MET: Mirena Extension Trial

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02985541
• Collaborator: (none)
• Enrollment: 364
• Locations: 49
• Arm: 1
• Actual Duration (Months): 53.2
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study is performed to assess if Mirena is effective and safe as a birth control method beyond 5 years of use. Further the menstrual blood loss (in women that had Mirena inserted for the indication heavy menstrual bleeding [HMB]) and safety will be assessed.

Condition or Disease	Intervention/Treatment	Phase
Contraception	Drug: Levonorgestrel IUS (Mirena, BAY86-5028)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 364 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multi-center, Open-label, Uncontrolled Study to Assess Contraceptive Efficacy and Safety of Mirena During Extended Use Beyond 5 Years in Women 18 to 35 Years of Age Including a Subgroup Evaluation of Treatment Effect on Heavy Menstrual Bleeding
• Actual Study Start Date: Dec 22, 2016
• Actual Primary Completion Date: May 28, 2021
• Actual Study Completion Date: May 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Levonorgestrel IUS (Mirena, BAY86-5028) Mirena during extended use (Years 6 to 8).	Drug: Levonorgestrel IUS (Mirena, BAY86-5028); Levonorgestrel (LNG) intrauterine delivery system (IUS) with an initial in vitro release rate of 20 μg levonorgestrel per day.

Outcome Measures

Primary Outcome Measures

1. Number of Pregnancies Per 100 Women Years (Pearl Index [PI]) Within Years 6 Thru 8 of Mirena Use [Years 6 to 8 of Mirena use]

   The Pearl Index (PI) is defined as the number of pregnancies per 100 women years. The 3-year PI (Years 6 to 8) was obtained by dividing the number of pregnancies the occurred during that time (starting at Day 1 Year 6 and up to Day 365 of Year 8) by the time (in 100 women years) that the women were at risk of getting pregnant during that time.

Secondary Outcome Measures

1. Menstrual Blood Loss (MBL) During a 30-day Period Starting at the Baseline Visit and at the End of Years 6, 7 and 8 [Baseline and end of Years 6, 7 and 8 of Mirena use]

   Menstrual blood loss (MBL) during a 30-day period starting at the baseline visit and at the end of Year 6, Year 7, and Year 8, measured by the alkaline hematin method. The assessment of this variable was restricted to women who had Mirena inserted for heavy menstrual bleeding (HMB).

2. Number of Participants With Menstrual Blood Loss (MBL) (>= 80 ml Per 30 Days) at End of Year 6, 7 and 8 of Mirena Use [At end of Year 6, 7 and 8 of Mirena use]

   Categorized menstrual blood loss (MBL) (≥ 80 mL per 30 days) at end of Year 6, Year 7, and Year 8. The assessment of this variable was restricted to women who had Mirena inserted for HMB.

3. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Years 6 to 8 of Mirena use]

   Adverse event (AE) was defined as any untoward medical occurrence (ie any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. Serious adverse event (SAE) was defined as any untoward medical occurrence that, at any dose 1) resulted in death, 2) was life-threatening, 3) required inpatient hospitalization or prolongation of existing hospitalization, 4) resulted in persistent or significant disability/incapacity, 5) was a congenital anomaly/birth defect, or 6) was another medically important serious event as judged by the investigator. Treatment-emergent adverse event (TEAE) was defined as an AE that occurred on Day 1 Year 6 of Mirena use or later.

Other Outcome Measures

1. Total LNG Concentrations in Plasma Estimated Based on the Final 8-year Population Pharmacokinetics (popPK) Model [At the beginning of Year 6 (baseline) and at the end of Years 6, 7, and 8 of Mirena use]

   A population pharmacokinetic (popPK) analysis was performed including sparse data from the study.

2. Participant's Satisfaction With Mirena by Visit [Baseline, at end of Year 6, 7 and 8 of Mirena use]

   Participants were asked to evaluate their satisfaction with Mirena on a 5-point scale as very satisfied, somewhat satisfied, neither satisfied or dissatisfied, dissatisfied or very dissatisfied.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed and dated informed consent

• Women, 18 to 35 years of age at the time of screening (visit 1) who are currently using Mirena for contraception or for contraception and heavy menstrual bleeding. The duration of use of the current Mirena has to be at least 4 years 6 months at the start of screening phase but not more than 5 years at visit 2 and the woman is willing to continue with its use and has a continuing need for contraception.

• Normal or clinically insignificant cervical smear not requiring further follow up

Exclusion Criteria:

• Menopausal symptoms with Follicle-stimulating hormone>30 mIU/ml

• Pregnancy or suspicion of pregnancy

• Uterine bleeding of unknown etiology

• Untreated acute cervicitis or vaginitis or other lower genital tract infections

• Increased susceptibility to pelvic infection

• Acute pelvic inflammatory disease (PID) or a history of PID unless successfully treated and which, in the investigator's opinion, has not negatively affected subject's fertility

• Congenital or acquired uterine anomaly if it distorts the uterine cavity

• History of, diagnosed or suspected genital or other malignancy and untreated cervical dysplasia

• Any active acute liver disease or liver tumor (benign or malignant)

• Clinically significant endometrial polyp(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mobile	Alabama	United States	36608-6703
2		Phoenix	Arizona	United States	85032
3		Scottsdale	Arizona	United States	85251
4		Tucson	Arizona	United States	85712
5		Encinitas	California	United States	92024
6		San Francisco	California	United States	94110
7		Ventura	California	United States	93003
8		Aurora	Colorado	United States	80045
9		Atlanta	Georgia	United States	30342
10		Idaho Falls	Idaho	United States	83404
11		Fort Wayne	Indiana	United States	46825
12		Newburgh	Indiana	United States	47630-8940
13		Frederick	Maryland	United States	21702
14		Pikesville	Maryland	United States	21208
15		Boston	Massachusetts	United States	02118
16		Saginaw	Michigan	United States	48604
17		Lincoln	Nebraska	United States	68510
18		Las Vegas	Nevada	United States	89106
19		Lebanon	New Hampshire	United States	03756-1000
20		Lawrenceville	New Jersey	United States	08648
21		Neptune	New Jersey	United States	07753
22		Albuquerque	New Mexico	United States	87109
23		New York	New York	United States	10032
24		Port Jefferson	New York	United States	11777
25		Asheville	North Carolina	United States	28801
26		Durham	North Carolina	United States	27713
27		Greensboro	North Carolina	United States	27408
28		Hickory	North Carolina	United States	28602
29		Morehead City	North Carolina	United States	28557
30		New Bern	North Carolina	United States	28562
31		Winston-Salem	North Carolina	United States	27103-1749
32		Franklin	Ohio	United States	45005-2593
33		Mayfield Heights	Ohio	United States	44124
34		Portland	Oregon	United States	97239
35		Erie	Pennsylvania	United States	16507
36		Philadelphia	Pennsylvania	United States	19104
37		Philadelphia	Pennsylvania	United States	19107
38		Chattanooga	Tennessee	United States	37404
39		Austin	Texas	United States	78758
40		Fort Worth	Texas	United States	76104-4145
41		Houston	Texas	United States	77030
42		Draper	Utah	United States	84020-7163
43		Midlothian	Virginia	United States	23114
44		North Chesterfield	Virginia	United States	23235
45		Roanoke	Virginia	United States	24013-2256
46		Virginia Beach	Virginia	United States	23456
47		Seattle	Washington	United States	98105
48		Seattle	Washington	United States	98122
49		Spokane	Washington	United States	99207-1240

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

• Study Protocol - Sep 20, 2017
• Statistical Analysis Plan - Jun 10, 2021

More Information

Additional Information:

• Click here to find results for studies related to Bayer Healthcare products.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02985541
• Other Study ID Numbers: 18649
• First Posted: Dec 7, 2016
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Birth Control; Heavy menstrual bleeding
• Additional relevant MeSH terms: Menorrhagia; Levonorgestrel

Study Results

Participant Flow

Pre-assignment Detail	A total of 364 women entered treatment period. Of these, 2 women were not valid for FAS (full analysis set)/SAF (safety analysis set)/PAS(primary analysis set) due to incomplete source data verification.

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Period Title: Overall Study
STARTED	364
Valid for FAS	362
Continued Into Year 7 of Mirena Use	305
Continued Into Year 8 of Mirena Use	243
COMPLETED	223
NOT COMPLETED	141

Baseline Characteristics

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Overall Participants	362
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.4 (3.1)
Sex: Female, Male (Count of Participants)
Female	362 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	41 11.3%
Not Hispanic or Latino	319 88.1%
Unknown or Not Reported	2 0.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.6%
Asian	9 2.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	51 14.1%
White	273 75.4%
More than one race	14 3.9%
Unknown or Not Reported	13 3.6%
Parity (Number) [Number]
Nulliparous	171 47.2%
Parous	191 52.8%

Outcome Measures

1. Primary Outcome

Title	Number of Pregnancies Per 100 Women Years (Pearl Index [PI]) Within Years 6 Thru 8 of Mirena Use
Description	The Pearl Index (PI) is defined as the number of pregnancies per 100 women years. The 3-year PI (Years 6 to 8) was obtained by dividing the number of pregnancies the occurred during that time (starting at Day 1 Year 6 and up to Day 365 of Year 8) by the time (in 100 women years) that the women were at risk of getting pregnant during that time.
Time Frame	Years 6 to 8 of Mirena use

Outcome Measure Data

Analysis Population Description

All women in the full analysis set (FAS) with an age of 33 years or younger at baseline visit (i.e. an age of 36 or younger at end of year 8).

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	346
Number (95% Confidence Interval) [Pregnancies per 100 women years]	0.28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Levonorgestrel IUS (Mirena, BAY86-5028)
	Comments	Cumulative failure rate (Kaplan-Meier) during Years 6-8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	3-year probability of getting pregnant
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.17 to 2.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Menstrual Blood Loss (MBL) During a 30-day Period Starting at the Baseline Visit and at the End of Years 6, 7 and 8
Description	Menstrual blood loss (MBL) during a 30-day period starting at the baseline visit and at the end of Year 6, Year 7, and Year 8, measured by the alkaline hematin method. The assessment of this variable was restricted to women who had Mirena inserted for heavy menstrual bleeding (HMB).
Time Frame	Baseline and end of Years 6, 7 and 8 of Mirena use

Outcome Measure Data

Analysis Population Description

Women who had Mirena inserted for HMB

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	6
Beginning of Year 6 (baseline)	0.000
End of Year 6	0.000
End of Year 7	0.000
End of Year 8	0.000

3. Secondary Outcome

Title	Number of Participants With Menstrual Blood Loss (MBL) (>= 80 ml Per 30 Days) at End of Year 6, 7 and 8 of Mirena Use
Description	Categorized menstrual blood loss (MBL) (≥ 80 mL per 30 days) at end of Year 6, Year 7, and Year 8. The assessment of this variable was restricted to women who had Mirena inserted for HMB.
Time Frame	At end of Year 6, 7 and 8 of Mirena use

Outcome Measure Data

Analysis Population Description

Women who had Mirena inserted for HMB

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	6
End of Year 6	0 0%
End of Year 7	0 0%
End of Year 8	0 0%

4. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	Adverse event (AE) was defined as any untoward medical occurrence (ie any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. Serious adverse event (SAE) was defined as any untoward medical occurrence that, at any dose 1) resulted in death, 2) was life-threatening, 3) required inpatient hospitalization or prolongation of existing hospitalization, 4) resulted in persistent or significant disability/incapacity, 5) was a congenital anomaly/birth defect, or 6) was another medically important serious event as judged by the investigator. Treatment-emergent adverse event (TEAE) was defined as an AE that occurred on Day 1 Year 6 of Mirena use or later.
Time Frame	Years 6 to 8 of Mirena use

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): All women who completed the baseline visit of the study, analyzed for the FAS.

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	362
Any AE	249 68.8%
Any SAE	14 3.9%

5. Other Pre-specified Outcome

Title	Total LNG Concentrations in Plasma Estimated Based on the Final 8-year Population Pharmacokinetics (popPK) Model
Description	A population pharmacokinetic (popPK) analysis was performed including sparse data from the study.
Time Frame	At the beginning of Year 6 (baseline) and at the end of Years 6, 7, and 8 of Mirena use

Outcome Measure Data

Analysis Population Description

Concentrations were estimated for women who had Mirena still in place.

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	361
At the beginning of Year 6 (baseline)	123 (38.3)
At the end of Year 6	114 (38.7)
At the end of Year 7	106 (39.2)
At the end of Year 8	100 (39.9)

6. Other Pre-specified Outcome

Title	Participant's Satisfaction With Mirena by Visit
Description	Participants were asked to evaluate their satisfaction with Mirena on a 5-point scale as very satisfied, somewhat satisfied, neither satisfied or dissatisfied, dissatisfied or very dissatisfied.
Time Frame	Baseline, at end of Year 6, 7 and 8 of Mirena use

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All women who completed the baseline visit of the study.

Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
Measure Participants	362
Baseline (very satisfied)	342 94.5%
Baseline (somewhat satisfied)	20 5.5%
Baseline (neither satisfied nor dissatisfied)	0 0%
Baseline (dissatisfied)	0 0%
Baseline (very dissatisfied)	0 0%
Year 6 (very satisfied)	279 77.1%
Year 6 (somewhat satisfied)	20 5.5%
Year 6 (neither satisfied nor dissatisfied)	3 0.8%
Year 6 (dissatisfied)	0 0%
Year 6 (very dissatisfied)	0 0%
Year 7 (very satisfied)	218 60.2%
Year 7 (somewhat satisfied)	20 5.5%
Year 7 (neither satisfied nor dissatisfied)	1 0.3%
Year 7 (dissatisfied)	3 0.8%
Year 7 (very dissatisfied)	1 0.3%
Year 8 (very satisfied)	207 57.2%
Year 8 (somewhat satisfied)	13 3.6%
Year 8 (neither satisfied nor dissatisfied)	3 0.8%
Year 8 (dissatisfied)	0 0%
Year 8 (very dissatisfied)	0 0%

Adverse Events

Time Frame	Years 6 to 8 of Mirena use
Arm/Group Title	Levonorgestrel IUS (Mirena, BAY86-5028)
Arm/Group Description	Mirena during extended use (Years 6 to 8).
All Cause Mortality
	Levonorgestrel IUS (Mirena, BAY86-5028)
	Affected / at Risk (%)	# Events
Total	0/362 (0%)
Serious Adverse Events
	Levonorgestrel IUS (Mirena, BAY86-5028)
	Affected / at Risk (%)	# Events
Total	14/362 (3.9%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/362 (0.3%)	1
Gastrointestinal disorders
Volvulus	1/362 (0.3%)	1
Infections and infestations
Tooth abscess	1/362 (0.3%)	1
Urinary tract infection	1/362 (0.3%)	1
Injury, poisoning and procedural complications
Uterine perforation	3/362 (0.8%)	3
Metabolism and nutrition disorders
Obesity	1/362 (0.3%)	1
Nervous system disorders
Radial nerve palsy	1/362 (0.3%)	1
Vertebral artery dissection	1/362 (0.3%)	1
Cerebellar stroke	1/362 (0.3%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/362 (0.3%)	1
Ectopic pregnancy with contraceptive device	1/362 (0.3%)	1
Product Issues
Embedded device	1/362 (0.3%)	1
Psychiatric disorders
Conversion disorder	1/362 (0.3%)	1
Suicidal ideation	2/362 (0.6%)	2
Bipolar disorder	1/362 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Levonorgestrel IUS (Mirena, BAY86-5028)
	Affected / at Risk (%)	# Events
Total	107/362 (29.6%)
Infections and infestations
Bacterial vaginosis	27/362 (7.5%)	40
Nasopharyngitis	21/362 (5.8%)	29
Urinary tract infection	27/362 (7.5%)	35
Investigations
Weight increased	33/362 (9.1%)	33
Psychiatric disorders
Anxiety	20/362 (5.5%)	22

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.