Clinical trial NCT02668185: Neuropeptide Treatment for Hot Flushes During the Menopause
Official title: Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Menopausal Flushing
Keywords: Menopausal flushing
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: AstraZeneca
name: National Institute for Health Research, United Kingdom
First posted: 2016-01-29
Enrollment: 37
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Total Number of Hot Flushes During the Final Week of Each 4 Weeks Treatment Period
timeFrame: Final week of each 4 week treatment period
Secondary outcomes:
measure: Hot Flush Severity
timeFrame: Twice daily, morning and night for 14 weeks
measure: Hot Flush Bother
timeFrame: twice daily (day/night) for 14 weeks
measure: Hot Flush Interference
timeFrame: Daily at bedtime for 14 weeks
measure: Skin Conductance Monitor Data.
timeFrame: Once per week for 48 hours over 14 weeks
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: NIHR/Wellcome Trust Imperial CRF
Study officials:
affiliation: Imperial College and NHS Trust
name: Waljit S Dhillo, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prague JK, Abbara A, Comninos AN, Jayasena CN, Higham CE, Adaway J, Keevil BG, Veldhuis JD, Dhillo WS. Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women. J Endocr Soc. 2019 Nov 14;4(2):bvz009. doi: 10.1210/jendso/bvz009. eCollection 2020 Feb 1.
citation: Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Mohideen P, Lin VH, Stern TP, Panay N, Hunter MS, Webber LC, Dhillo WS. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018 Aug;25(8):862-869. doi: 10.1097/GME.0000000000001090.
citation: Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Nash Z, Doyle C, Papadopoulou DA, Bloom SR, Mohideen P, Panay N, Hunter MS, Veldhuis JD, Webber LC, Huson L, Dhillo WS. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017 May 6;389(10081):1809-1820. doi: 10.1016/S0140-6736(17)30823-1. Epub 2017 Apr 3.