Dose-ranging, PK, Safety, Efficacy Study of Osanetant in Patients With Moderate/Severe VMS Associated With Menopause

AUC (area under the curve) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC (area under the curve) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Cmax (maximum concentration) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Cmax (maximum concentration) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Area under the concentration time curve (AUC) from the time of dosing (0 hour) to the time of the last quantifiable (positive) concentration (Tlast) of ACER-801, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only AUClast (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Area under the concentration time curve (AUC) from the time of dosing (0 hour) to the time of the last quantifiable (positive) concentration (Tlast) of ACER-801, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only AUClast (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Area under the concentration time curve (AUC) from the time of dosing (0 hour) to the time of the last quantifiable (positive) concentration (Tlast) of ACER-801 metabolite, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only AUClast (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Area under the concentration time curve (AUC) from the time of dosing (0 hour) to the time of the last quantifiable (positive) concentration (Tlast) of ACER-801 metabolite, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only AUClast (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC from the time of dosing (0 hour) extrapolated to infinity, calculated as AUClast + Clast/λz, where Clast was the last quantifiable concentration, and λz was the terminal elimination rate constant Reliability of AUCinf values was contingent upon AUCext and λz Profiles with AUCext ≤20% and a λz which met reporting criteria were considered reliable and AUCinf was reported. For profiles that did not meet these criteria, AUCinf and any parameter requiring AUCinf for computation were not reported.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC from the time of dosing (0 hour) extrapolated to infinity, calculated as AUClast + Clast/λz, where Clast was the last quantifiable concentration, and λz was the terminal elimination rate constant Reliability of AUCinf values was contingent upon AUCext and λz Profiles with AUCext ≤20% and a λz which met reporting criteria were considered reliable and AUCinf was reported. For profiles that did not meet these criteria, AUCinf and any parameter requiring AUCinf for computation were not reported.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC from the time of dosing (0 hour) extrapolated to infinity, calculated as AUClast + Clast/λz, where Clast was the last quantifiable concentration, and λz was the terminal elimination rate constant Reliability of AUCinf values was contingent upon AUCext and λz Profiles with AUCext ≤20% and a λz which met reporting criteria were considered reliable and AUCinf was reported. For profiles that did not meet these criteria, AUCinf and any parameter requiring AUCinf for computation were not reported.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC from the time of dosing (0 hour) extrapolated to infinity, calculated as AUClast + Clast/λz, where Clast was the last quantifiable concentration, and λz was the terminal elimination rate constant Reliability of AUCinf values was contingent upon AUCext and λz Profiles with AUCext ≤20% and a λz which met reporting criteria were considered reliable and AUCinf was reported. For profiles that did not meet these criteria, AUCinf and any parameter requiring AUCinf for computation were not reported.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Terminal elimination half-life of ACER-801

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Terminal elimination half-life of ACER-801

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Terminal elimination half-life of ACER-801 metabolite

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Terminal elimination half-life of ACER-801 metabolite

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

MR = Metabolite:Parent Ratio calculated as Cm,day14/ Cp,day1 and AUCt,m,day14/ AUCt,p,day1, where m and p are the metabolite and parent drug, respectively, and t is the dosing interval (12 h). AUC = area under the curve

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

AUC (area under the curve) MR = Metabolite:Parent Ratio calculated as Cm,day14/ Cp,day1 and AUCt,m,day14/ AUCt,p,day1, where m and p are the metabolite and parent drug, respectively, and t is the dosing interval (12 h).

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

MR = Metabolite:Parent Ratio calculated as Cm,day14/ Cp,day1 and AUCt,m,day14/ AUCt,p,day1, where m and p are the metabolite and parent drug, respectively, and t is the dosing interval (12 h). ACER-801 (parent); Cmax (maximum concentration)

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

MR = Metabolite:Parent Ratio calculated as Cm,day14/ Cp,day1 and AUCt,m,day14/ AUCt,p,day1, where m and p are the metabolite and parent drug, respectively, and t is the dosing interval (12 h). ACER-801 (parent); Cmax (maximum concentration)

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

An Adverse Event (AE) is defined as any untoward medical occurrence associated with the use of the investigational product in humans, whether or not considered related to investigational product. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with any use of the investigational product, without any judgment about causality and irrespective of route of administration, formulation, or dose, including an overdose.

Time frame: 2 weeks

Population: Safety Population

An AE is considered serious if, in the view of either the investigator or Acer, it results in any of the following outcomes: Death, Is immediately life threatening; Requires in-patient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability or incapacity; Results in a congenital abnormality or birth defect; Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above.

Time frame: 2 weeks

Population: Safety population

Discontinuation or withdrawal from the study.

Time frame: Over 2 weeks

Population: Safety population

A physician or appropriately qualified delegate conducted a full physical examination at baseline and at Day 14. The investigator decides if findings are considered abnormal at baseline and at Day 14 and whether the change is clinically significant. Only clinically significant changes will be reported.

Time frame: At Day 14 relative to Baseline

Population: Safety Population

Blood samples not available/collected for testing. Blood samples will be measured for Bone Specific Alkaline Phosphatase (BSAP), osteocalcin, amino terminal propeptide of type 1 collagen (P1NP) and Collagen Type- C-Telopeptide (CTX). Only clinically significant changes will be reported.

Time frame: 2 weeks

Population: Safety population. Hormone testing was not conducted. Blood samples not available/collected for testing.

Blood samples will be measured for prothrombin time, partial thromboplastin time, international normalized ratio. Only clinically significant changes will be reported.

Time frame: 2 weeks

Population: Safety population; transient changes from normal to low or high values were reported but none were deemed clinically significant.

Blood samples will be measured for hemoglobin, hematocrit, white blood count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, red blood cell count (including mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration). Only clinically significant changes will be reported.

Time frame: Over 2 weeks

Population: Safety population; transient changes from normal to low or high values were reported but none were deemed clinically significant.

Blood samples not available/collected for testing. Blood samples will be measured for catecholamines, vasopressin, gonadotropins, estradiol, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), cortisol, thyroid-stimulating hormone (TSH), T3 (Total and Free), T4 (Total and Free), prolactin, sex hormone binding globulin (SHBG), and insulin. Only clinically significant changes will be reported.

Time frame: 2 weeks

Population: Safety population. Hormone testing was not conducted. Blood samples not available/collected for testing.

Blood samples will be measured for albumin, alkaline phosphatase, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, calcium, carbon dioxide, chloride, potassium, sodium, total cholesterol, creatinine, gamma glutamyl transferase, glucose, lactate dehydrogenase, phosphorus, total protein, uric acid. Only clinically significant changes will be reported.

Time frame: 2 weeks

Population: Safety population; transient changes from normal to low or high values were reported but none were deemed clinically significant.

Urine samples will be measured for pH, specific gravity, protein, glucose, ketones, bilirubin. Only clinically significant changes will be reported.

Time frame: 2 weeks

Population: Safety population; transient changes from normal to low or high values were reported but none were deemed clinically significant.

maximum concentration of ACER-801 measured at Day 14 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Cmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

maximum concentration of ACER-801 measured at Day 1 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Cmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

peak concentration of ACER-801 metabolite measured at Day 1 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Cmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

peak concentration of ACER-801 metabolite measured at Day 14 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Cmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

time to reach maximum concentration of ACER-801 at Day 14 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Tmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

time to reach maximum concentration of ACER-801 measured at Day 1 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Tmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Time to reach maximum concentration of ACER-801 metabolite at Day 14 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Tmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 14

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

time to reach maximum concentration of ACER-801 metabolite at Day 1 Blood sampling included predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hrs (prior to evening dose) and 15 hrs post morning dose. Only Tmax (mean, SD) data are available due to abbreviated data analyses.

Time frame: Day 1

Population: All subjects in the safety population who have sufficient plasma concentration above the limit of quantitation. PK is not tested in placebo arm.

Frequency is the number of vasomotor symptoms (hot flashes) recorded by the subject in the continuous diary. Week 1

Time frame: At Week 1 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included. A negative change indicates a reduction.

Frequency is the number of vasomotor symptoms (hot flashes) recorded by the subject in the continuous diary. Week 2

Time frame: At Week 2 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included. A negative change indicates a reduction.

The hot flash severity score is a composite of the frequency and severity of hot flashes, and was calculated as follows: \[number of mild hot flashes on Day Y x 1\] + \[number of moderate hot flashes on Day Y x 2\] + \[number of severe hot flashes on Day Y x 3\]. The value at Week 2 was subtracted from the value at Baseline to yield the impact on hot flash severity score. A negative change indicates a reduction in severity.

Time frame: At Week 2 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included.

The hot flash severity score is a composite of the frequency and severity of hot flashes, and was calculated as follows: \[number of mild hot flashes on Day Y x 1\] + \[number of moderate hot flashes on Day Y x 2\] + \[number of severe hot flashes on Day Y x 3\]. The value at Week 1 was subtracted from the value at Baseline to yield the impact on the composite hot flash severity score. A negative change indicates a reduction.

Time frame: At Week 1 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included.

Patients recorded in a continuous diary the number of individual hot flashes experienced and rated the severity of each on a scale of mild, moderate, or severe where mild is assigned a value of 1, moderate a value of 2, and severe a value of 3 during data analysis. Daily severity was calculated as \[(1 × number of mild hot flashes) + (2 × number of moderate hot flashes) + (3 × number of severe hot flashes)\]/total number of hot flashes reported. The value at Week 2 was subtracted from the value at Baseline to yield the impact on severity score. A negative change indicates a reduction.

Time frame: At Week 2 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included.

Patients recorded in a continuous diary the number of individual hot flashes experienced and rated the severity of each on a scale of mild, moderate, or severe where mild is assigned a value of 1, moderate a value of 2, and severe a value of 3 during data analysis. Daily severity was calculated as \[(1 × number of mild hot flashes) + (2 × number of moderate hot flashes) + (3 × number of severe hot flashes)\]/total number of hot flashes reported. The value at Week 1 was subtracted from the value at Baseline to yield the impact on severity score. A negative change indicates a reduction in severity.

Time frame: At Week 1 relative to Baseline

Population: Modified intent to treat population included all subjects in the safety population who had at least1 baseline and postbaseline result for an vasomotor symptom parameter. All patients were included.