ROBI: Treatment of Unacceptable Bleeding Patterns in ETG Implant Users With an Oral Contraceptive

• Sponsor: University of California, Davis (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01963403
• Collaborator: Washington University School of Medicine (Other)
• Enrollment: 26
• Locations: 2
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 13
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This double-blinded, placebo-controlled, randomized trial will compare the effects of the use of a combined oral contraceptive pill to a placebo pill for women who are experiencing irregular and/or heavy bleeding associated with the use of an etonogestrel (ETG) implant.

The hypothesis of the study is:

• Use of combined oral contraceptive will significantly improve bleeding patterns for users of ETG implant

• Continuation rate of ETG implant users will be increased by use of combined oral contraceptive in women desiring ETG implant removal because of the undesirable bleeding

• Adverse events will be uncommon and acceptable to women who use a combined oral contraceptive with the ETG implant

Condition or Disease	Intervention/Treatment	Phase
Abnormal Uterine Bleeding, Unspecified; Uterine Bleeding Heavy	Drug: EE 30mcg/LNG 150mcg; Drug: Placebo	Phase 4

Detailed Description

Women who are experiencing irregular and/or heavy bleeding associated with the use of an etonogestrel (ETG) implant will be recruited for this study. Women who have bothersome bleeding will be randomized to use either a combined oral contraceptive pill or a placebo pill.

Participants will take one pill every day and record their bleeding patterns on a daily diary.

Participants will have one screening/enrollment visit, two in-person follow up visits, and one telephone follow up contact. Subjects will be enrolled for a total of 84 days (three months).

Participants will be assigned to a treatment group at her screening/enrollment visit. Her first follow up visit will occur 22-28 days after her enrollment. Participants can choose to:

• Continue use of assigned treatment medication

• Discontinue use of assigned treatment medication, but use an open-label combined oral contraceptive pill

• Discontinue the use of assigned treatment medication, decline use of an open-label combined oral contraceptive pill

• Discontinue use of ETG implant.

Participants who choose to continue use of ETG implant will have a follow up telephone contact 50-56 days after her enrollment visit. A final in-person visit will occur 78-84 days after enrollment. Bleeding patterns will be assessed by daily bleeding diaries completed by the participant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Relief of Bleeding on the Implant: Treatment of Unacceptable Bleeding Patterns in ETG Implant Users With a Combined Oral Contraceptive: A Placebo-Controlled Randomized Trial
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EE 30mcg/LNG 150mcg combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days)	Drug: EE 30mcg/LNG 150mcg; 1 pill per day; daily during study participation (up to 84 days); Other Names: Levlen28 Levora Portia 28 Altavera
Placebo Comparator: Placebo Placebo	Drug: Placebo; 1 pill per day; daily during study participation (up to 84 days)

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Bleeding Improvement [Bleeding improvement will be evaluated during first cycle of study treatment (28 days)]

   Bleeding improvement will be measured by participant response to the question of whether she feels her bleeding is improved and she is satisfied with the treatment.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [Adverse events will be evaluated at each contact (visits at 1 and 3 months, phone contact at 2 months) with the participant]

   Participants will be evaluated for adverse events while using a combined oral contraceptive with ETG implant.

Other Outcome Measures

1. Number of Participants withTreatment Success or Failure [Evaluated at follow up visits at 1 month and, if subject continues after 1st month, again at 3 months]

   Treatment success will be measured by desire to continue treatment because the initial treatment made the bleeding better. Partial failure of the study treatment will be measured by the desire to continue treatment because the initial treatment did not work Complete failure of treatment will be measured by the desire to: discontinue treatment because it did not work; no further treatment requested ETG implant removal Desire to use non-study treatment

2. Bleeding Patterns and Number of Participants With Bleeding Improvement [Evaluated at follow up visits at 1 month and, if subject continues after 1st month, again at 3 months]

   Bleeding improvement in women who received placebo but opted for open-label treatment after first cycle Bleeding improvement over the 84 days of study participation Bleeding patterns in placebo vs. combined oral contraceptive users

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women who have an ETG implant in place

• Women who subjectively experience the side effect of an undesirable bleeding profile such as bleeding irregularity or heavy flow after ETG implant was placed and who desire intervention for this side effect by either treatment of bleeding or removal of the implant

• Age 14 years an older, inclusive

Exclusion Criteria:

• Irregular or heavy bleeding from an etiology other than ETG use (e.g. fibroids, cervical polyp, or other organic cause of bleeding)

• Has attempted prescription treatment for menstrual side effects while using ETG implant

• Has one or more of the conditions considered Category 3 (risks outweigh benefits) or Category 4 (unacceptable health risk) for estrogen-containing oral contraceptives by the Center for Disease Control Medical Eligibility Criteria for Contraceptive Use:

• Current or history of heart or vascular diseases, including deep venous thrombosis, pulmonary embolism, known thrombogenic mutations, peripartum cardiomyopathy, and complicated valvular heart disease

• Hypertension, even if adequately controlled

• Diabetes with vascular involvement

• Headaches with focal aura, or migraines in women age 35 and older even without focal aura

• Major surgery with prolonged immobilization

• Breast cancer (current or past)

• Severe (decompensated) cirrhosis

• Acute or flare viral hepatitis

• Breastfeeding less than 1 month postpartum

• Post-partum less than 3 weeks

• 35 years of age and older and smoking

• Multiple risk factors for arterial cardiovascular disease

• Systemic Lupus Erythematosus with positive or unknown antiphospholipid antibodies

• Current symptomatic gallbladder disease or history of cholestasis related to past combined oral contraceptive use

• On certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine, lamotrigine)

• On Ritonavir-boosted protease inhibitors for antiretroviral therapy

• Issues or concerns, in the judgment of the investigator, that may compromise the safety of the subject, impact the subject's adherence to the protocol requirements, or confound the reliability of the data acquired in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Davis Department of Obstetrics and Gynecology	Sacramento	California	United States	95817
2	Washington University School of Medicine, Department of Obstetrics and Gynecology	St. Louis	Missouri	United States	63110

Sponsors and Collaborators

• University of California, Davis
• Washington University School of Medicine

Investigators

• Principal Investigator: Mitchell Creinin, MD, University of California, Davis
• Study Director: Melody Hou, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mitchell Creinin, MD, Professor and Director of Family Planning, University of California, Davis
• ClinicalTrials.gov Identifier: NCT01963403
• Other Study ID Numbers: 478388; MISP 50618
• First Posted: Oct 16, 2013
• Last Update Posted: May 12, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Mitchell Creinin, MD, Professor and Director of Family Planning, University of California, Davis: etonogestrel implant; birth control; irregular bleeding; heavy bleeding
• Additional relevant MeSH terms: Uterine Hemorrhage; Hemorrhage

Study Results

Participant Flow

Arm/Group Title	EE 30mcg/LNG 150mcg	Placebo
Arm/Group Description	combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)	Placebo Placebo: 1 pill per day; daily during study participation (up to 84 days)
Period Title: Overall Study
STARTED	13	13
COMPLETED	11	9
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	EE 30mcg/LNG 150mcg	Placebo	Total
Arm/Group Description	combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)	Placebo Placebo: 1 pill per day; daily during study participation (up to 84 days)	Total of all reporting groups
Overall Participants	13	13	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.4 (3.8)	25.8 (5.0)	25.6 (4.3)
Sex: Female, Male (Count of Participants)
Female	13 100%	13 100%	26 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	12 92.3%	13 100%	25 96.2%
Unknown or Not Reported	1 7.7%	0 0%	1 3.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 7.7%	2 15.4%	3 11.5%
Native Hawaiian or Other Pacific Islander	1 7.7%	1 7.7%	2 7.7%
Black or African American	4 30.8%	3 23.1%	7 26.9%
White	5 38.5%	5 38.5%	10 38.5%
More than one race	1 7.7%	1 7.7%	2 7.7%
Unknown or Not Reported	1 7.7%	1 7.7%	2 7.7%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	26 100%
Primary reason for implant (Count of Participants)
Contraception	11 84.6%	12 92.3%	23 88.5%
Bleeding Problem	1 7.7%	1 7.7%	2 7.7%
Dysmenorrhea	1 7.7%	0 0%	1 3.8%
Duration of implant use (days) [Median (Full Range) ]
Median (Full Range) [days]	343	109	144.5
intervention requested before enrollment (Count of Participants)
implant removal	2 15.4%	3 23.1%	5 19.2%
Hormonal treatment	6 46.2%	4 30.8%	10 38.5%
'Some treatment'	5 38.5%	6 46.2%	11 42.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Bleeding Improvement
Description	Bleeding improvement will be measured by participant response to the question of whether she feels her bleeding is improved and she is satisfied with the treatment.
Time Frame	Bleeding improvement will be evaluated during first cycle of study treatment (28 days)

Outcome Measure Data

Analysis Population Description

1 person in each group LTFU at one month, which was the primary outcome

Arm/Group Title	EE 30mcg/LNG 150mcg	Placebo
Arm/Group Description	combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)	Placebo Placebo: 1 pill per day; daily during study participation (up to 84 days)
Measure Participants	12	12
Significant improvement	11 84.6%	5 38.5%
Slight improvement	1 7.7%	3 23.1%
No change	0 0%	2 15.4%
Slightly worse	0 0%	2 15.4%
Significantly worse	0 0%	0 0%

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Participants will be evaluated for adverse events while using a combined oral contraceptive with ETG implant.
Time Frame	Adverse events will be evaluated at each contact (visits at 1 and 3 months, phone contact at 2 months) with the participant

Outcome Measure Data

Analysis Population Description

Outcomes at one month; 1 person LTFU at one month in each group

Arm/Group Title	EE 30mcg/LNG 150mcg	Placebo
Arm/Group Description	combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)	Placebo Placebo: 1 pill per day; daily during study participation (up to 84 days)
Measure Participants	12	12
Headache	5 38.5%	4 30.8%
Nausea/vomiting	1 7.7%	1 7.7%
Cramping	0 0%	2 15.4%
Mood change	0 0%	1 7.7%
None of above	6 46.2%	4 30.8%

3. Other Pre-specified Outcome

Title	Number of Participants withTreatment Success or Failure
Description	Treatment success will be measured by desire to continue treatment because the initial treatment made the bleeding better. Partial failure of the study treatment will be measured by the desire to continue treatment because the initial treatment did not work Complete failure of treatment will be measured by the desire to: discontinue treatment because it did not work; no further treatment requested ETG implant removal Desire to use non-study treatment
Time Frame	Evaluated at follow up visits at 1 month and, if subject continues after 1st month, again at 3 months

Outcome Measure Data

Analysis Population Description

one month evaluation; 1 subject LTFU at one month in each group

Arm/Group Title	EE 30mcg/LNG 150mcg	Placebo
Arm/Group Description	combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)	Placebo Placebo: 1 pill per day; daily during study participation (up to 84 days)
Measure Participants	12	12
Continued assigned treatment	8 61.5%	5 38.5%
Desired COC prescription	4 30.8%	4 30.8%
Desired no treatment	0 0%	2 15.4%
Implant removal	0 0%	1 7.7%

4. Other Pre-specified Outcome

Title	Bleeding Patterns and Number of Participants With Bleeding Improvement
Description	Bleeding improvement in women who received placebo but opted for open-label treatment after first cycle Bleeding improvement over the 84 days of study participation Bleeding patterns in placebo vs. combined oral contraceptive users
Time Frame	Evaluated at follow up visits at 1 month and, if subject continues after 1st month, again at 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Used COC at Any Time During 3 Months	No Use of COC at Any Time During 3 Months
Arm/Group Description
Measure Participants	16	5
Bleeding improvement	12 92.3%	5 38.5%
No bleeding improvement	4 30.8%	0 0%

Adverse Events

Time Frame	Up to 84 days on either medication or placebo.
Adverse Event Reporting Description	Adverse events for the drug arms reported combined arms. Placebo adverse events are reported for the single arm.
Arm/Group Title	EE 30mcg/LNG 150mcg		Placebo
Arm/Group Description	Combined oral contraceptive pill: ethinyl estradiol (EE) 30mcg/levonorgestrel 150mcg); 1 pill per day; daily during study participation (up to 84 days) EE 30mcg/LNG 150mcg: 1 pill per day; daily during study participation (up to 84 days)		Placebo: 1 pill per day; daily during study participation (up to 84 days)
All Cause Mortality
	EE 30mcg/LNG 150mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Serious Adverse Events
	EE 30mcg/LNG 150mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	EE 30mcg/LNG 150mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		8/12 (66.7%)
Gastrointestinal disorders
Nausea/vomiting	1/12 (8.3%)	1	1/12 (8.3%)	1
General disorders
Headache	5/12 (41.7%)	5	4/12 (33.3%)	4
Cramping	0/12 (0%)	0	2/12 (16.7%)	2
Mood change	0/12 (0%)	0	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.