E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Reproductive-aged women with moderate to severe symptoms related to endometriosis. Subjects will have been diagnosed with endometriosis by laparoscopy or laparotomy within 10 years before visit 1B (screening). |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Information not present in EudraCT |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-To evaluate the superiority of ERB-041 relative to placebo on the relief of endometriosis-related symptoms (dysmenorrhea, pelvic pain, and deep dyspareunia) in reproductive-aged women using the Biberoglu & Behrman (B&B) scale administered by the physician investigator. -To compare the safety profile of ERB-041 with placebo during 12 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
Compare ERB-041 with placebo: Treatment Phase: -Clinical assessment of endometriosis using B&B scale -Subject assessment of symptoms using 11-point daily subject-reported severity scale -Assessment of change in subject-reported use of rescue medication -Evaluation of number of subject withdrawals secondary to symptoms associated with endometriosis -Assessment of HRQL measured by the EHP-30 questionnaire -Pharmacokinetic analysis Pilot and validate administration of: -Novel daily subject assessment instrument to measure symptoms associated with endometriosis -Novel subject assessment instrument to measure subject satisfaction with treatment Post-treatment Phase: -Evaluation of number of subjects whose symptoms recur and time to recurrence -Clinical assessment of endometriosis using criteria from the B&B scale -Subject assessment of symptoms using a daily subject-reported 11-point severity scale |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Subjects must have had a surgical diagnosis (laparoscopy or laparotomy) of endometriosis established within 10 years before visit 1B (screening). Operative report review will be required for verification. If multiple surgeries have been performed within the previous 10 years, the operative report of the most recent laparoscopy or laparotomy will be used for eligibility requirements and source documentation. ·-Subjects must be nonpregnant, nonlactating women aged 18 to 45 years, inclusive, at the time of visit 1B (screening). ·- Subjects not undergoing a washout from oral contraceptives must have a history of regular menstrual periods (3 or more consecutive days of uterine bleeding requiring sanitary protection), with cycle lengths of 21 to 35 days, for at least 3 consecutive months before visit 1B (screening). ·- After discontinuation of oral contraceptives, subjects must have had 1 spontaneous period (ie, after the oral contraceptives withdrawal bleed) before visit 1B (screening). ·- Subjects must be sexually active (vaginal intercourse). “Sexually active” is defined as full vaginal penetration at least 2 times per month or 2 failed attempts at vaginal intercourse. ·- Subjects must be willing to use highly effective nonhormonal methods of birth control (eg, sterilization, diaphragm with spermicide, or condom with spermicide) for the duration of study participation. ·- Subject must have a telephone line (analog preferred) or wireless communication instrument. ·- Subject should be able to understand the use of a personal digital assistant (PDA) device. ·- In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study. ·- Subjects must be willing to refrain from the use of prohibited medications during the treatment and posttreatment phases of the study. ·- During the treatment phase, subjects must be willing to use no more than the rescue medication regimen historically established during the pretreatment phase. ·- Rescue medication is limited to intake of 1 dose of analgesic per episode. If pain recurs, the subject is permitted to take a dose for each recurring episode up to the daily recommended dose for that rescue medication. Chronic narcotic use is not permitted. ·- Subjects must exhibit a positive response regarding the symptom of pelvic pain. A positive response is reported by the subject, reflects the worst episode before analgesic use, and is determined as follows: o At Visit 1B (Screening): i. Subjects must have moderate to severe pelvic pain for at least 3 months before visit 1B (screening), as exhibited by a pelvic pain score of 3 or 4 on the B&B scale (the B&B scale includes the symptom of pelvic pain and assigns a point score for the degree of reported severity); AND ii. The subject must report a pelvic pain score of at least 4 on the numeric rating scale (NRS, question 3) included in the Pelvic Pain Classification Tool (PPCT) on the basis of 1-month recall of the severity of her nonmenstrual pelvic pain before taking pain medication (if applicable). o At Visit 2 (Randomization): i. The subject must have a pelvic pain score of 3 or 4 on the B&B scale (this pelvic pain score will be considered baseline); AND ii. The subject must report a pelvic pain score of at least 4 on the NRS on the basis of 1-month recall of the severity of her nonmenstrual pelvic pain before taking pain medication (if applicable). ·- Subjects must sign and date an institutional review board (IRB)-approved written informed consent form before any screening procedures are performed. |
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E.4 | Principal exclusion criteria |
Subjects who desire to become pregnant during the study. - Subjects who have undergone hysterectomy and/or bilateral oophorectomy - Subjects who are not candidates for estrogen therapy. - Subjects who are pregnant or who were pregnant before visit 1B (screening). - Subjects who are breastfeeding. - Subjects who are not sexually active. - The use of the following drugs within 30 days before visit 1B (screening): a. Oral contraceptives, dermal patch containing contraceptives, injectable or implantable or insertable contraceptive hormones. b. Oral, transdermal, or vaginally applied estrogens, progestogens, and/or androgens. c. Aromatase inhibitors (eg, anastrozole). - The use of the following drugs within 90 days before visit 1B (screening): a. Progestin containing intrauterine device (IUD). b. Monthly dose gonadotropin-releasing hormone (GnRH) analogs (eg, leuprolide acetate, 3.75 mg formulation). c. Use of psychoactive medications (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants), if used for chronic pain. d. Use of selective estrogen receptor modulators (SERMs), including raloxifene, tamoxifen, and clomiphene. - The use of the following drugs within 10 months before visit 1B (screening): a. Injectable/implantable progestogens (eg, medroxyprogesterone acetate depot formulation). b. Three (3)-month dose GnRH analogs (eg, leuprolide acetate, 11.25 mg formulation). - Use of antiepileptic medications (eg, carbamazepine, gabapentin, lamotrigine). - Transvaginal ultrasound (TVUS) findings requiring immediate surgical intervention, as determined by the investigator, and/or evidence of findings indicative of a secondary cause of pelvic pain other than endometriosis. - A history of endometriosis-related symptoms that are completely relieved by mild analgesics. - Abnormal cervical cytology smear (based on the Bethesda 2001 system). Subjects with reported atypical squamous cells of undetermined significance (ASCUS) may be considered if human papilloma virus (HPV) result is negative. - Presence or history of the following: a. Pelvic pain secondary to other disease processes (eg, pelvic masses other than endometriomas, genitourinary disease, fibromyalgia, pelvic inflammatory disease, gastrointestinal disease, irritable bowel syndrome). b. Known history of or suspected endometrial hyperplasia or carcinoma. c. Thrombophlebitis, thrombosis or thromboembolic disorders, deep vein thrombosis, pulmonary embolism, or known coagulopathy. d. Ischemic heart disease, myocardial infarction, or unstable angina within 6 months before screening. e. Cerebrovascular or cardiovascular disease. f. Neuro-ocular disorders (eg, optic neuritis or retinal vein thrombosis). g. Cholestasis or symptomatic gallstones (subjects who have had a cholecystectomy may be enrolled). h. Valvular heart disease. i. Breast cancer. j. Estrogen-dependent neoplasia (eg, endometrial carcinoma, melanoma). k. Liver tumors (benign or malignant). l. Diabetes with vascular involvement, or uncontrolled diabetes.m. Undiagnosed abnormal genital bleeding within the past 6 months. - Presence of the following: a. Abnormality suggestive of malignancy noted on mammogram, breast examination, and/or ultrasound findings. b. Malignancy, or treatment for malignancy, within the previous 10 years. History or active presence of basal cell or squamous cell carcinoma of the skin does not exclude the subject. History of nonmelanoma skin cancer does not exclude the subject. c. Body mass index (BMI) above 40 kg/m2. d. Persistent elevated blood pressure. Elevated blood pressure is defined as >140 mm Hg systolic or >90 mm Hg diastolic on hypertensive therapy when measured after the subject sits for 3 minutes. e. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) values ³1.5 times the upper limit of normal (ULN) for the laboratory used. f. Serum creatinine value ³1.5 times the ULN for the laboratory used. g. Alkaline phosphatase value ³1.5 times the ULN for the laboratory used. h. Total bilirubin value ³1.5 times the ULN for the laboratory used. Subjects with a preexisting diagnosis of Gilbert’s syndrome may be included after approval by the Wyeth Research (WR) medical monitor. i. Fasting total cholesterol value ≥250 mg/dL (³6.5 mmol/L) or triglycerides value ≥250 mg/dL (³2.8 mmol/L). j. Fasting blood glucose ≥125 mg/dL (≥6.9 mmol/L). k. Positive cervical cultures for gonorrhea or Chlamydia infection. Subjects with positive culture results may be treated and, if repeat results are negative, allowed into the study. l. Headaches with focal neurologic symptoms. m. Planned major surgery requiring immobilization. - Known alcohol or drug abuse. - Presence of a malabsorption disorder. - Clinically important abnormalities on initial physical examination or pretreatment laboratory tests. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The change in individual severity scores for the 3 symptoms of endometriosis (dysmenorrhea, pelvic pain, and deep dyspareunia [co-primary endpoints]) from baseline to last on-therapy cycle based on the B&B scale administered by the physician investigator. |
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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 | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Information not present in EudraCT |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |