 0.625 mg daily of synthetic conjugated estrogens A experienced a statistically significant reduction in the average number of hot flushes and galvanic skin responses. The polysomnographic change in sleep measures did not reach statistical significance, but the data suggest an overall improvement in sleep quality in the treatment group.