Tamoxifen/BTB: Treatment of Unfavorable Bleeding Patterns in Contraceptive Implant Users

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02903121
• Collaborator: Merck Women's Health Investigator Initiated Studies Program (Other)
• Enrollment: 109
• Location: 1
• Arms: 2
• Actual Duration (Months): 28.5
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

The etonogestrel (ENG) subdermal contraceptive implant (ENG implant) is a highly effective method of preventing pregnancy, but it has bleeding side effects that make it unappealing for many women. The only study to demonstrate a sustained reduction in bleeding lasting for two months was the selective estrogen receptor modulator (SERM) tamoxifen in users of the levonogestrel (LNG) contraceptive implant. Based on the investigators encouraging preliminary data of tamoxifen and ENG implant users, the investigators plan to perform additional studies on the impact of tamoxifen on the breakthrough bleeding experience by ENG implant users.

Condition or Disease	Intervention/Treatment	Phase
Bleeding; Implants; Breakthrough Bleeding	Drug: Tamoxifen; Drug: Placebo; Drug: Tamoxifen (open label)	Phase 4

Detailed Description

The investigators will perform a 2 phase trial for treatment of women experiencing frequent or prolonged bleeding while using the ENG contraceptive implant. The first phase will consist of a randomized, controlled, double blind placebo-controlled clinical trial over a 90-day reference period and the second phase will allow both study arms to receive open-label treatment over an additional 90-day reference period. The primary outcome of the study will be the total number of consecutive bleeding-free days in first 30 days from Day 1 of first treatment (TX1).

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Treatment of Unfavorable Bleeding Patterns in Contraceptive Implant Users
• Actual Study Start Date: Jan 20, 2017
• Actual Primary Completion Date: Jun 5, 2019
• Actual Study Completion Date: Jun 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tamoxifen Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding	Drug: Tamoxifen; Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study; Other Names: Nolvadex Genox Tamifen ; Drug: Tamoxifen (open label); Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study; Other Names: Nolvadex Genox Tamifen
Placebo Comparator: Placebo Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding	Drug: Placebo; Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study

Outcome Measures

Primary Outcome Measures

1. Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1) [Day 1 to Day 30]

   Bleeding free days in the first 30 days

Secondary Outcome Measures

1. Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1. [Day 1 to Day 90]

   bleeding free days in the first 90 days

Other Outcome Measures

1. Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90 [Day 1 of treatment number 4 to Day 90 (second 90 day reference period)]

   bleeding free days in the second 90 days

2. Patient Satisfaction With Bleeding Pattern [Day 1 of treatment 1 to day 180]

   Patient satisfaction with bleeding pattern. Assessed by visual analog scale to determine satisfaction with bleeding patterns on a scale of 0-100 mm, where 0 mm represents not satisfied at all and 100 mm is totally satisfied.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• English or Spanish speaking

• women aged 15-45 years of age

• Currently using the ENG-implant for at least 1 month and use proven on exam (palpation of implant at screening visit)

• Willing to continue using the implant for at least 6 months

• 7 days of continuous bleeding/spotting, or 2 or more episodes of bleeding/spotting in the last 30 days.

• Cellphone that is able to receive and respond to a daily text or email message .

Exclusion Criteria:

• Postpartum within six months

• post-abortion within six weeks

• currently pregnant

• currently breast-feeding

• undiagnosed abnormal uterine bleeding pre-dating placement of contraceptive implant

• bleeding dyscrasia

• anticoagulation use

• active cervicitis

• allergy to tamoxifen

• history of venous thromboembolism

• current or past breast or uterine malignancy

• use of medication contraindicated with tamoxifen (coumadin, letrozole, bromocriptine, rifampicin, aminoglutethimide, phenobarbital).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Oregon Health and Science University
• Merck Women's Health Investigator Initiated Studies Program

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 7, 2019

More Information

Publications

None provided.

• Responsible Party: Alison Edelman, Professor, OB/GYN, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT02903121
• Other Study ID Numbers: OHSU IRB 16519
• First Posted: Sep 16, 2016
• Last Update Posted: Jul 15, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Alison Edelman, Professor, OB/GYN, Oregon Health and Science University: Unscheduled bleeding; Long acting contraception
• Additional relevant MeSH terms: Metrorrhagia; Hemorrhage; Tamoxifen

Study Results

Participant Flow

Arm/Group Title	Tamoxifen	Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Period Title: Overall Study
STARTED	57	52
COMPLETED	34	38
NOT COMPLETED	23	14

Baseline Characteristics

Arm/Group Title	Tamoxifen	Placebo	Total
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study	Total of all reporting groups
Overall Participants	55	52	107
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	24.5 (5.1)	23.4 (4.5)	23.9 (4.8)
Sex: Female, Male (Count of Participants)
Female	55 100%	52 100%	107 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	30 54.5%	32 61.5%	62 57.9%
Hispanic	8 14.5%	10 19.2%	18 16.8%
Asian	7 12.7%	4 7.7%	11 10.3%
Black	1 1.8%	2 3.8%	3 2.8%
More than one	7 12.7%	4 7.7%	11 10.3%
Other or unspecified	2 3.6%	0 0%	2 1.9%
Marital Status (Count of Participants)
Single or divorced	13 23.6%	18 34.6%	31 29%
Partnered or Married	42 76.4%	34 65.4%	76 71%
Education (Count of Participants)
High school or less	10 18.2%	7 13.5%	17 15.9%
College (any or more)	45 81.8%	45 86.5%	90 84.1%
Days of implant use at study entry (Days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Days]	370.8 (267.7)	469.1 (274.5)	418.6 (274.2)

Outcome Measures

1. Primary Outcome

Title	Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1)
Description	Bleeding free days in the first 30 days
Time Frame	Day 1 to Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tamoxifen	Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Measure Participants	55	52
Mean (Standard Deviation) [days]	18.5 (17)	8.7 (8.4)

2. Secondary Outcome

Title	Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1.
Description	bleeding free days in the first 90 days
Time Frame	Day 1 to Day 90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tamoxifen	Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Measure Participants	46	42
Median (Full Range) [days]	60	52

3. Other Pre-specified Outcome

Title	Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90
Description	bleeding free days in the second 90 days
Time Frame	Day 1 of treatment number 4 to Day 90 (second 90 day reference period)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tamoxifen	Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Measure Participants	39	42
Median (Full Range) [days]	56	67.5

4. Other Pre-specified Outcome

Title	Patient Satisfaction With Bleeding Pattern
Description	Patient satisfaction with bleeding pattern. Assessed by visual analog scale to determine satisfaction with bleeding patterns on a scale of 0-100 mm, where 0 mm represents not satisfied at all and 100 mm is totally satisfied.
Time Frame	Day 1 of treatment 1 to day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tamoxifen	Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study	Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Measure Participants	38	40
Median (Full Range) [mm]	67.5	54.25

Adverse Events

Time Frame	180 day duration of study participation
Arm/Group Title	Tamoxifen		Placebo
Arm/Group Description	Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study		Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
All Cause Mortality
	Tamoxifen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/55 (0%)		0/52 (0%)
Serious Adverse Events
	Tamoxifen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/55 (0%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Tamoxifen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/55 (81.8%)		12/52 (23.1%)
Blood and lymphatic system disorders
Fluid retention	10/55 (18.2%)		1/52 (1.9%)
Gastrointestinal disorders
Nausea, Vomiting	5/55 (9.1%)		2/52 (3.8%)
Nervous system disorders
Headache, migraine	16/55 (29.1%)		1/52 (1.9%)
Hot flashes	6/55 (10.9%)		3/52 (5.8%)
Weakness, fatigue, dizziness	6/55 (10.9%)		1/52 (1.9%)
Psychiatric disorders
Mood changes	11/55 (20%)		2/52 (3.8%)
Reproductive system and breast disorders
Cramping, changes in menstrual fluid	3/55 (5.5%)		0/52 (0%)
Yeast infection, bacterial vaginosis	5/55 (9.1%)		0/52 (0%)
Skin and subcutaneous tissue disorders
Acne	0/55 (0%)		3/52 (5.8%)

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.