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

Study Overview
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Brief Summary
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In this clinical research study, subjects will be given the study drug, ACER-801 (osanetant) or placebo (looks like the study drug but contains no active ingredients). The study drug works on a receptor in the brain and the intended purpose is for the study treatment of moderate to severe Vasomotor Symptoms (VMS) also referred to as hot flashes or flushes associated with menopause. Hot flashes are a change in your temperature that occurs due to changes in your hormones.

Detailed Description
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This is a Phase 2a, randomized, double-blind, placebo-controlled, dose-ranging study in post menopausal women in which the pharmacokinetics, safety and efficacy of ACER-801 (osanetant 50 mg twice daily [BID], 100 mg BID, and 200 mg BID) will be compared to placebo. Subjects will enter a Screening Period to determine eligibility. Subjects will be required to complete hot flash diaries for 2 weeks prior to randomization. Eligible subjects will be admitted to a Clinical Research Unit and remain in the clinic for 14 days after completion of treatment and all study assessments. The study includes a 14 day safety follow-up assessment. Subjects will be randomized in a 1:1:1:1 ratio.

Official Title
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A Phase 2A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of ACER-801 for Treatment of Moderate to Severe Vasomotor Symptoms (VMS) Associated With Menopause

Conditions
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Post-menopausal Vasomotor Symptoms

Intervention / Treatment
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* Drug: ACER-801 50 mg BID
* Drug: ACER-801 100 mg BID
* Drug: ACER-801 200 mg BID
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Post-menopausal female subjects 40-65 years of age, inclusive. Menopause will be defined as: At least 12 months of spontaneous, continuous amenorrhea, or At least 6 months of spontaneous, continuous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL at screening, or At least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. At baseline women: With an average number of moderate to severe hot flashes/day for 2 weeks prior to randomization (per continuous hot flash diary). That have a change of < 50% in average 24-hour hot flash frequency 2 weeks prior to randomization. Moderate: defined as sensation of heat with sweating, able to continue activity. Severe: defined as sensation of heat with sweating, causing cessation of activity. Key Exclusion Criteria: Any active comorbid disease deemed by the investigator to be clinically significant, which could impact safety during study conduct including renal or hepatic impairment. Use of any prohibited medications. Body mass index (BMI) >35 kg/m2. Any active ongoing condition that could cause difficulty in interpreting vasomotor symptoms. Inability to complete questionnaires and continuous hot flash diary for any reason. Subjects who, in the opinion of the investigator, should not participate in the study for any other reason.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized in a 1:1:1:1 ratio to ACER-801 per one of the following dosing schedules prior to dosing: 50 mg BID, 100 mg BID, 200 mg BID, or Placebo BID Each arm is administered orally for 14 consecutive days (28 doses).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACER-801 50 mg BID<br>ACER-801 (osanetant) 50 mg BID (1 x 50 mg and 3 x placebo, twice daily) | Drug: ACER-801 50 mg BID<br>* 50 mg BID (twice daily)<br>* Other names: osanetant;|
| Experimental: ACER-801 100 mg BID<br>ACER-801 (osanetant) 100 mg BID (2 x 50 mg and 2 x placebo, twice daily) | Drug: ACER-801 100 mg BID<br>* 100 mg BID (twice daily)<br>* Other names: osanetant;|
| Experimental: ACER-801 200 mg BID<br>ACER-801 (osanetant) 200 mg BID (3 x 50 mg and 1 x placebo, twice daily) | Drug: ACER-801 200 mg BID<br>* 200 mg BID (twice daily)<br>* Other names: osanetant;|
| Placebo Comparator: Placebo<br>Placebo (4 x Placebo of ACER-801 twice daily) | Drug: Placebo<br>* Placebo<br>* Other names: Placebo of ACER-801;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) of ACER-801 | maximum concentration of ACER-801 | Day 1, Day 14 | 
| Time to reach maximum concentration (tmax) of ACER-801 |  | Day 1, Day 14 | 
| Area under the concentration curve from dosing to the time of the last measured concentration (AUClast) of ACER-801 |  | Day 1, Day 14 | 
| Area under the concentration curve from t0 to infinite time (AUCinf) of ACER-801 |  | Day 1, Day 14 | 
| Metabolite:parent ratio of Cmax (MRCmax) of ACER-801 | ACER-801 (parent); Cmax (maximum concentration) | Day 1, Day 14 | 
| Metabolite:parent ratio of AUC (MRauc) of ACER-801 | ACER-801 (parent); AUC (area under the curve) | Day 1, Day 14 | 
| Half-life (t1/2) of ACER-801 |  | Day 1, Day 14 | 
| Accumulation ratio for Cmax (ARcmax) of ACER-801 | Cmax (maximum concentration) | Day 14 | 
| Accumulation ratio for AUC (ARcauc) of ACER-801 | AUC (area under the curve) | Day 14 | 
| Peak Plasma Concentration (Cmax) of ACER-801 metabolite |  | Day 1, Day 14 | 
| Time to reach maximum concentration (tmax) of ACER-801 metabolite |  | Day 1, Day 14 | 
| Area under the concentration curve from dosing to the time of the last measured concentration (AUClast) of ACER-801 metabolite |  | Day 1, Day 14 | 
| Area under the concentration curve from t0 to infinite time (AUCinf) of ACER-801 metabolite |  | Day 1, Day 14 | 
| Metabolite:parent ratio of Cmax (MRcmax) of ACER-801 metabolite | ACER-801 (parent); Cmax (maximum concentration) | Day 1, Day 14 | 
| Accumulation ratio for AUC (MRauc) of ACER-801 metabolite | AUC (area under the curve) | Day 1, Day 14 | 
| Half-life (t1/2) of ACER-801 metabolite |  | Day 1, Day 14 | 
| Accumulation ratio for Cmax (ARcmax) of ACER-801 metabolite | Cmax (maximum concentration) | Day 14 | 
| Accumulation ratio for AUC (ARcauc) of ACER-801 metabolite | AUC (area under the curve) | Day 14 | 
| 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. | At Day 14 relative to Baseline | 
| 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. | Over 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. | Over 2 weeks | 
| Number and percentage of subjects who discontinued from the study | Discontinuation or withdrawal from the study. | Over 2 weeks | 
| 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. | Over 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. | 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. | Over 2 weeks | 
| Number of subjects with a clinically significant change from baseline for clinical laboratory evaluations: HORMONES | 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. | Over 2 weeks | 
| Number of subjects with a clinically significant change from baseline for clinical laboratory evaluations: BONE DENSITY MARKERS | 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. | Over 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. | Over 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in frequency of vasomotor symptoms (hot flashes) from baseline | Frequency is the number of vasomotor symptoms (hot flashes) recorded by the subject in the continuous diary. | At Week 1 and Week 2 relative to Baseline | 
| Change in severity of vasomotor symptoms (hot flashes) from baseline | 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. | At Week 1 and Week 2 relative to Baseline | 
| Change in severity score vasomotor symptoms (hot flashes) from baseline | 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]. Higher scores mean greater severity of hot flashes. | At Week 1 and Week 2 relative to Baseline |