Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia.

Two randomized, double-blind, 26-week core studies (Eastern [EH] and Western Hemisphere [WH]) tested the hypothesis that asenapine is superior to olanzapine for persistent negative symptoms of schizophrenia; 26-week extension studies assessed the comparative long-term efficacy and safety of these agents. In the core studies, 949 people were randomized to asenapine (n = 241 and 244) or olanzapine (n = 240 and 224); 26-week completion rates with asenapine were 64.7% and 49.6% (olanzapine, 80.4% and 63.8%) in the EH and WH, respectively. In the EH and WH extensions, respectively (asenapine, n = 134 and 86; olanzapine, n = 172 and 110), 52-week completion rates were 84.3% and 66.3% with asenapine (olanzapine, 89.0% and 80.9%). Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in either core study, but asenapine was superior to olanzapine at week 52 in the WH extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS positive subscale score at various assessment times in both core studies and the WH extension study. Incidence of treatment-emergent adverse events was comparable between treatments across studies. Weight gain was consistently lower with asenapine. Extrapyramidal symptom-related adverse event incidence was higher with asenapine (EH: 8.3%; 95% confidence interval [CI], 5.1%-12.5%; WH: 16.4%; 95% CI, 11.9%-21.6%) than olanzapine (EH: 3.3%; 95% CI, 1.4%-6.4%; WH: 12.1%; 95% CI, 8.1%-17.0%), but Extrapyramidal Symptom Rating Scale-Abbreviated total score changes did not significantly differ between treatments. In conclusion, asenapine superiority over olanzapine was not observed in the core studies. Both treatments improved persistent negative symptoms, but discontinuation rates were higher with asenapine.

Endometrial effects of tibolone.

BACKGROUND AND OBJECTIVES: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d). METHODS: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA. RESULTS: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%). CONCLUSION: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.

Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women.

OBJECTIVE: To address the endometrial safety of tibolone. DESIGN: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). SETTING: Multi-country, multi-center ambulatory care setting. PATIENT(S): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women. INTERVENTION(S): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA. MAIN OUTCOME MEASURE(S): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA. RESULT(S): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized. CONCLUSION(S): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.