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Dose-finding Study for the Ultralow-dose Levonorgestrel Intrauterine Contraceptive System (LCS)

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ClinicalTrials.gov Identifier: NCT00185380
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : March 10, 2010
Last Update Posted : June 10, 2015
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Participant);   Primary Purpose: Prevention
Condition Contraception
Interventions Drug: Levonorgestrel IUS (BAY86-5028, G04209B)
Drug: Levonorgestrel IUS (BAY86-5028, G04209C)
Drug: Levonorgestrel IUS (Mirena, BAY86-5028)
Enrollment 742
Recruitment Details Parous or nulliparous women in good general health and in need of contraception were recruited from medical clinics between April and Nov 2005.
Pre-assignment Details Most screening failures were in-/exclusion criteria not met and over-screening. Randomized: 742 women, Treated: 738 women. Full analysis set (FAS), safety analysis set (SAF) and per protocol analysis set (PPS) were identical (738 subjects).
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Period Title: Overall Study
Started 240 246 256
Subjects Received Treatment 239 245 254
Completed 174 174 182
Not Completed 66 72 74
Reason Not Completed
Adverse Event             41             43             48
Lost to Follow-up             0             4             3
Pregnancy             1             4             0
Protocol Violation             2             2             1
Withdrawal by Subject             1             2             0
Failed insertion             1             1             2
Planned pregnancy             9             12             12
No need for contraception             3             3             3
Could not attend visits             2             0             4
personal reason             6             1             1
Arm/Group Title LCS12 LCS16 IUS20 (Mirena) Total
Hide Arm/Group Description Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro Total of all reporting groups
Overall Number of Baseline Participants 239 245 254 738
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 239 participants 245 participants 254 participants 738 participants
32.2  (5.44) 32.1  (5.31) 32.0  (5.21) 32.1  (5.31)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 239 participants 245 participants 254 participants 738 participants
Female
239
 100.0%
245
 100.0%
254
 100.0%
738
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Whilst 742 subjects were randomized, only 738 were treated.
1.Primary Outcome
Title Pearl Index
Hide Description The Pearl Index (PI) is defined as the number of pregnancies per 100 woman years. The 3-year PI was obtained by dividing the number of pregnancies that occurred during the first three years of treatment by the time (in 100 women years) that the women were under risk of getting pregnant.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized women with a successful insertion were analyzed according to the treatment actually received and were included in the FAS, which was the set used for all safety and efficacy analyses. The PPS was identical to the FAS.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 239 245 254
Median (95% Confidence Interval)
Unit of Measure: Number per 100 women years
0.17
(0.00 to 0.93)
0.82
(0.27 to 1.92)
0.00
(0.00 to 0.59)
2.Secondary Outcome
Title Number of Subjects With Total or Partial Expulsions
Hide Description The numbers of subjects with partial or total IUS expulsions (device displaced from its correct position within the uterus) were to be given by treatment.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects who had an IUS inserted).
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 239 245 254
Measure Type: Number
Unit of Measure: participants
total expulsion 0 3 0
partial expulsion 1 2 4
3.Secondary Outcome
Title Bleeding Pattern by 90-day Reference Periods - Reference Period 1
Hide Description Subjects kept a bleeding diary and recorded any bleeding every day by category: none, spotting, light, normal or heavy. Any missing data were obtained by direct questioning.
Time Frame day 1 to day 90
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects with an insertion) and included subjects with bleeding or spotting or both.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 228 241 244
Mean (Standard Deviation)
Unit of Measure: days
Number of bleeding days (light, normal or heavy) 15.1  (10.1) 15.4  (12.2) 14.3  (12.9)
Number of bleeding/spotting days 39.9  (18.7) 39.2  (19.7) 36.6  (19.8)
Number of spotting only days 24.8  (14.1) 23.8  (12.9) 22.2  (13.5)
4.Secondary Outcome
Title Bleeding Pattern by 90-day Reference Periods - Reference Period 2
Hide Description Subjects kept a bleeding diary and recorded any bleeding every day by category: none, spotting, light, normal or heavy. Any missing data were obtained by direct questioning.
Time Frame day 91 to day 180
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects with an insertion) and included subjects with bleeding or spotting or both.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 225 230 239
Mean (Standard Deviation)
Unit of Measure: days
Number of bleeding days (light, normal or heavy) 8.2  (8.0) 7.7  (8.0) 7.6  (9.1)
Number of bleeding/spotting days 22.6  (14.3) 21.8  (14.3) 21.8  (16.8)
Number of spotting only days 14.4  (10.3) 14.1  (9.8) 14.2  (11.5)
5.Secondary Outcome
Title Bleeding Pattern by 90-day Reference Periods - Reference Period 3
Hide Description Subjects kept a bleeding diary and recorded any bleeding every day by category: none, spotting, light, normal or heavy. Any missing data were obtained by direct questioning.
Time Frame day 181 to day 270
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects with an insertion) and included subjects with bleeding or spotting or both.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 220 224 230
Mean (Standard Deviation)
Unit of Measure: days
Number of bleeding days (light, normal or heavy) 6.4  (7.3) 5.4  (6.9) 5.3  (7.3)
Number of bleeding/spotting days 18.3  (12.9) 16.7  (12.6) 16.8  (14.2)
Number of spotting only days 12.0  (9.3) 11.3  (8.4) 11.5  (9.5)
6.Secondary Outcome
Title Bleeding Pattern by 90-day Reference Periods - Reference Period 4
Hide Description Subjects kept a bleeding diary and recorded any bleeding every day by category: none, spotting, light, normal or heavy. Any missing data were obtained by direct questioning.
Time Frame day 271 to day 360
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects with an insertion) and included subjects with bleeding or spotting or both.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 217 218 225
Mean (Standard Deviation)
Unit of Measure: days
Number of bleeding days (light, normal or heavy) 5.5  (6.7) 4.7  (6.4) 4.2  (6.3)
Number of bleeding/spotting days 16.7  (11.4) 15.0  (11.6) 15.2  (12.3)
Number of spotting only days 11.2  (8.5) 10.2  (7.9) 11.0  (9.2)
7.Secondary Outcome
Title Bleeding Pattern by 90-day Reference Periods - Reference Period 12
Hide Description Subjects kept a bleeding diary and recorded any bleeding every day by category: none, spotting, light, normal or heavy. Any missing data were obtained by direct questioning.
Time Frame day 991 to day 1080
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed on the FAS (all subjects with an insertion) and included subjects with bleeding or spotting or both.
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description:
Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro
Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro
Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
Overall Number of Participants Analyzed 165 169 178
Mean (Standard Deviation)
Unit of Measure: days
Number of bleeding days (light, normal or heavy) 3.6  (6.0) 3.0  (4.5) 1.9  (3.6)
Number of bleeding/spotting days 12.8  (10.7) 10.6  (9.3) 8.8  (8.6)
Number of spotting only days 9.2  (8.4) 7.7  (6.9) 6.9  (6.7)
Time Frame [Not Specified]
Adverse Event Reporting Description An additional pregnancy was not recorded as an SAE.
 
Arm/Group Title LCS12 LCS16 IUS20 (Mirena)
Hide Arm/Group Description Levonorgestrel intrauterine contraceptive system (LCS) releasing 12 microg/24h in vitro Levonorgestrel intrauterine contraceptive system (LCS) releasing 16 microg/24h in vitro Levonorgestrel intrauterine system (IUS) releasing 20 microg/24h in vitro
All-Cause Mortality
LCS12 LCS16 IUS20 (Mirena)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
LCS12 LCS16 IUS20 (Mirena)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   12/239 (5.02%)   12/245 (4.90%)   16/254 (6.30%) 
Endocrine disorders       
Goitre * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Eye disorders       
Blindness unilateral * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Gastrointestinal disorders       
Abdominal pain * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Gastroduodenal ulcer * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Gastrooesophageal reflux disease * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Vomiting * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
General disorders       
Chest pain * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Hernia obstructive * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Hepatobiliary disorders       
Biliary dyskinesia * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Cholecystitis * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Cholecystitis chronic * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Infections and infestations       
Appendicitis * 1  0/239 (0.00%)  1/245 (0.41%)  2/254 (0.79%) 
Cervicitis * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Clostridium difficile colitis * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Encephalitis herpes * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Pelvic inflammatory disease * 1  0/239 (0.00%)  1/245 (0.41%)  1/254 (0.39%) 
Pneumonia * 1  1/239 (0.42%)  1/245 (0.41%)  0/254 (0.00%) 
Post procedural infection * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Pyelonephritis * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Injury, poisoning and procedural complications       
Brain contusion * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Post procedural haematoma * 1  1/239 (0.42%)  0/245 (0.00%)  1/254 (0.39%) 
Post procedural haemorrhage * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Road traffic accident * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Skull fractured base * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Subdural haematoma * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Traumatic intracranial haemorrhage * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Investigations       
Body temperature increased * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Musculoskeletal and connective tissue disorders       
Arthritis reactive * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Intervertebral disc protrusion * 1  0/239 (0.00%)  1/245 (0.41%)  1/254 (0.39%) 
Rotator cuff syndrome * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Benign breast neoplasm * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Leiomyoma * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Malignant melanoma * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Ovarian germ cell teratoma benign * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Phaeochromocytoma * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Nervous system disorders       
Paraesthesia * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Post-traumatic epilepsy * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Pregnancy, puerperium and perinatal conditions       
Abortion spontaneous * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Ectopic pregnancy * 1  1/239 (0.42%)  2/245 (0.82%)  0/254 (0.00%) 
Pregnancy * 1  0/239 (0.00%)  1/245 (0.41%)  0/254 (0.00%) 
Psychiatric disorders       
Alcohol abuse * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Reproductive system and breast disorders       
Cervical dysplasia * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Ovarian cyst * 1  0/239 (0.00%)  0/245 (0.00%)  5/254 (1.97%) 
Vaginal haemorrhage * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea * 1  0/239 (0.00%)  1/245 (0.41%)  1/254 (0.39%) 
Surgical and medical procedures       
Abdominal hernia repair * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Adhesiolysis * 1  1/239 (0.42%)  0/245 (0.00%)  0/254 (0.00%) 
Knee arthroplasty * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
Mammoplasty * 1  0/239 (0.00%)  0/245 (0.00%)  1/254 (0.39%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (11.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LCS12 LCS16 IUS20 (Mirena)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   187/239 (78.24%)   198/245 (80.82%)   218/254 (85.83%) 
Gastrointestinal disorders       
Abdominal distension * 1  40/239 (16.74%)  49/245 (20.00%)  50/254 (19.69%) 
Abdominal pain * 1  19/239 (7.95%)  19/245 (7.76%)  23/254 (9.06%) 
Nausea * 1  18/239 (7.53%)  20/245 (8.16%)  22/254 (8.66%) 
Abdominal pain lower * 1  16/239 (6.69%)  19/245 (7.76%)  21/254 (8.27%) 
General disorders       
Oedema * 1  15/239 (6.28%)  21/245 (8.57%)  19/254 (7.48%) 
Infections and infestations       
Vulvovaginal candidiasis * 1  23/239 (9.62%)  30/245 (12.24%)  21/254 (8.27%) 
Sinusitis * 1  16/239 (6.69%)  20/245 (8.16%)  22/254 (8.66%) 
Influenza * 1  14/239 (5.86%)  22/245 (8.98%)  20/254 (7.87%) 
Urinary tract infection * 1  22/239 (9.21%)  18/245 (7.35%)  13/254 (5.12%) 
Vaginal infection * 1  14/239 (5.86%)  11/245 (4.49%)  21/254 (8.27%) 
Nasopharyngitis * 1  14/239 (5.86%)  13/245 (5.31%)  18/254 (7.09%) 
Bronchitis * 1  8/239 (3.35%)  7/245 (2.86%)  16/254 (6.30%) 
Vaginitis bacterial * 1  12/239 (5.02%)  9/245 (3.67%)  8/254 (3.15%) 
Injury, poisoning and procedural complications       
Procedural pain * 1  18/239 (7.53%)  21/245 (8.57%)  24/254 (9.45%) 
Investigations       
Weight increased * 1  38/239 (15.90%)  39/245 (15.92%)  31/254 (12.20%) 
Musculoskeletal and connective tissue disorders       
Back pain * 1  18/239 (7.53%)  14/245 (5.71%)  23/254 (9.06%) 
Nervous system disorders       
Headache * 1  63/239 (26.36%)  63/245 (25.71%)  82/254 (32.28%) 
Psychiatric disorders       
Mood altered * 1  43/239 (17.99%)  30/245 (12.24%)  38/254 (14.96%) 
Depression * 1  13/239 (5.44%)  6/245 (2.45%)  10/254 (3.94%) 
Reproductive system and breast disorders       
Breast discomfort * 1  52/239 (21.76%)  51/245 (20.82%)  62/254 (24.41%) 
Ovarian cyst * 1  21/239 (8.79%)  24/245 (9.80%)  60/254 (23.62%) 
Breast pain * 1  20/239 (8.37%)  35/245 (14.29%)  27/254 (10.63%) 
Dysmenorrhoea * 1  14/239 (5.86%)  19/245 (7.76%)  18/254 (7.09%) 
Skin and subcutaneous tissue disorders       
Acne * 1  64/239 (26.78%)  61/245 (24.90%)  73/254 (28.74%) 
Seborrhoea * 1  16/239 (6.69%)  18/245 (7.35%)  21/254 (8.27%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (11.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The sponsor is interested in the publication of the results of every study. As some of the information concerning the study drug and the sponsor's development activities may be strictly confidential, any publication manuscript (including conference contributions, etc.) must first be reviewed by the sponsor before its submission or presentation.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: BAYER
EMail: clinical-trials-contact@bayerhealthcare.com
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00185380     History of Changes
Other Study ID Numbers: 91412
2004-002291-42 ( EudraCT Number )
308901 ( Other Identifier: Company internal )
First Submitted: September 13, 2005
First Posted: September 16, 2005
Results First Submitted: December 10, 2009
Results First Posted: March 10, 2010
Last Update Posted: June 10, 2015