alexander teichmann, md, phd 1 1 frauenklinik, klinikum aschaffenburg, aschaffenburg, germany
DESCRIPTION
Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive, Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive. Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany. - PowerPoint PPT PresentationTRANSCRIPT
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Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive,
Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive
Alexander Teichmann, MD, PhD1
1Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany.
On behalf of:Cornelis Kluft, PhD2; Gary Grubb, MD, MPH3;
Ginger Constantine, MD3; Daniele Spielmann, MD, MSc4
2Gaubius Laboratory, TNO Quality of Life, Biomedical Research, Leiden, The Netherlands; 3Research Headquarters, Wyeth Research,
Collegeville, PA, USA; 4Wyeth Research, Paris, France.
Study funded by Wyeth Research, Collegeville, PA, USA.
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Continuous LNG/EE
• Continuous levonorgestrel (LNG)/ethinyl estradiol (EE) is taken every day, 365 days a year, without a hormone-free interval
– Elimination of the hormone-free interval may reduce the total number of bleeding days
• Contains LNG (90 µg) and EE (20 µg) at the lowest combination of doses currently available in the United States
– Because of the low dose, the yearly cumulative hormone exposure is lower than that for many cyclic or extended-use oral contraceptives (OCs)
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Study Objectives
• Primary objective
– To evaluate the contraceptive efficacy of continuous LNG/EE
• Secondary objective
– To compare continuous LNG/EE to a similarly formulated 21/7 cyclic OC (LNG 100 µg/EE 20 µg) with respect to vaginal bleeding, safety, and metabolic effects
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Study Design
• Phase III, randomized, open-label, 1-year study conducted at 44 sites in Europe
– Czech Republic, Finland, Germany, Hungary, Italy, The Netherlands, Norway, Poland
• Women were randomly assigned to take 13 pill packs of either continuous LNG/EE or the LNG 100/EE 20, cyclic 21/7-day OC
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Key Inclusion Criteria
• Healthy women aged 18 to 49 years who were sexually active and willing to rely on a combination OC as their only means of contraception
• Regular (21- to 35-day) menstrual cycles in the previous 3 months
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Key Exclusion Criteria
• Standard OC contraindications
• 34 years of age and smoking 15 cigarettes per day
• Use of Depo-Provera within 10 months of screening
• Use of any of the following within 60 days of screening:– Intrauterine device, implantable contraceptive, or Lunelle
– Hepatic enzyme-inducing drugs
– Experimental drugs
– Noncontraceptive estrogens, progestins, or androgens
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Study Procedures
• Women were instructed to begin taking the study drug on the first day of their menstrual bleeding
• Women recorded vaginal bleeding and adverse events (AEs) on daily diary cards
• Bleeding terms were defined according to the World Health Organization
– Bleeding: required sanitary protection
– Spotting: bleeding that did not require sanitary protection
– Amenorrhea: no bleeding or spotting
• A subset of women who met predetermined criteria were also screened for 4 metabolic panels
– Included carbohydrate, fasting lipid, hemostasis, and bone maker panels
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Subject DispositionSubjects randomly assigned to a
treatment group N = 651
Continuous LNG/EEn = 328
LNG 100/EE 20cyclic 21/7-day OC n = 323
No drug takenn = 5 Took 1 dose of study drug
n = 641
No drug takenn = 5
Continuous LNG/EEn = 323
LNG 100/EE 20cyclic 21/7-day OC n =
318
Completed continuous LNG/EE arm
n = 216
Discontinuationsn = 69
Discontinuationsn = 107
Completed LNG 100/EE 20
cyclic 21/7-day OC arm n = 249
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Discontinuations
ReasonContinuous
LNG/EE, n (%)
LNG 100/EE 20 cyclic 21/7-day OC,
n (%)P value
Total 107 (33.1) 69 (21.7) 0.001
Accidental pregnancy 0 (0.0) 3 (0.9) 0.122
Investigator request 1 (0.3) 2 (0.6) 0.621
Lost to follow-up 5 (1.5) 2 (0.6) 0.451
Planning pregnancy 3 (0.9) 3 (0.9) 1.000
Protocol violation 9 (2.8) 11 (3.5) 0.656
AEs 72 (22.3) 31 (9.7) <0.001
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Contraceptive Efficacy
• There were no on-treatment pregnancies among women in the continuous LNG/EE group
• Women in the LNG 100/EE 20, cyclic 21/7-day OC group had 3 on-treatment pregnancies
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Bleeding Profile for the Continuous LNG/EE Group
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10 11 12 13
Pill pack of continuous LNG/EE
Per
cen
tag
e o
f w
om
en
Amenorrhea Spotting only Bleeding +/- spotting
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Median Number of Total Bleeding/Spotting Days
0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10 11 12 13
Pill pack
Nu
mb
er
of
da
ys
Continuous LNG/EE
LNG 100/EE 20, cyclic 21/7-day OC
13
Median Number of Bleeding and Spotting Days for Continuous LNG/EE
048
1216202428
1 2 3 4 5 6 7 8 9 10 11 12 13
Pill pack
Nu
mb
er o
f d
ays
Median number of bleeding days
Median number of spotting days
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Bleeding Summary
• For continuous LNG/EE, the percentage of women achieving amenorrhea generally increased with each pill pack to 53% at pill pack 13
• The median number of bleeding/spotting days decreased over time for both study groups
– The median number of unscheduled bleeding days was 0 for pill pack 2 to 13 for continuous LNG/EE
– Median number of spotting days was 0 for pill packs 8 to 13 for continuous LNG/EE
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Adverse Events
Continuous LNG/EE, n (%)
LNG 100/EE 20, cyclic 21/7-day OC,
n (%)
Total treatment-emergent AEs
282 (87.3) 270 (84.9)
Discontinuations due to AEs
72 (22.3) 31 (9.7)
Total serious AEs 6 (1.8) 12 (3.8)
Serious AEs related to drug
1 (0.3) 2 (0.6)
Type of serious AE 1 Cervical dysplasia1 Ovarian cyst,
1 depression
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Most Common Treatment Emergent AEs (5% of Patients)
0
10
20
30
40
50
Headac
he
Abdom
inal
pai
n
Met
rorrh
agia
Dysm
enorrh
ea
Nau
sea
Bac
k pai
nAcn
e
Vagin
al h
emorrh
age
Pe
rce
nta
ge
of
su
bje
cts
Continuous LNG/EE LNG 100/EE 20 cyclic 21/7-day OC
*
*
* P <0.05
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Differences in Treatment Emergent AEs Based on Mid-point Analyses
Vaginalbleeding*
Breastpain
Nausea
Pill packs 1 to 6
Continuous LNG/EE 105 (32.5) 22 (6.8) 23 (7.1)
LNG 100/EE 20 cyclic 21/7-day OC 38 (11.9) 22 (6.9) 31 (9.7)
P value <0.001 1.000 0.257
Pill packs 7 to 13
Continuous LNG/EE 41 (15.8) 2 (0.8) 7 (2.7)
LNG 100/EE 20 cyclic 21/7-day OC 29 (10.4) 13 (4.6) 20 (7.1)
P value 0.073 0.007 0.018
*Vaginal bleeding is a combination of COSTART terms metrorrhagia, menorrhagia, and vaginal and uterine hemorrhage.
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Mean Change in Body Weight
Continuous LNG/EE
LNG 100/EE 20 cyclic 21/7-day
OC
Mean weight at baseline, kg 63.5 64.2
Mean change from baseline at post-treatment, kg
+0.56* +0.39
Pairwise P value at post-treatment
0.516
*P <0.01 vs. baseline.
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Mean Change From Baseline in Blood Pressure
Continuous LNG/EE LNG 100/EE 20 cyclic 21/7-day OC
Pill pack 3
Post-treatment
Pill pack 3
Post-treatment
Systolic, mmHg 0.57 -0.96 0.28 0.17
Diastolic, mmHg 0.39 0.07 0.11 1.10*
*P <0.05 vs baseline.All pairwise P values not significant.
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Cervical Smear Results
Satisfactory for evaluation
Total epithelial cell
abnormalities— squamous cell,
n (%) ASCUS
Low grade
SIL
High grade
SIL
Pill pack 7
Continuous LNG/EE, n
226 20 (8.8%) 5 12 3
LNG 100/EE 20 cyclic 21/7 day OC, n
250 11 (4.4%) 3 6 2
Post-study
Continuous LNG/EE, n
246 10 (4.0%) 5 5 0
LNG 100/EE 20 cyclic 21/7 day OC, n
245 15 (6.1%) 7 5 3
ASCUS, atypical squamous cells of undetermined significance; SIL, squamous intraepithelial lesions.
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Safety Summary
• There was no statistical difference in the total number of AEs reported by each study group– Significantly more women reported metrorrhagia
(P <0.001) and vaginal hemorrhage (P = 0.011) in the continuous LNG/EE group
• The bleeding-related treatment-emergent AEs that were initially significantly higher for continuous LNG/EE in pill packs 1 to 6 were no longer different by pill packs 7 to 13
• During pill packs 7 to 13, women in the continuous LNG/EE group reported significantly less breast pain and nausea than the LNG 100/EE 20 cyclic 21/7-day OC group
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Summary of Metabolic Substudy
• Twenty-nine metabolic parameters were assessed and 20 were not significantly different between study groups
• Those that were statistically significantly different were not deemed clinically important
• These results have been presented elsewhere
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Summary and Conclusions
• Continuous LNG/EE demonstrated a similar safety profile to an established 21/7-day cyclic OC
• Over time, continuous LNG/EE offered women the ability to achieve amenorrhea and reduce the number of bleeding days
• Continuous LNG/EE did not demonstrate clinically important differences compared to the LNG 100/EE 20 cyclic 21/7-day OC in metabolic parameters commonly affected by OCs
• There were no on-treatment pregnancies in the continuous LNG/EE group and 3 in the LNG 100/EE 20 cyclic 21/7-day OC group