Neuropeptide Treatment for Hot Flushes During the Menopause

Study Overview
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Brief Summary
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Placebo-controlled, double-blinded, cross-over clinical trial of a new investigational product

Detailed Description
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Double-blinded, placebo-controlled, 2-way crossover study in 30 menopausal women with untreated hot flushes treated with a neurokinin 3 receptor (NK3R) antagonist Aims: To investigate whether an NK3R antagonist can reduce menopausal flushing Treatment: 4 weeks administration of active drug and placebo in random order

Official Title
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Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes

Conditions
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Menopausal Flushing

Intervention / Treatment
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* Drug: NK3R antagonist - AZD4901
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Menopausal women (≥12 months since last menstrual period or bilateral oophorectomy or with a follicle stimulating hormone (FSH) level ≥20 milli-international units/millilitre (mIU/mL) and an estradiol level <190pmol/l in the absence of a reliable menstrual marker (hysterectomy with ovarian preservation or endometrial ablation)) aged 40-62 years with >7 hot flushes/day some of which are reported as severe or bothersome who have not been on treatment for menopausal symptoms for the preceding 8 weeks. Exclusion Criteria: Significant illness, as judged by the Investigator, within 2 weeks of first study visit. Volunteer has clinical, laboratory, or electrocardiogram (ECG) evidence of uncontrolled hypertension (defined as systolic blood pressure of ≥ 160 mmHg and/or diastolic blood pressure of ≥100 mmHg); uncontrolled diabetes; or significant pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the Investigator. Participant has a history of Gilbert's syndrome, infectious hepatitis, or other significant hepatic disease (e.g. chronic hepatitis, cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, non-alcoholic steatohepatitis, or hereditary liver disease) in the opinion of the Investigator. Participant has a history of surgery which in the opinion of the investigator could cause malabsorption (e.g. gastric or small intestinal surgery or gastric bypass surgery or banding), or patient has a disease that causes malabsorption. Clinically significant abnormal ECG and/or abnormalities in ECG at screening as judged by the Investigator. A marked prolongation of QT/corrected QT (QTc) interval (e.g. repeated demonstration of a QTc interval > 450 ms). Confirmed history of ischaemic heart disease. Past (within 1 year of enrollment) or present alcohol or substance abuse Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within at least 3 months of the first administration of AZD4901 in this study. The period of exclusion begins 3 months after the final dose. (Note: patients consented and screened, but not randomised in a previous study are not excluded.) Participant has a history of neoplastic disease within 5 years prior to signing informed consent or is currently on ongoing treatment to prevent cancer recurrence. Involvement in the planning and/or conduct of the study (applies to any AstraZeneca employee and their close relatives and/or staff at the study site directly involved in the study, regardless of their role in accordance with their internal procedures) Inability to understand or cooperate with the requirements of the study Participant is legally or mentally incapacitated Participant has significant psychiatric disease or treatment for psychiatric disease e.g. selective serotonin re-uptake inhibitors (SSRIs) which in the opinion of the Investigator may influence the results of the study. Participant has abnormal screening laboratory values as per the guidelines listed below or other clinically significant, unexplained laboratory abnormality according to the Investigator: Aspartate aminotransferase (AST) >1.5 times upper limit of normal (ULN) Alanine aminotransferase (ALT) > 1.5 times ULN Total bilirubin >1.5 times ULN Serum creatinine >2.0 times ULN Clinically relevant disease and abnormalities (past or present), which in the opinion of the Investigator, may either put the patient at risk to participate in this study or may influence the results of the study or the patient's ability to participate in the study. Participant has a history of hyperthyroidism or hypothyroidism or abnormal screening thyroid tests, as judged by the Investigator. Patients with hypothyroidism who are stable on treatment with normal thyroid function tests may be included in the study if in the opinion of the Investigator this will not influence the results of the study. Participant has seizures, patients with history of seizures or with conditions that increase the risk of seizures. Participant has a history of hypersensitivity to more than 2 chemical classes of drugs, including prescription and over-the-counter medications. Participant has taken any potent or moderate CYP3A4 or CYP2C9 inhibitors, potent or moderate CYP3A4 or CYP2C9 inducers, hormonal contraceptives, antiandrogenic drugs, or other medications specified for the time frame

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 62 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active drug first<br>Baseline period - 2 weeks NK3R antagonist - AZD4901 - 40mg bd - 4 weeks Washout period - 2 weeks Matched placebo orally bd - 2 weeks Monitoring period - 2 weeks | Drug: NK3R antagonist - AZD4901<br>* Neurokinin 3 receptor antagonist<br>* Other names: nil others;|
| Placebo Comparator: Placebo<br>Baseline period - 2 weeks Matched placebo orally bd - 2 weeks Washout period - 2 weeks NK3R antagonist - AZD4901 - 40mg bd - 4 weeks Monitoring period - 2 weeks | Drug: Placebo<br>* Placebo<br>* Other names: nil others;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Hot Flushes During the Final Week of Each 4 Weeks Treatment Period | To ensure accurate records, participants recorded their flushes in real time using either a tally chart on a piece of paper (n=34) or an application on their smartphone such as Tally Counter (Pixel Research Labs, Minneapolis-Saint Paul, MN, USA; n=3), and then collated their total number of flushes twice daily on waking to record previous overnight symptoms and before bed to record daytime symptoms. | Final week of each 4 week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hot Flush Severity | Score on a scale - HF severity (rated as 1-nil, 2-mild, 3-moderate, 4-severe, as per Joffe 2014) recorded twice daily (day/night as described above for HF frequency). Scores are summed. | Twice daily, morning and night for 14 weeks | 
| Hot Flush Bother | Score on a scale - HF bother (rated as 1-none, 2-a little, 3-moderate, 4-a lot, as per Joffe 2014) will be recorded twice daily (day/night as described above for HF frequency). The data will be analysed as detailed above for the HF frequency. Scores are summed. | twice daily (day/night) for 14 weeks | 
| Hot Flush Interference | Score on a scale Menopause Specific Quality of Life (MENQOL) questionnaire 0=not bothered at all - 6=extremely bothered. 4 domains, mean calculated for set of questions in each domain. Overall score is a mean of the means. Highr scor = higher interference. | Daily at bedtime for 14 weeks | 
| Skin Conductance Monitor Data. | Mean number of flushes detected during the 48 hours by the skin conductance monitoring will be compared each week when the patients receive AZD4901 versus placebo | Once per week for 48 hours over 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopausal flushing