Download Continuous LNG/EE, n

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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 Disposition
Subjects randomly assigned to a
treatment group N = 651
Continuous LNG/EE
n = 328
No drug taken
n=5
LNG 100/EE 20
cyclic 21/7-day OC n = 323
Took 1 dose of study drug
n = 641
Continuous LNG/EE
n = 323
No drug taken
n=5
LNG 100/EE 20
cyclic 21/7-day OC n = 318
Discontinuations
n = 69
Discontinuations
n = 107
Completed
continuous
LNG/EE arm
n = 216
Completed
LNG 100/EE 20
cyclic 21/7-day OC arm
n = 249
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Discontinuations
Continuous
LNG/EE, n (%)
LNG 100/EE 20
cyclic 21/7-day OC,
n (%)
P value
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
72 (22.3)
31 (9.7)
<0.001
Reason
Total
AEs
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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
Percentage of women
Amenorrhea
Spotting only
Bleeding +/- spotting
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9 10 11 12 13
Pill pack of continuous LNG/EE
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Median Number of
Total Bleeding/Spotting Days
Number of days
Continuous LNG/EE
LNG 100/EE 20, cyclic 21/7-day OC
10
8
6
4
2
0
1
2
3
4
5
6
7
8
Pill pack
9 10 11 12 13
13
Number of days
Median Number of Bleeding and
Spotting Days for Continuous LNG/EE
28
24
20
16
12
8
4
0
Median number of bleeding days
Median number of spotting days
1 2 3 4
5 6 7 8 9 10 11 12 13
Pill pack
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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 treatmentemergent 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)
1 Cervical dysplasia
1 Ovarian cyst,
1 depression
Type of serious AE
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Most Common Treatment Emergent AEs
(5% of Patients)
LNG 100/EE 20 cyclic 21/7-day OC
50
* P <0.05
40
30
*
20
*
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Percentage of subjects
Continuous LNG/EE
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Differences in Treatment Emergent AEs
Based on Mid-point Analyses
Vaginal
bleeding*
Breast
pain
Nausea
105 (32.5)
22 (6.8)
23 (7.1)
38 (11.9)
22 (6.9)
31 (9.7)
<0.001
1.000
0.257
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)
0.073
0.007
0.018
Pill packs 1 to 6
Continuous LNG/EE
LNG 100/EE 20 cyclic 21/7-day OC
P value
Pill packs 7 to 13
P value
*Vaginal bleeding is a combination of COSTART terms metrorrhagia, menorrhagia,
and vaginal and uterine hemorrhage.
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Mean Change in Body Weight
Mean weight at baseline, kg
Mean change from baseline
at post-treatment, kg
Pairwise P value at posttreatment
*P <0.01 vs. baseline.
Continuous
LNG/EE
LNG 100/EE 20
cyclic 21/7-day
OC
63.5
64.2
+0.56*
+0.39
0.516
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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
Posttreatment
Pill
pack 3
Posttreatment
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
Total epithelial
cell
abnormalities—
squamous cell,
n (%)
226
LNG 100/EE
20 cyclic 21/7
day OC, n
ASCUS
Low
grade
SIL
High
grade
SIL
20 (8.8%)
5
12
3
250
11 (4.4%)
3
6
2
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
Satisfactory
for evaluation
Pill
Continuous
pack 7 LNG/EE, n
Poststudy
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