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

Phase 1

Completed

• Conditions: Post-menopausal Vasomotor Symptoms
• Interventions: Drug: ACER-801 50 mg BID; Drug: ACER-801 100 mg BID; Drug: ACER-801 200 mg BID; Drug: Placebo

• Registration Number: NCT05325775
• Lead Sponsor: Acer Therapeutics Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-03-27
• Study Start: 2022-03-30
• Study First Submitted QC: 2022-04-06
• Study First Posted: 2022-04-13
• Primary Completion: 2023-03-04
• Study Completion: 2023-03-04
• Results First Submitted: 2024-03-03
• Status Verified: 2024-06
• Results First Submitted QC: 2024-07-15
• Last Update Submitted: 2024-07-15
• Results First Posted: 2024-08-07
• Last Update Posted: 2024-08-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 49

Inclusion Criteria

1. Post-menopausal female subjects 40-65 years of age, inclusive.

   Menopause will be defined as:

   1. At least 12 months of spontaneous, continuous amenorrhea, or
   2. At least 6 months of spontaneous, continuous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL at screening, or
   3. At least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

2. At baseline women:

   1. With an average number of moderate to severe hot flashes/day for 2 weeks prior to randomization (per continuous hot flash diary).

   2. 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

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Exclusion Criteria

1. Any active comorbid disease deemed by the investigator to be clinically significant, which could impact safety during study conduct including renal or hepatic impairment.
2. Use of any prohibited medications.
3. Body mass index (BMI) >35 kg/m2.
4. Any active ongoing condition that could cause difficulty in interpreting vasomotor symptoms.
5. Inability to complete questionnaires and continuous hot flash diary for any reason.
6. Subjects who, in the opinion of the investigator, should not participate in the study for any other reason.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ACER-801 50 mg BID	ACER-801 50 mg BID	ACER-801 (osanetant) 50 mg BID (1 x 50 mg and 3 x placebo, twice daily)
ACER-801 100 mg BID	ACER-801 100 mg BID	ACER-801 (osanetant) 100 mg BID (2 x 50 mg and 2 x placebo, twice daily)
ACER-801 200 mg BID	ACER-801 200 mg BID	ACER-801 (osanetant) 200 mg BID (4 x 50 mg and 0 x placebo, twice daily)
Placebo	Placebo	Placebo (4 x Placebo of ACER-801 twice daily)

Primary Outcome Measures

Name	Time	Method
Peak Plasma Concentration (Cmax) of ACER-801	Day 14	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.
Peak Plasma Concentration (Cmax) of ACER-801 Metabolite	Day 14	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 to Reach Maximum Concentration (Tmax) of ACER-801	Day 14	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 to Reach Maximum Concentration (Tmax) of ACER-801 Metabolite	Day 14	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.
Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801	Day 14	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.
Area Under the Concentration Curve From Dosing to the Time of the Last Measured Concentration (AUClast) of ACER-801 Metabolite	Day 14	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.
Half-life (T1/2) of ACER-801	Day 14	Terminal elimination half-life of ACER-801
Half-life (T1/2) of ACER-801 Metabolite	Day 14	Terminal elimination half-life of ACER-801 metabolite
Number and Percentage of Adverse Events ≥ 5%	2 weeks	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.
Number and Percentage of Serious Adverse Events (SAE)	2 weeks	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.
Number and Percentage of Subjects Who Discontinued From the Study	Over 2 weeks	Discontinuation or withdrawal from the study.
Number of Patients With a Clinically Significant Change From Baseline in Abnormalities Detected During Physical Examination	At Day 14 relative to Baseline	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.
Accumulation Ratio for Cmax (ARcmax) of ACER-801	Day 14	Cmax (maximum concentration) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.
Accumulation Ratio for AUC (ARauc) of ACER-801	Day 14	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.
Accumulation Ratio for Cmax (ARcmax) of ACER-801 Metabolite	Day 14	Cmax (maximum concentration) Accumulation Ratio calculated as Cmax,Day14/ Cmax,Day1 and AUCt,Day14/ AUCt,Day1, where the dosing interval t is 12h.
Accumulation Ratio for AUC (ARauc) of ACER-801 Metabolite	Day 14	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.
Metabolite: Parent Ratio of AUC (MRauc)	Day 14	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).
Metabolite:Parent Ratio of Cmax (MRcmax)	Day 14	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)
Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801	Day 14	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.
Area Under the Concentration Curve From t0 to Infinite Time (AUCinf) of ACER-801 Metabolite	Day 14	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.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: HEMATOLOGY	Over 2 weeks	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.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: SERUM CHEMISTRY	2 weeks	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.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: COAGULATION	2 weeks	Blood samples will be measured for prothrombin time, partial thromboplastin time, international normalized ratio. Only clinically significant changes will be reported.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: URINALYSIS	2 weeks	Urine samples will be measured for pH, specific gravity, protein, glucose, ketones, bilirubin. Only clinically significant changes will be reported.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: BONE DENSITY MARKERS	2 weeks	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.
Number of Subjects With a Clinically Significant Change From Baseline for Clinical Laboratory Evaluations: HORMONES	2 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Change in Frequency of Vasomotor Symptoms (Hot Flashes) From Baseline	At Week 1 relative to Baseline	Frequency is the number of vasomotor symptoms (hot flashes) recorded by the subject in the continuous diary.; Week 1
Change in Frequency Vasomotor Symptoms (Hot Flashes) From Baseline	At Week 2 relative to Baseline	Frequency is the number of vasomotor symptoms (hot flashes) recorded by the subject in the continuous diary.; Week 2
Change in Severity of Vasomotor Symptoms (Hot Flashes) From Baseline	At Week 2 relative to 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.; 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.
Change in Hot Flash Severity Score Vasomotor Symptoms From Baseline	At Week 1 relative to Baseline	The hot flash severity score is a composite of the frequency and severity of hot flashes, and was calculated as follows: \[number of mild hot flashes on Day Y x 1\] + \[number of moderate hot flashes on Day Y x 2\] + \[number of severe hot flashes on Day Y x 3\].; 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.
Change in Hot Flash Severity Score of Vasomotor Symptoms From Baseline	At Week 2 relative to Baseline	The hot flash severity score is a composite of the frequency and severity of hot flashes, and was calculated as follows: \[number of mild hot flashes on Day Y x 1\] + \[number of moderate hot flashes on Day Y x 2\] + \[number of severe hot flashes on Day Y x 3\].; 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.

Trial Locations

Locations (1)

Spaulding Clinical Research; 🇺🇸 West Bend, Wisconsin, United States