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

Time to Reach Maximum Concentration (Tmax) of ACER-801 Metabolite

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

Time to Reach Maximum Concentration (Tmax) of ACER-801 Metabolite

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

Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801

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

Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801

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

Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801 Metabolite

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

Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801 Metabolite

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

Half-life (T1/2) of ACER-801

Terminal elimination half-life of ACER-801

Time frame: Day 1

Half-life (T1/2) of ACER-801

Terminal elimination half-life of ACER-801

Time frame: Day 14

Half-life (T1/2) of ACER-801 Metabolite

Terminal elimination half-life of ACER-801 metabolite

Time frame: Day 1

Half-life (T1/2) of ACER-801 Metabolite

Terminal elimination half-life of ACER-801 metabolite

Time frame: Day 14

Number and Percentage of Adverse Events ≥ 5%

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

Number and Percentage of Serious Adverse Events (SAE)

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

Number and Percentage of Subjects Who Discontinued From the Study

Discontinuation or withdrawal from the study.

Time frame: Over 2 weeks

Number of Patients With a Clinically Significant Change From Baseline in Abnormalities Detected During Physical Examination

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

Accumulation Ratio for Cmax (ARcmax) of ACER-801

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

Accumulation Ratio for AUC (ARauc) of ACER-801

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

Accumulation Ratio for Cmax (ARcmax) of ACER-801 Metabolite

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

Accumulation Ratio for AUC (ARauc) of ACER-801 Metabolite

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

Metabolite: Parent Ratio of AUC (MRauc)

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

Metabolite: Parent Ratio of AUC (MRauc)

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

Metabolite:Parent Ratio of Cmax (MRcmax)

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

Metabolite:Parent Ratio of Cmax (MRcmax)

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

Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801

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

Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801

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

Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801 Metabolite

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

Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801 Metabolite

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

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: HEMATOLOGY

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

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: SERUM CHEMISTRY

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

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: COAGULATION

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

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: URINALYSIS

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

Time frame: 2 weeks

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: BONE DENSITY MARKERS

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

Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: HORMONES

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