Common use of Study Design Clause in Contracts

Study Design. The Phase 2 study will be a randomized, double-blind, multicenter, placebo-controlled trial covering 1 [*] of observation, followed by randomization of qualified subjects to [*] months of treatment and a 1 [*] safety follow-up period. Patients will be postmenopausal women defined as having [*] months of spontaneous amenorrhea, or [*] months of spontaneous amenorrhea with serum FSH levels of > 40 IU/L, or as women who are [*]-weeks post-surgical oophorectomy. Moderate hot flashes are defined as a sensation of heat with flushing but as not being incapacitating, while severe hot flashes are defined as the same but with the element of incapacitation in that the subject must stop current activity. To ensure adequate evidence of therapeutic effect is available, study participants will be required to have frequent hot flashes defined as [*] hot flashes per [*] or [*] to [*] hot flashes per [*]. During the period of observation, patient will document hot flash frequency and severity to prospectively ensure qualification on that criterion. Efficacy will be assessed as the reduction in frequency and severity of hot flashes compared to placebo. The estimated subject number and dose groups are outlined below: Observation ER-306323, Phase 2 Dose-finding Study All subjects Group 1 Group 2 Group 3 Group 4 Dose (mg) Dose 1 Dose 2 Dose 3 Placebo N (active) [*] [*] [*] N (placebo) [*] It is estimated that the Phase 2 study will require about [*] evaluable subjects to achieve its stated goals. The Phase 2 study will provide evidence of dose-dependent efficacy for ER-306323 and will also provide adequate statistical power to select the optimal dose for Phase 3. The criteria for dose selection will be based on an integration of the major efficacy and safety variables of the study. In addition, the Phase 2 data will also provide statistical evidence of effect of ER-306323 on markers of bone resorption and accretion while providing preliminary evidence of effect of ER-306323 on bone density. Like the Phase lb study, the Phase 2 study will continue to provide additional pharmacodynaraics effects of ER-306323 such as estrogenic effects on serum gonadotropins and serum lipids. Markers of bone effect will again be collected such as serum osteocalcin, bone procoilagen 1 carboxy-terminal propeptide (PICP), N-propeptide of Type-1 collagen (PIMP) and bone-specific alkaline phosphatase. Additional safety information on cardiac (QT) safety and endometrial safety of ER-306323 will be evaluated in more detail through endometrial biopsy in a subset of patients in each treatment group. Finally, estrogenic effect. of ER-306323 on coagulation factors will also be assessed.

Study Design. The Phase 2 3 study will be a randomized, double-blind, multicenter, placebo-controlled trial covering 1 [*] of observation, followed by randomization of qualified subjects to [*] months of treatment and a 1 [*] safety follow-up period. Two doses of ER 206323 will be studied. Patients will be postmenopausal women defined as being 45 years old or greater and having [*] months of spontaneous amenorrhea, or [*] months of spontaneous amenorrhea with serum FSH levels of > 40 [*] IU/L, or as women who are [*]-weeks post-surgical oophorectomy. Moderate As for the Phase 2 study, hot flashes are defined as a sensation of heat with flushing but as not being incapacitating, while severe hot flashes are defined as the same but with the element of incapacitation in that the subject must stop current activity. To ensure adequate evidence of therapeutic effect is available, study participants flash frequency and severity will be required established during a pretreatment period of observation and qualifying patients will be then eligible to have frequent hot flashes defined as enroll in the study. As before, the criterion for entry will be a frequency of [*] ]hot flashes per [*] day or [*] to [*] hot flashes per [*]. During the period of observation, patient will document hot flash frequency and severity to prospectively ensure qualification on that criterion. Efficacy will be assessed as the reduction in frequency and severity of hot flashes compared to placebo. The estimated subject number and dose groups are outlined below: * Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission. Observation ER-306323, Phase 2 Dose-finding 3 Confirmatory Efficacy and Endometrial Safety Study All subjects Group 1 Group 2 Group 3 Group 4 Dose (mgrag) Dose 1 Dose 2 Dose 3 Placebo [*] [*] [*] N (active) [*] [*] [*] N (placebo) [*] It is estimated that the Phase 2 3 study will require about [*] evaluable subjects to achieve its stated goalsprovide adequate evidence of clinical safety for ER-306323. Since [*]doses of ER-306323 will be administered in this trial, there will be at least [*] patients available to provide endometrial safety data on this product. While powered beyond this need, the Phase 3 study will provide confirmatory evidence of efficacy for ER-306323. The [*] doses to be employed in the Phase 3 trial will include the [*] as identified in the Phase 2 study will as well as [*] provide evidence of dose-dependent efficacy for ER-306323 and will also provide adequate statistical power to select the optimal dose for Phase 3[*]. The criteria for dose selection Efficacy will be based on an integration difference in efficacy [*]. Endometrial safety will be based on self-reported vaginal bleeding, endometrial ultrasound and endometrial biopsy data. Endometrial biopsy data will be assessed according to objective common criteria by a panel of the major [*]pathologists in [*] independent medical institutions. The Phase 3 study will provide additional long-term safety information on serum lipids and on coagulation markers such as [*]. Influence of ethnicity on efficacy and safety variables of the study. In addition, the Phase 2 data will be assessed and drug-drug interaction effects will also provide statistical evidence be evaluated where appropriate. BMD will also be assessed at start and end of treatment and treatment effect of ER-306323 on markers of bone resorption and accretion while providing preliminary evidence of effect of ER-306323 on bone density. Like the Phase lb study, the Phase 2 study will continue be compared to provide additional pharmacodynaraics effects of ER-306323 such as estrogenic effects on serum gonadotropins and serum lipids[*]. Markers of bone effect will again be collected such as serum osteocalcin, bone procoilagen 1 carboxy-terminal propeptide (PICP), N-propeptide of Type-1 collagen (PIMP) and bone-specific alkaline phosphatase. Additional safety information on cardiac (QT) safety and endometrial safety of ER-306323 will be evaluated in more detail through endometrial biopsy in a subset of patients in each treatment group. Finally, estrogenic effect. of ER-306323 on coagulation factors metabolism will also be assessed. Finally, overall clinical and laboratory safety will be assessed throughout the study.