LCS12 vs Combined Oral Contraceptive (COC) User Satisfaction Study

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate user satisfaction and tolerability in young women (18-29 years of age) using the LCS12 compared with young women using a COC (Yasmin) over a period of 18 months. Subjects in the LCS12 arm will be offered continued use of LCS12 for the full, intended duration of use (up to 3 years) by continuing in a optional, extension phase. Safety data only will be collected during the extension phase of the study. Secondary objectives are to observe the tolerability, discontinuation rates, adverse event profiles, occurrences of unintended pregnancies (including calculation of Pearl Index [PI]), and bleeding profiles with the two birth-control methods. Additionally, data on missed tablets in the combined oral contraceptive (COC) group, and intrauterine delivery system (IUS) expulsions in the LCS12 group will be recorded. In the LCS12 group, physician satisfaction with the IUS inserter, evaluation of the visibility and texture of the removal threads, and evaluation of the visibility of the LCS12 on ultrasound (in a subset of subjects) will be collected. Finally, in the COC group, information will be collected on the psychosocial impact of missed or delayed pill intake.

Official Title
-----------------
Multicenter, Randomized, Open-label, Parallel-group Study to Evaluate User Satisfaction With and Tolerability of the Low-dose Levonorgestrel (LNG) Intrauterine Delivery System (IUS) With 12 µg LNG/Day Initial in Vitro Release Rate (LCS12) in Comparison to a Combined Oral Contraceptive Containing 30 µg Ethinyl Estradiol and 3 mg Drospirenone (Yasmin®) in Young Women (18-29 Years) Over 18 Months of Use

Conditions
-----------------
Contraception

Intervention / Treatment
-----------------
* Drug: Levonorgestrel IUD (LCS, BAY86-5028)
* Drug: Yasmin (EE30/DRSP, BAY86-5131)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has signed and dated the Informed Consent Form (ICF). The subject is generally healthy, requesting contraception, and is between 18 and 29 years of age (inclusive) at Screening. In the opinion of the investigator, the subject is in good health; without uterine conditions that would preempt insertion of LCS12; without conditions/history that would contraindicate the use of oral contraceptives. Subject has normal or clinically insignificant cervical smear (ie, one that does not require further follow up). A cervical smear must be taken at the Screening Visit or a documented normal result has to have been obtained within 6 months of Screening. Subjects with atypical squamous cells of undetermined significance (ASCUS) can be included in the study if they have a Human Papilloma Virus (HPV) deoxyribonucleic acid (DNA) test that, according to the standards of the local laboratory, is negative for high-risk HPV. As determined by subject's history, subject has regular (ie, endogenous cyclicity without hormonal contraceptive use) menstrual cycles (length of cycle 21-35 days). Subject is willing and able to attend the scheduled study visits and to comply with the study procedures. Exclusion Criteria: Pregnancy or current lactation (less than 6 weeks since vaginal or Cesarean delivery or abortion). Note: Postpartum LCS12 insertions should be postponed until the uterus is fully involuted, and not earlier than 6 weeks after delivery. If involution is substantially delayed, the investigator should consider waiting until 12 weeks postpartum. Infected abortion or postpartum endometritis within 3 months prior to the Screening Visit (Visit 1) Chronic, daily use of drugs that may increase serum potassium levels, such as nonsteroidal anti-inflammatory drugs (NSAIDs, eg. ibuprofen and naproxen), potassium-sparing diuretics (eg. spironolactone), potassium supplementation, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, aldosterone antagonists, and heparin. Abnormal uterine bleeding of unknown origin/undiagnosed abnormal genital bleeding Any genital infection (until successfully treated) Abnormal cervical smear result (see inclusion criteria) Acute, current or history of recurrent pelvic inflammatory disease Congenital or acquired uterine anomaly or any distortion of the uterine cavity (eg, by fibroids) that, in the opinion of the investigator, would cause problems during insertion, retention, or removal of LCS12.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 29 Years

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCS12 (Skyla, BAY86-5028)<br>Participants received LCS12 (low dose levonorgestrel [LNG] intrauterine delivery system [IUS]) with an initial in vitro release rate of 12 μg LNG per day for 18 months with optional extension to 36 months | Drug: Levonorgestrel IUD (LCS, BAY86-5028)<br>* LCS12 insertion will occur at randomization visit (Visit 2). Duration of study treatment is 18 months with optional extension to 36 months for subjects in this group only.<br>|
| Active Comparator: EE30/DRSP (Yasmin, BAY86-5131)<br>Participants received combined oral contraceptive (COC) tablet Yasmin containing 30 μg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP) for 18 months/19 cycles | Drug: Yasmin (EE30/DRSP, BAY86-5131)<br>* Combined oral contraceptive (COC; Yasmin; 0.03 mg ethinyl estradiol and 3 mg drospirenone); Subjects will start taking COC at / on the day of visit 2 and continue taking one pill / day without any breaks for the entire study duration of 18 months.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Satisfaction Rate at 18 Months (Last Observation Carried Forward, LOCF) | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Satisfaction Rating by the 5-point Likert Item at 6 Months | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 6 months | 
| Overall Satisfaction Rating by the 5-point Likert Item at 12 Months | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 12 months | 
| Overall Satisfaction Rating by the 5-point Likert Item at 18 Months | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 18 months | 
| Overall Satisfaction Rating by the 5-point Likert Item at End of Study (EOS) | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| Overall Satisfaction Rate at 6 Months (LOCF) | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 6 months | 
| Overall Satisfaction Rate at 12 Months (LOCF) | Satisfaction was to be assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied The overall satisfaction rate was to be the percentage of subjects selecting 1. Very satisfied or 2. Satisfied for the above question. | At 12 months | 
| User Satisfaction - Acceptability of the Administration of Study Treatment | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Choices Upon Completion of the Study | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Amount of Menstrual Bleeding | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Satisfaction With Menstrual Bleeding Pattern | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Frequency of Experiencing Unexpected Bleeding | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Satisfaction With Menstrual Bleeding Absence | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Comparison of Menstrual Pain Intensity Between Now and Before Treatment | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| User Satisfaction - Rating of Usual Menstrual Pain Intensity | The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| EVAPIL-R Scores at Screening - Composite Score | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, with higher values indicating more severe symptoms/less tolerability. | At screening | 
| EVAPIL-R Scores at Screening - Bother Score | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, , with higher values indicating more severe symptoms/less tolerability. | At screening | 
| EVAPIL-R Scores at 6 Months | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, with higher values indicating more severe symptoms/less tolerability. | At 6 months | 
| EVAPIL-R Scores at 12 Months - Bother Score | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, with higher values indicating more severe symptoms/less tolerability. | At 12 months | 
| EVAPIL-R Scores at 12 Months - Composite Score | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, with higher values indicating more severe symptoms/less tolerability. | At 12 months | 
| EVAPIL-R Scores at 18 Months/EOS | The EVAPIL-R scale is a self-questionnaire aimed to assess tolerability of oral contraceptives. A composite score was derived from 16 items and the ratings for presence/absence (rated as 1/0), frequency (rated with values from 0 to 2), intensity (rated from 1 to 3) and bother (rated from 1 to 4) for each item. To calculate the composite score, the bother rating of each item was multiplied by an item- specific multiplier and a weight. Range is 0-12, with higher values indicating more severe symptoms/less tolerability. The 18-month Treatment Visit served as the End-of-Study (EOS) Visit for participant in the COC group and LCS12 participant who did not enter the Extension Phase. | At 18 months/EOS | 
| Cumulative Drop-out Rate | The drop-out rate is the amount of participants that could not complete the study for various reasons. Discontinuation rates due to the following reasons and overall discontinuations were calculated: • LCS12 expulsions • Bleeding pattern alterations • Bleeding pattern alterations with increased bleeding (amount) • Bleeding pattern alterations with decreased bleeding (amount) • Adverse Events The analyses described above were also done by parity. Furthermore, overall discontinuation rates were analyzed by Kaplan-Meier analyses and presented as cumulative half-yearly drop-out rates. | Up to 6, 12, 18, 24 and 36 months | 
| Pearl Index (PI) | The Pearl Index was defined as the number of pregnancies per 100 woman years (WYs). Given the assumption that the number of pregnancies follows a Poisson distribution, the Pearl Index thus is the mean of this distribution. | Up to 18, 24, 36 months | 
| Compliance Rate for Yasmin Pill Intake |  | Up to 18 months | 
| User Satisfaction - Acceptability of the Administration of Study Treatment | The degree of user satisfaction was assessed at the end-of-study visit using an eight item questionnaire. One of the items assessed was acceptability of study treatment which was categorized into the following: acceptable without I/D, acceptable with some I/D, not acceptable with moderate I/D, and not acceptable with extreme I/D. | At 6 months | 
| User Satisfaction - Acceptability of the Administration of Study Treatment | The degree of user satisfaction was assessed at the end-of-study visit using an eight item questionnaire. One of the items assessed was acceptability of study treatment which was categorized into the following: acceptable without I/D, acceptable with some I/D, not acceptable with moderate I/D, and not acceptable with extreme I/D. | At 12 months |