| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of moderate to severe vasomotor symptoms (hot flushes) associated with menopause |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020408 |
| E.1.2 | Term | Hot flushes |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
· To assess the efficacy of PD 0299685 in the treatment of moderate to severe vasomotor symptoms associated with the menopause;
· To characterise the dose range and dose response relationships of PD 0299685 in the treatment of moderate to severe vasomotor symptoms associated with the menopause
· To assess the safety and tolerability of PD 0299685.
|
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Female patients must meet the following criteria to be eligible to participate in the study:
• Good health as determined by medical history, physical examination, vital signs;
• Age: ≥40 years and ≤70 years old;
• Postmenopausal women defined as:
• At least 6 months of spontaneous amenorrhea, and serum follicle-stimulating hormone (FSH) >40 mIU/mL and estradiol concentrations ≤25 pg/mL;
• Surgical bilateral oophorectomy, with or without hysterectomy, at least 6 weeks ago, and serum follicle-stimulating hormone (FSH) >40 mIU/mL and estradiol concentrations ≤25 pg/mL.
• Must have an average of at least 50 moderate to severe vasomotor symptoms per week during the screening period;
• Vasomotor symptoms are defined as the combined daytime hot flashes and night sweats in a 24-hr period;
• Number of vasomotor symptoms must be collected for 14 days, including at least 7 consecutive days. Seven consecutive days during the screening period will be used to compute the mean count of weekly vasomotor symptoms for the eligibility criteria and baseline assessment;
• Vasomotor symptom data must be collected following the appropriate wash out periods for medications listed in the exclusion criteria.
• Non clinically significant ECG abnormalities at screening, including QTc interval ≤450 msec;
• Mammogram performed at screening within this protocol, or within last 9 months, that shows no evidence of cancer, or suspicion of cancer, warranting further investigation. Documentation of the mammogram report is required prior to randomization.
• Papanicolaou (Pap) smear (cervical cytology) test performed at screening within this protocol, or within last 9 months that shows no evidence of malignant or pre-malignant abnormalities. Documentation of Pap smear is required prior to randomization.
• An evaluable screening endometrial biopsy containing sufficient tissue for diagnosis in all patients that have a uterus.
• Patients with insufficient tissue obtained by biopsy may be included in the study only when accompanied by a transvaginal ultrasound (TVU) within the past 3 months that demonstrates endometrial thickness <5 mm. Documentation of TVU is required prior to randomization.
• Willing and able to provide written informed consent to participate;
• Patients who are willing and able to comply with scheduled visits, trial related activities, procedures and lifestyle guidelines. |
|
| E.4 | Principal exclusion criteria |
Patients will not be allowed to participate in the study if any of the following conditions exist:
• Receiving estrogen monotherapy or estrogen/progesterone containing drug products. The following periods should be followed before baseline assessments and procedures are performed for patients previously on estrogen alone or estrogen/progesterone containing products:
• 1 week or longer for prior vaginal hormonal products (rings, creams, gels);
• 4 weeks or longer for prior transdermal estrogen alone or estrogen/ progesterone products;
• 8 weeks or longer for prior oral estrogen, progesterone, and/or androgen therapy;
• 8 weeks or longer for prior intrauterine progesterone therapy;
• 3 months or longer for prior progesterone implants and estrogen alone injectable drug therapy;
• 6 months or longer for prior estrogen pellet therapy or progesterone injectable drug therapy.
• Use of tamoxifen, raloxifene, or clonidine less than 4 weeks before collection of screening/baseline Hot Flash diary data and during the conduct of the study;
• Use of gabapentin or pregabalin less than 4 weeks before collection of screening/baseline Hot Flash diary data and during the conduct of the study;
• Use of soy, black cohosh, phytoestrogens, vitamin E (regular multivitamins containing vitamin E are allowed), evening primrose oil, or any non-prescription/over-the-counter (OTC) treatment for hot flashes for less than 4 weeks before collection of screening/baseline Hot Flash diary data and during the conduct of the study;
• Use of any drugs having pharmacology of serotonin reuptake inhibition (SRI), or combined serotonin/ noradrenalin receptor reuptake inhibition (SNRI) less than 4 weeks before collection of screening/baseline Hot Flash diary data and during the conduct of the study;
• Use of any central nervous system (CNS)-active medication, including prescription and non-prescription/ over-the-counter (OTC) treatment for insomnia, less than 1 week before the collection of screening/baseline Hot Flash diary data and during the conduct of the study;
• History of allergic reaction or significant adverse reaction to gabapentin or pregabalin;
• Creatinine clearance (CLcr) ≤60 mL/min (estimated from serum creatinine, body weight, age, and sex using the Cockcroft-Gault equation);
• Clinically significant abnormal screening ECG or clinical laboratory (clinical chemistry, hematology, urinalysis) measurements;
• Prior participation in a clinical trial involving PD 0299685;
• Significant medical or psychiatric illness within the past 12 months;
• Participation in a study of an investigational or marketed drug during the 30-day period before the start of the study or during the conduct of the study;
• Smoking of >1 pack of cigarettes per day (or patients who cannot avoid nicotine overnight);
• Substance abuse or dependence within the past 12 months, including suspicion or confirmation of excessive alcohol usage by 2 of 4 positive responses to the 4 question CAGE questionnaire;
• Positive urine drug screen at screening;
• Any findings indicating simple or complex hyperplasia or endometrial cancer through endometrial biopsy collected during screening.
• Other severe acute or chronic medical or psychiatric condition or laboratory assay abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
· Change from baseline in average daily frequency of moderate to severe vasomotor symptoms (combined daytime hot flashes and night sweats) to Week 4;
· Change from baseline in average daily frequency of moderate to severe vasomotor symptoms (combined daytime hot flashes and night sweats) to Week 12;
· Change from baseline in average daily severity of moderate to severe vasomotor symptoms (combined daytime hot flashes and night sweats) to Week 4;
· Change from baseline in average daily severity of moderate to severe vasomotor symptoms (combined daytime hot flashes and night sweats) to Week 12.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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