Menopausal Flushing
Conditions
Keywords
Menopausal flushing
Brief summary
Placebo-controlled, double-blinded, cross-over clinical trial of a new investigational product
Detailed description
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
Interventions
DRUGNK3R antagonist - AZD4901
Neurokinin 3 receptor antagonist
DRUGPlacebo
Placebo
Sponsors
Medical Research Council
AstraZeneca
National Institute for Health Research, United Kingdom
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 62 Years
Healthy volunteers
Yes
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
1. Significant illness, as judged by the Investigator, within 2 weeks of first study visit. 2. 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. 3. 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. 4. 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. 5. Clinically significant abnormal ECG and/or abnormalities in ECG at screening as judged by the Investigator. 6. A marked prolongation of QT/corrected QT (QTc) interval (e.g. repeated demonstration of a QTc interval \> 450 ms). 7. Confirmed history of ischaemic heart disease. 8. Past (within 1 year of enrollment) or present alcohol or substance abuse 9. 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.) 10. 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. 11. 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) 12. Inability to understand or cooperate with the requirements of the study 13. Participant is legally or mentally incapacitated 14. 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. 15. 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 16. 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. 17. 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. 18. Participant has seizures, patients with history of seizures or with conditions that increase the risk of seizures. 19. Participant has a history of hypersensitivity to more than 2 chemical classes of drugs, including prescription and over-the-counter medications. 20. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Hot Flushes During the Final Week of Each 4 Weeks Treatment Period | Final week of each 4 week 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hot Flush Bother | twice daily (day/night) for 14 weeks | 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. |
| Hot Flush Severity | Twice daily, morning and night for 14 weeks | 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. |
| Hot Flush Interference | Daily at bedtime for 14 weeks | 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. |
| Skin Conductance Monitor Data. | Once per week for 48 hours over 14 weeks | 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 |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Participants Crossover study - all participants | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (4 Weeks) | Physician Decision | 2 | 0 |
| Second Intervention (4 Weeks) | Physician Decision | 1 | 3 |
| Washout Period (2 Weeks) | Adverse Event | 1 | 0 |
| Washout Period (2 Weeks) | Physician Decision | 0 | 2 |
Baseline characteristics
| Characteristic | Overall Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| Race/Ethnicity, Customized Asian, Pakistani | 1 Participants |
| Race/Ethnicity, Customized Black Carribean | 5 Participants |
| Race/Ethnicity, Customized Mixed white and black carribean | 1 Participants |
| Race/Ethnicity, Customized White British | 17 Participants |
| Race/Ethnicity, Customized White European | 2 Participants |
| Race/Ethnicity, Customized White Other | 1 Participants |
| Race/Ethnicity, Customized White Unspecified | 1 Participants |
| Region of Enrollment United Kingdom | 37 participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 3 / 28 | 0 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
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.
Time frame: Final week of each 4 week treatment period
Population: Whole group intention to treat analysis irrespective of treatment assignment order, adjusted means from crossover analysis with 95% CIs: percentage change in total no. hot flush frequency during final week of 4 week treatment period with MLE4901 and placebo vs with total no. hot flush frequency during the final week of the 2 week baseline period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Drug | Total Number of Hot Flushes During the Final Week of Each 4 Weeks Treatment Period | 19.35 hot flushes |
| Placebo | Total Number of Hot Flushes During the Final Week of Each 4 Weeks Treatment Period | 49.01 hot flushes |
p-value: <0.000195% CI: [17.39, 42.87]generalised linear mixed model with a Po
Secondary
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.
Time frame: twice daily (day/night) for 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Active Drug | Hot Flush Bother | 2.92 score on a scale |
| Placebo | Hot Flush Bother | 5.56 score on a scale |
p-value: <0.05Mixed Models Analysis
Secondary
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.
Time frame: Daily at bedtime for 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Active Drug | Hot Flush Interference | 7.94 Score by participant on 'interference sc |
| Placebo | Hot Flush Interference | 26.48 Score by participant on 'interference sc |
p-value: <0.05Mixed Models Analysis
Secondary
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.
Time frame: Twice daily, morning and night for 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Active Drug | Hot Flush Severity | 3.27 numerical rating of severity by particip |
| Placebo | Hot Flush Severity | 5.70 numerical rating of severity by particip |
p-value: <0.05Mixed Models Analysis
Secondary
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
Time frame: Once per week for 48 hours over 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Active Drug | Skin Conductance Monitor Data. | 16.22 Number of hot flushes detected by monito |
| Placebo | Skin Conductance Monitor Data. | 26.91 Number of hot flushes detected by monito |
p-value: <0.05Mixed Models Analysis