| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of moderate to extremely severe vasomotor symptoms in healthy postmenopausal women |
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| MedDRA Classification |
| 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 evaluate the safety and tolerability of two doses of GSK232802 administered once daily for 12 weeks in healthy postmenopausal women with moderate to extremely severe VMS.
•To evaluate the effect of two doses of GSK232802, administered over a 12-week treatment period, on change in frequency and severity of VMS from baseline compared to placebo.
•To characterize the PK of GSK232802 (and its primary oxidative metabolite GSK1132184A) and evaluate the relationship between individual measures of exposure to GSK232802, as estimated by population PK methods, versus frequency and severity of VMS, safety, and PD endpoints, as appropriate.
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the change in frequency and severity of VMS at Weeks 4 and 8 of the treatment period for time to onset of efficacy for GSK232802 compared to placebo.
•To compare the proportion of subjects who achieve a reduction in frequency and severity of VMS of at least 50%, at least 75%, and 100% from baseline to Week 12, after treatment with GSK232802 versus placebo.
•To assess effects of GSK232802 on the following parameters over a 12-week treatment period in healthy postmenopausal women with moderate to extremely severe VMS:
•Questionnaires for menopause-related quality of life, sleep quality, fatigue, depressive symptoms, and work productivity.
•VVA symptoms.
•PD markers: including serum hormone levels and serum bone biomarkers.
•Body composition
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1.Postmenopausal women aged 40 to 65 years old; postmenopausal defined as:
i.Amenorrheic for at least 12 consecutive months* OR
ii.At least 6 weeks post-surgical bilateral oophorectomy† with or without hysterectomy.
*Note: Although duration of amenorrhea is initially determined by subject history at the time of the screening visit (Visit 1), menopausal status must be confirmed by demonstrating levels of follicle stimulating hormone (FSH) >40 IU/mL and estradiol <30ng/L at entry. Screening reports provided by the Central Laboratory must be carefully reviewed to determine menopause eligibility prior to conducting Visit 2 assessments.
†For women who are surgically menopausal, a copy of the pathology report demonstrating both ovaries have been removed and/or biochemical evidence of post-menopausal status as noted above is required prior to conducting Visit 2 assessments.
2.A minimum average frequency of seven daily moderate to extremely severe hot flashes or episodes of night sweats sufficient to cause the patient to seek treatment (these episodes must be documented during the baseline period and the subject must have recorded frequency and severity of symptoms for a minimum of eight days in order to be eligible for randomization). This average frequency will be calculated by summing the number of moderate, severe, and extremely severe VMS events during the baseline period and dividing by the total number of non-missing days during this period, with details related to the definition of non-missing days described in Section 6.3.1.
3.BMI within the range 19 to 35 kg/m2, inclusive.
4.Subject has provided signed and dated written informed consent before admission to the study.
5.Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1.Investigator considers subject unfit for the study as a result of medical history, physical examination, or screening tests.
2.Use of prescription or non-prescription drugs including:
i.Hormone therapy (estrogen or estrogen/progestin combination or related products) within the following time period before the first dose of investigational product and during the study:
•4 weeks for prior vaginal hormonal products or transdermal estrogen or estrogen/progestin products.
•4 weeks for oral estradiol or SERM products.
•8 weeks for prior oral conjugated estrogen or estrogen/progestin products or for prior intrauterine progestin therapy.
•3 months for prior progestin implants or injectable estrogen.
•6 months for prior estrogen pellet therapy or injectable progestin.
ii.Use of putative therapies for VMS relief. Use of non-medication treatments for VMS, such as acupuncture and biofeedback.
iii.Use of weight loss drugs within 3 months of the first dose of investigational product.
iv.Use of pravastatin [Pravachol/Lipostat], rosuvastatin [Crestor], or pitavastatin [Livalo] within 5 half-lives of the first dose of investigational product (note: half-lives will be provided in the SPM. Uses of other statins, for example simvastatin [Zocor], atorvastatin [Lipitor], fluvastatin [Lescol], lovastatin [Mevacor] are allowed).
v.Use of bupropion, orphenadine [Norflex], cyclophosphamide, efavirenz, ifosfamide, or methadone (because of the potential for GSK232802 to inhibit CYP2B6), or use of paclitaxel, torsemide, amodiaquine, or repaglinide (because of the potential for GSK232802 to inhibit CYP2C8).
vi.Women on a concurrent anti-depressant, anti-hypertensive, or lipid-lowering therapy (except for medications specifically excluded above) may be included in the study, as long as they have been stable on these medications for at least 1 month.
3.Use of investigational drug within the past 30 days or 5 half-lives (whichever is longer) before the first dose of investigational product.
4.Uterine disease or medical condition including:
•Bi-layer endometrial thickness greater than 5mm as determined by TVUS, or for women with a non-informative TVUS, a single layer thickness of greater than 3 mm determined by SIS; presence of fibroids that obscure evaluation of endometrium by TVUS;
•History of uterine cancer; evidence of endometrial hyperplasia or cancer as assessed by endometrial biopsy before enrollment (Note: if a subject has insufficient tissue for diagnosis at screening, but bi-layer endometrial thickness by TVUS is 5mm or single wall thickness by SIS is 3mm, she may still be eligible for study entry if she meets the remaining inclusion/exclusion criteria);
•Evidence of an endometrial polyp with hyperplastic or malignant epithelium;
•Unexplained or unusual endometrial bleeding; or uterine surgery (within the past 6 months);
•Abnormal cervical Pap smear with evidence of cervical dysplasia greater than or equal to low grade squamous intraepithelial lesion (LSIL) or with a diagnosis of atypical squamous cells of undetermined significance (ASCUS) that is HPV High Risk positive, or glandular lesions including but not limited to atypical glandular cells of undetermined significance (AGUS), adenocarcinoma in situ (AIS) or malignancy
Please see protocol for full exclusion criteria. This list is abbreviated.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety: Incidence and severity of AEs. Change from baseline in: vital signs, physical examination, clinical chemistry, hematology, thyroid-stimulating hormone (TSH), thyroxine (T4), fasting lipid profile, and thrombotic and inflammatory markers. Absolute change in bi-layer endometrial thickness measured by transvaginal ultrasound (TVUS) or saline infusion sonohysterography (SIS), endometrial biopsy pathology, and the occurrence of withdrawal bleeding.
• Efficacy: The primary efficacy endpoints include the following co-primary measures of VMS, with the second endpoint tested in a step-down fashion (see Section 6.3.1):
• Mean change in frequency of VMS from baseline to Week 12
• Mean change in severity of VMS from baseline to Week 12
• PK: Plasma concentrations of GSK232802 and GSK1132184A allowing for characterization of population PK parameters and individual exposure to GSK232802 and GSK1132184A.
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
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| 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
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| The end of the trial is the last visit, visit 9 for every subject. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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