Efficacy and Safety Study for the Treatment of Dysfunctional Uterine Bleeding

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether the study drug is safe and effective in the treatment of dysfunctional uterine bleeding.

Detailed Description
-----------------
This study has previously been posted by Berlex, Inc. Berlex, Inc. has been renamed to Bayer HealthCare Pharmaceuticals, Inc.Bayer HealthCare Pharmaceuticals, Inc.is the sponsor of the trial.

Official Title
-----------------
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo- Controlled, 7 Cycle Duration (196 Days), Phase 3 Study of Oral Estradiol Valerate/Dienogest Tablets for the Treatment of Dysfunctional Uterine Bleeding.

Conditions
-----------------
Metrorrhagia

Intervention / Treatment
-----------------
* Drug: Estradiol valerate/Dienogest (Natazia, Qlaira, BAY86-5027)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women 18 years or older With diagnosis of dysfunctional uterine bleeding without organic pathology And with at least one of the following symptoms: prolonged, frequent, or excessive bleeding Exclusion Criteria: The use of steroidal oral contraceptives, or any drug that could alter oral contraception metabolism will be prohibited during the study. Women with history of endometrial ablation or dilatation or curettage within 2 months prior to study start will be excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol valerate/Dienogest (Natazia, Qlaira, BAY86-5027)<br>A blister card consists of 28 pills taken orally once a day for 28 days (one cycle): 2 days of 3 mg estradiol valerate (EV); 5 days of 2 mg EV + 2 mg dienogest (DNG); 17 days of 2 mg EV + 3 mg DNG; 2 days of 1 mg EV; 2 days of placebo | Drug: Estradiol valerate/Dienogest (Natazia, Qlaira, BAY86-5027)<br>* 2 days of 3 mg estradiol valerate (EV);5 days of 2 mg EV + 2 mg dienogest (DNG);17 days of 2 mg EV + 3 mg DNG;2 days of 1 mg EV;2 days of placeboA blister card consists of 28 pills taken orally once a day for 28 days (one cycle)<br>|
| Placebo Comparator: Placebo<br>Matching placebo to be taken orally daily | Drug: Placebo<br>* Matching placebo to be taken orally daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With no Dysfunctional Uterine Bleeding (DUB) Symptoms | Up to 8 criteria had to be met for complete response during 90-day period. No bleeding episodes (BE) >7 days, no >4 BE, no BE with MBL >=80 mL, no >1 BE increase from baseline, no increase from baseline in an individual participant's total number of bleeding days and total number of bleeding days not >24 days. Additionally, for participants included with prolonged bleeding: decrease between maximum duration during run-in and efficacy >=2 days excessive bleeding: MBL associated with each episode decreased by >=50% from average of qualifying episodes during run-in. | during a time period of 90 days under treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Cured From Prolonged Bleeding | Prolonged bleeding was defined as 2 or more bleeding episodes, each lasting 8 or more days in a 90-day period. Participants were considered cured if they had no bleeding episodes lasting more than 7 days and the decrease between the maximum duration during the run-in phase and the maximum duration during the efficacy phase was at least 2 days. | during a time period of 90 days under treatment | 
| Proportion of Participants Cured From Frequent Bleeding | Frequent bleeding was defined as greater than 5 bleeding episodes, with a minimum of 20 bleeding days overall in a 90-day period. Participants were considered cured if they had no more than 4 bleeding episodes and the total number of bleeding days did not exceed 24 days and there was no increase in the total number of bleeding days in the efficacy phase as compared to the run-in phase. | during a time period of 90 days under treatment | 
| Proportion of Participants Cured From Excessive Bleeding | Excessive bleeding was defined as 2 or more bleeding episodes each with blood loss volume of 80 mL or more in a 90-day period. Participants were considered cured if (1) the blood loss volume associated with each episode was less than 80 mL and (2) the blood loss volume associated with each bleeding episode represented a decrease of at least 50% from the average of the qualifying bleeding episodes, where the qualifying bleeding episodes were those with a blood loss volume ≥ 80 mL (per episode) that occurred during the run-in phase. | during a time period of 90 days under treatment | 
| Proportion of Participants With Improvement in the Investigator's Global Assessment Scale at Treatment Day 84 | The investigators assessed the participants' change in DUB symptoms at day 84 (visit 7) compared with admission to the study according to a scale of 1 (very much improved) to 7 (very much worse), using the following information: central laboratory data, physical examination, e-diary data, and participant interview. Improvement was defined as being classified as a score of 3 or less. | from baseline up to treatment day 84 | 
| Proportion of Participants With Improvement in the Investigator's Global Assessment Scale at Treatment Day 196 | The investigators assessed the participants' change in DUB symptoms at day 196 (visit 11) compared with admission to the study according to a scale of 1 (very much improved) to 7 (very much worse), using the following information: central laboratory data, physical examination, e-diary data, and participant interview. Improvement was defined as being classified as a score of 3 or less. | from baseline up to treatment day 196 | 
| Proportion of Participants With Improvement in the Participant's Overall Assessment Scale at Treatment Day 84 | Participants assessed their overall improvement at day 84 (visit 7) compared with their condition at admission to the study on a scale of 1 (very much improved) to 7 (very much worse). Improvement was defined as being classified as a score of 3 or less. | from baseline up to treatment day 84 | 
| Proportion of Participants With Improvement in the Participant's Overall Assessment Scale at Treatment Day 196 | Participants assessed their overall improvement at day 196 (visit 11) compared with their condition at admission to the study on a scale of 1 (very much improved) to 7 (very much worse). Improvement was defined as being classified as a score of 3 or less. | from baseline up to treatment day 196 | 
| Change From Baseline in Blood Loss Volume for All Participants to the Reference Period of 90 Days Under Treatment | Menstrual blood loss was determined using the alkaline hematin method for the 90 days before treatment (baseline) and for 90 days under treatment. A negative value indicates a reduction in blood loss after treatment. | Baseline and reference period of 90 days under treatment | 
| Menstrual Blood Loss Volume for All Participants at Cycle 1 | Menstrual blood loss volume was determined using the alkaline hematin method after participants were on treatment for one cycle | 28 days | 
| Menstrual Blood Loss Volume for All Participants at Cycle 3 | Menstrual blood loss volume was determined using the alkaline hematin method after participants were on treatment for 3 cycles | 28 days | 
| Menstrual Blood Loss Volume for All Participants at Cycle 7 | Menstrual blood loss volume was determined using the alkaline hematin methods after participants were on treatment for 7 cycles | 28 days | 
| Change From Baseline in Blood Loss Volume for Participants With Excessive Bleeding to the Reference Period of 90 Days Under Treatment | The blood loss volume for participants with excessive bleeding (2 or more bleeding episodes each with blood loss volume of 80 mL or more during the run-in phase) was determined for the 90 days before treatment (ie, run-in phase) and for the 90 days under treatment. A negative value indicates a reduction in blood loss while under treatment compared to before treatment. | baseline and reference period of 90 days under treatment | 
| Menstrual Blood Loss Volume for Participants With Excessive Bleeding at Cycle 1 | The blood loss volume for participants with excessive bleeding (2 or more bleeding episodes each with blood loss volume of 80 mL or more during the run-in phase) was determined using the alkaline hematin method after participants were on treatment for one cycle. | 28 days | 
| Menstrual Blood Loss Volume for Participants With Excessive Bleeding at Cycle 3 | The blood loss volume for participants with excessive bleeding (2 or more bleeding episodes each with blood loss volume of 80 mL or more during the run-in phase) was determined using the alkaline hematin method after participants were on treatment for 3 cycles. | 28 days | 
| Menstrual Blood Loss Volume for Participants With Excessive Bleeding at Cycle 7 | The blood loss volume for participants with excessive bleeding (2 or more bleeding episodes each with blood loss volume of 80 mL or more during the run-in phase) was determined using the alkaline hematin method after participants were on treatment for 7 cycles. | 28 days | 
| Change From Baseline in Number of Bleeding Days to the Reference Period of 90 Days Under Treatment | The number of bleeding days was determine for the 90 days before treatment (baseline) and for 90 days while under treatment. A negative value indicates a reduction in the number of bleeding days while under treatment compared to baseline. | baseline and reference period of 90 days under treatment | 
| Change From Baseline in Number of Bleeding Episodes to the Reference Period of 90 Days Under Treatment | A bleeding episode was one that lasted for at least 2 days, and where the bleeding days were separated by no more than 1 bleeding-free day. An episode stopped with 2 consecutive bleeding-free days. The number of episodes was determined for the 90 days before treatment and for the 90 days under treatment. A negative values indicates a reduction from baseline in the number of episodes while under treatment. | baseline and reference period of 90 days under treatment | 
| Change From Baseline in Number of Sanitary Protection Used at 90 Days of Treatment | The number of total sanitary protection items used during the 90-day run-in phase before treatment (baseline) and the number of total sanitary protection items used during the 90 days while under treatment was determined. A negative value indicates a reduction in the number of sanitary protection items used while under treatment compared to the number used before treatment. | baseline and reference period of 90 days under treatment | 
| Change From Baseline in Psychological General Well-Being Index (PGWBI) Scores at Treatment Day 84 | The PGWBI questionnaire consisted of 22 questions that were answered using a 6-grade Likert scale. The minimum overall score was 22 and the maximum was 132. The higher the score, the better the well being of the participant. The observation phase was the last 4 weeks. The following 6 dimensions were derived from the questionnaire: anxiety, depressed mood, positive well-being, self-control, health, and vitality and the highest possible scores were 30, 18, 24, 18, 18, and 24, respectively. | baseline and treatment day 84 | 
| Change From Baseline in Psychological General Well-Being Index (PGWBI) Scores at Treatment Day 196 | The PGWBI questionnaire consisted of 22 questions that were answered using a 6-grade Likert scale. The minimum overall score was 22 and the maximum was 132. The higher the score, the better the well being of the participant. The observation phase was the last 4 weeks. The following 6 dimensions were derived from the questionnaire: anxiety, depressed mood, positive well-being, self-control, health, and vitality and the highest possible scores were 30, 18, 24, 18, 18, and 24, respectively. | baseline and treatment day 196 | 
| Change From Baseline in McCoy Female Sexuality Questionnaire (MFSQ) Scores at Treatment Day 84 | The MFSQ was designed to measure aspects of female sexuality and asked about the participants' sexual experience during the last 4 weeks. Higher scores represent higher, more complete, or better integrated levels of female sexual function. Minimum and maximum possible values are 19 and 133. | baseline and treatment day 84 | 
| Change From Baseline in McCoy Female Sexuality Questionnaire (MFSQ) Scores at Treatment Day 196 | The MFSQ was designed to measure aspects of female sexuality and asked about the participants' sexual experience during the last 4 weeks. Higher scores represent higher, more complete, or better integrated levels of female sexual function. Minimum and maximum possible values are 19 and 133. | baseline and treatment day 196 | 
| Change From Baseline in EuroQoL (Quality of Life) 5 Dimensional Health Questionnaire (EQ-5D) Scores at Treatment Day 84 | The Health State Classification of the EQ-5D comprised 5 questions addressing mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Participants were asked to indicate their current health state by ticking the most appropriate of 3 statements about each of the questions (ie, no problems, some problems, extreme problems). The best possible answers were (1,1,1,1,1), which equals a valuation score of 1.0. The worst possible answers were (3,3,3,3,3), which equals a valuation score of .594. The change from the baseline score at day 84 is presented. | baseline and treatment day 84 | 
| Change From Baseline in EuroQoL (Quality of Life) 5 Dimensional Health Questionnaire (EQ-5D) Scores at Treatment Day 196 | The Health State Classification of the EQ-5D comprised 5 questions addressing mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Participants were asked to indicate their current health state by ticking the most appropriate of 3 statements about each of the questions (ie, no problems, some problems, extreme problems). The best possible answers were (1,1,1,1,1), which equals a valuation score of 1.0. The worst possible answers were (3,3,3,3,3), which equals a valuation score of .594. The change from the baseline score at day 196 is presented. | baseline and treatment day 196 | 
| Change From Baseline in Visual Analogue Scale (VAS) of the EQ-5D Score at Treatment Day 84 | The visual analogue scale (ie, thermometer) had endpoints of 100 (best imaginable health state) at the top, and 0 (worst imaginable health state) at the bottom. Participants rated their current health state by drawing a line from the box marked 'your own health state today' to the appropriate point on the thermometer scale. The change from baseline at day 84 is presented. | baseline and treatment day 84 | 
| Change From Baseline in Visual Analogue Scale (VAS) of the EQ-5D Score at Treatment Day 196 | The visual analogue scale (ie, thermometer) had endpoints of 100 (best imaginable health state) at the top, and 0 (worst imaginable health state) at the bottom. Participants rated their current health state by drawing a line from the box marked 'your own health state today' to the appropriate point on the thermometer scale. The change from baseline at day 196 is presented. | baseline and treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Change in the Employment Status) at Treatment Day 84 | Participants were asked if there was any change in her employment status in the last 12 weeks. The proportion of participants with a change is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Days Missed From Work) at Treatment Day 84 | Participants were asked how many days and hours they missed from work during the past 12 weeks because of problems associated with DUB, not including the time missed to participate in this study. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Productivity While Working) at Treatment Day 84 | Participants were asked to rate on a scale of 0 to 10, how much their DUB affected productivity while working during the past 12 weeks, where 0 represented that DUB had no effect on work and 10 represented that DUB completely prevented her from working. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Regular Daily Activities) at Treatment Day 84 | Participants were asked to rate on a scale of 0 to 10 how much DUB affected their ability to do their regular daily activities, other than work at a job, during the past 12 weeks where 0 represented that DUB had no effect on daily activities and 10 represented that DUB completely prevented her from doing daily activities. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Unscheduled Outpatient Visit at Hospital) at Treatment Day 84 | Participants were asked if they had any unscheduled outpatient visits to a hospital because of DUB during the past 12 weeks, not including visits that were due to participation in this study. The proportion of participants with such visits is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Unscheduled Visit to Physician) at Treatment Day 84 | Participants were asked if they had any unscheduled visits to a physician (non-hospital medical care) because of DUB during the past 12 weeks, not including visits that were due to participation in this study. The proportion of participants with such visits is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Additional Unscheduled Procedures) at Treatment Day 84 | Participants were asked if they had any unscheduled procedures (eg, laparoscopy, laboratory tests, ultrasound) because of DUB during the past 12 weeks. The proportion of participants with such procedures is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Received Ambulatory Services) at Treatment Day 84 | Participants were asked if they had received ambulatory services (eg, home help, child care) because of DUB during the past 12 weeks. The proportion of participants who received such services is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Out-of-pocket Expenses) at Treatment Day 84 | Participants were asked to specify if they had out-of-pocket expenses because of DUB during the past 12 weeks, including over-the-counter medication (the name of the medication, the number of packages, and the cost per package), co-payments due to prescribed medication, and costs to travel to and from medical appointments. The proportion of participants with such expenses is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Any Medical Treatment) at Treatment Day 84 | Participants were asked if they had any medical treatment (eg, prescribed medication, other treatment) because of DUB during the past 12 weeks. The proportion of participants with such treatment is displayed. | treatment day 84 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Change in the Employment Status) at Treatment Day 196 | Participants were asked if there was any change in employment status in the last 12 weeks. The proportion of participants with a change is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Days Missed From Work) at Treatment Day 196 | Participants were asked how many days and hours were missed from work during the past 12 weeks because of problems associated with DUB, not including the time missed to participate in this study. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Productivity While Working) at Treatment Day 196 | Participants were asked to rate on a scale of 0 to 10, how much DUB affected their productivity while working during the past 12 weeks, where 0 represented that DUB had no effect on work and 10 represented that DUB completely prevented her from working. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Regular Daily Activities) at Treatment Day 196 | Participants were asked to rate on a scale of 0 to 10 how much DUB affected their ability to do regular daily activities, other than work at a job, during the past 12 weeks where 0 represented that DUB had no effect on daily activities and 10 represented that DUB completely prevented her from doing her daily activities. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Unscheduled Outpatient Visit at Hospital) at Treatment Day 196 | Participants were asked if they had any unscheduled outpatient visits to a hospital because of DUB during the past 12 weeks, not including visits that were due to participation in this study. The proportion of participants with such visits is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Unscheduled Visit to Physician) at Treatment Day 196 | Participants were asked if they had any unscheduled visits to a physician (non-hospital medical care) because of DUB during the past 12 weeks, not including visits that were due to participation in this study. The proportion of participants with such visits is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Additional Unscheduled Procedures) at Treatment Day 196 | Participants were asked if they had any unscheduled procedures (eg, laparoscopy, laboratory tests, ultrasound) because of DUB during the past 12 weeks. The proportion of participants with such procedures is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Received Ambulatory Services) at Treatment Day 196 | Participants were asked if they had received ambulatory services (eg, home help, child care) because of DUB during the past 12 weeks. The proportion of participants who had received such services is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Out-of-pocket Expenses) at Treatment Day 196 | Participants were asked to specify out-of-pocket expenses because of DUB during the past 12 weeks, including over-the-counter medication, co-payments due to prescribed medication, and costs to travel to and from medical appointments. The proportion of participants with such expenses is displayed. | treatment day 196 | 
| Resource Use Assessment by Use of a Self Administered Questionnaire (Any Medical Treatment) at Treatment Day 196 | Participants were asked if they had any medical treatment (eg, prescribed medication, other treatment) because of DUB during the past 12 weeks. The proportion of participants with such treatment is displayed. | treatment day 196 | 
| Change From Baseline in Hematocrit (Hct) Concentrations at Treatment Day 196 | Hematocrit was measured before treatment and after 196 days under treatment. A positive value indicates an increase in hematocrit from baseline at treatment day 196. | baseline and treatment day 196 | 
| Change From Baseline in Serum Ferritin Concentration at Treatment Day 84 | Serum ferritin was measured before treatment and after 84 days under treatment. A positive value indicates an increase in serum ferritin from baseline at treatment day 84. | baseline and treatment day 84 | 
| Change From Baseline in Serum Ferritin Concentration at Treatment Day 196 | Serum ferritin was measured before treatment and after 196 days under treatment. A positive value indicates an increase in serum ferritin from baseline at treatment day 196. | baseline and treatment day 196 | 
| Change From Baseline in Hemoglobin Concentration at Treatment Day 84 | Hemoglobin was measured before treatment and after 84 days under treatment. A positive value indicates an increase in hemoglobin from baseline at treatment day 84. | baseline and treatment day 84 | 
| Change From Baseline in Hemoglobin Concentration at Treatment Day 196 | Hemoglobin was measured before treatment and after 196 days under treatment. A positive value indicates an increase in hemoglobin from baseline at treatment day 196. | baseline and treatment day 196 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dysfunctional Uterine Bleeding