Fraser IS, 1 Parke S, 2 Mellinger U, 2 Machlitt A, 2 Jensen JT 4

Transcription

1 An oral contraceptive comprising oestradiol valerate/dienogest is effective in the treatment of heavy and/or prolonged menstrual bleeding: a pooled analysis Fraser IS, 1 Parke S, 2 Mellinger U, 2 Machlitt A, 2 Jensen JT 4 1 University of Sydney, Sydney, NSW, Australia; 2 Bayer Schering Pharma AG, Berlin, Germany; 3 Oregon Health & Science University, Portland, OR, USA

2 Background Abnormal uterine bleeding (AUB) is the most frequent gynaecological symptom observed by specialist obstetriciangynaecologists 1 Heavy and prolonged menstrual bleeding (HPMB) without recognizable organic pathology is a specific symptom and working diagnosis within AUB An oral contraceptive comprised of oestradiol valerate and dienogest (E 2 V/DNG; Qlaira ) was hypothesized to have properties that would make it suitable for the treatment of HPMB 1 Kacmar et al. Am J Obstet Gynecol 2004;191:

3 Study objectives A pooled analysis of data from two identically designed studies was conducted to evaluate the efficacy of E 2 V/DNG for the treatment of HPMB without organic pathology These multicentre, double-blind, randomised and placebocontrolled studies were conducted in parallel in the USA/Canada and Europe/Australia Enrolled patients were studied over a 10-month (286-day) period Both studies had identical designs and analysis plans 3

4 Study participants Eligible women were aged 18 years or older and were healthy apart from a diagnosis of HPMB Women were excluded if they had a menstrual bleeding disorder that was the result of organic pathology Other conditions were excluded by medical history, transvaginal ultrasound and endometrial biopsy HPMB was confirmed by electronic diary data and objective menstrual blood loss (MBL) quantification using a derivation of the alkaline haematin method 4

5 Study definitions of HPMB HPMB without organic pathology included: Prolonged bleeding 2 or more episodes, each of 8 or more days Frequent bleeding More than 5 episodes involving 20 or more bleeding days in total Excessive bleeding 2 or more episodes, each with a blood loss volume of 80 ml or greater These assessments were made over 90-day periods 5

6 Study outcomes The primary efficacy variable was the proportion of women with a return to menstrual normality ( complete response ) To be considered a complete responder, women had to meet a composite of up to 8 individual criteria of menstrual normality Important secondary efficacy variables included changes in: Objectively measured MBL volume Haemoglobin and iron metabolism 6

7 Criteria for complete response Efficacy condition Definition 1 No bleeding episodes lasting more than 7 days 2 No more than 4 bleeding episodes 3 No bleeding episodes with a blood loss volume of 80 ml or more 4 No more than 1 bleeding episode increase from baseline 5 Total number of bleeding days 24 or less 6 No increase from baseline in the total number of bleeding days 7 8 Decrease of 2 days or more between the maximum duration of a bleeding episode in the run-in phase and efficacy phase (if enrolled with prolonged bleeding) Blood loss volume associated with each episode less than 80 ml and decreased by at least 50% (if enrolled with excessive bleeding) 7

8 Study design 90-day efficacy phase E 2 V/DNG 90-day run-in phase (confirmation of diagnosis) 196 days Placebo 90-day efficacy phase The 90-day efficacy phase had to start on day 1 of a cycle 8

9 Flow of participants through the two studies Screened N=1652 Randomized N=421 Excluded N=1231 Consent withdrawn (N=188) In-/exclusion criteria not met (N=885) Patient lost to follow-up (N=95) Other (N=63) E 2 V/DNG N=269 2:1 Placebo N=152 Received study treatment N=264 Received study treatment N=147 Discontinued study medication (N=67) Study medication never administered (N=5) Unknown (N=4) Discontinued study medication (N=32) Study medication never administered (N=5) Unknown (N=2) Completed study N=202 Completed study N=116 Completed study treatment N=193 Completed study treatment N=113 9

10 Demographics and bleeding symptoms at baseline E 2 V/DNG (N=269) Placebo (N=152) Age, years 38.3 ± ± 7.2 Weight, kg 71.0 ± ± 11.2 Body mass index, kg/m ± ± 3.4 Ethnicity, N (%) Caucasian 215 (79.9) 126 (82.9) Black 39 (14.5) 14 (9.2) Hispanic 8 (3.0) 6 (3.9) Bleeding symptoms, N (%) Prolonged 46 (17.1) 22 (14.5) Frequent 4 (1.5) 2 (1.3) Excessive 227 (84.4) 136 (89.5) Data are presented as mean ± standard deviation unless otherwise stated Some participants had more than one bleeding symptom 10

11 Women (%) Complete response rate % (95% CI %) p< Intention-to-treat (ITT) population excluding patients with missing data CI, confidence interval E 2 V/DNG (N=188) 2.7% (95% CI %) Placebo (N=110) 11

12 Median MBL (ml) Median MBL per cycle Placebo E 2 V/DNG 20 0 Baseline Cycle ITT population For comparative purposes, baseline was calculated as one-third of the median MBL during the 90-day run-in phase p< for the reduction in MBL between the run-in and efficacy phases 12

13 Median MBL (ml) Median MBL volume per cycle: non-responders Baseline 1 Placebo E 2 V/DNG Cycle Non-responders were those women who did not fulfil all of the criteria for a complete response For comparative purposes, baseline was calculated as one-third of the median MBL during the 90-day run-in phase 13

14 Mean change in MBL volume over 90 days Mean change in MBL volume (ml) E 2 V/DNG (N=187) 414 ml Placebo (N=106) 109 ml 500 p< ITT population Represents change from the 90-day run-in phase to the 90-day efficacy phase 14

15 Median MBL volume (ml) Median absolute MBL over 90 days % reduction p< % reduction ml 494 ml 434 ml ml 0 Run-in phase E 2 V/DNG Efficacy phase Run-in phase Placebo Efficacy phase ITT population 15

16 Women with MBL of 80 ml or more (%) Proportion of women with heavy bleeding episodes of 80 ml or more % 91.8% 93.6% % 20 0 Run-in phase E 2 V/DNG Efficacy phase Run-in phase Placebo Efficacy phase ITT population 16

17 Iron metabolism Adjusted mean change at day 196 Haemoglobin, g/dl Haematocrit, % Ferritin, ng/ml E 2 V/DNG Placebo N=245 N= ± ± 1.0 N=244 N= ± ± 3.1 N=249 N= ± ± 12.2 Data are presented as mean ± standard deviation unless otherwise stated Adjusted mean difference: E 2 V/DNG placebo (95% CI) P-value +0.5 ( ) p< ( ) p= ( ) p< ITT population 17

18 Conclusions E 2 V/DNG is an effective treatment in women with HPMB without recognizable organic pathology; E 2 V/DNG restored a completely normal menstrual bleeding pattern in a high proportion of subjects (42.0%) The difference versus placebo was highly significant A large, rapid and sustained reduction in MBL (76.2%) was demonstrated in women who received E 2 V/DNG and was associated with improvements in iron metabolism parameters This reduction in MBL appears to be greater than with other combined oral contraceptives 18

19 THANK YOU!