Trial Outcomes & Findings for Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients (NCT NCT02035787)

NCT ID: NCT02035787

Last Updated: 2024-12-18

Results Overview

Complete Response is subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma percentage of individuals achieved complete disease regression as defined by no evidence of microscopic viable hyperplasia or carcinoma on endometrial biopsy.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

20 participants

Primary outcome timeframe

Up to 6 months

Results posted on

2024-12-18

Participant Flow

Subjects were enrolled in the study between 02/27/2014 and 10/12/2023, at three sites in the United States.

Twenty participants joined the study.

Participant milestones

Participant milestones
Measure	Complex Atypical Hyperplasia Subjects with biopsy-proven complex atypical hyperplasia	Grade 1 Endometrial Adenocarcinoma Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Overall Study- 12 Months STARTED	12	8
Overall Study- 12 Months COMPLETED	4	6
Overall Study- 12 Months NOT COMPLETED	8	2
Overall Study -6 Months STARTED	12	8
Overall Study -6 Months COMPLETED	7	7
Overall Study -6 Months NOT COMPLETED	5	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Complex Atypical Hyperplasia Subjects with biopsy-proven complex atypical hyperplasia	Grade 1 Endometrial Adenocarcinoma Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Overall Study- 12 Months Adverse Event	3	0
Overall Study- 12 Months Complete response	4	1
Overall Study- 12 Months Protocol Violation	1	1

Baseline Characteristics

Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Complex Atypical Hyperplasia n=12 Participants Subjects with biopsy-proven complex atypical hyperplasia	Grade 1 Endometrial Adenocarcinoma n=8 Participants Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma	Total n=20 Participants Total of all reporting groups
Age, Continuous	40.5 years STANDARD_DEVIATION 16.77 • n=5 Participants	42.75 years STANDARD_DEVIATION 17.87 • n=7 Participants	41.4 years STANDARD_DEVIATION 16.78 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	8 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=5 Participants	8 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	12 participants n=5 Participants	8 participants n=7 Participants	20 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 6 months

Population: Subjects who are with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma, started the study treatment, and an endometrial biopsy was performed to assess the treatment response, regardless of completion of the study medication.

Outcome measures

Outcome measures
Measure	Whole Group n=15 Participants Subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma.	Grade 1 Endometrial Adenocarcinoma Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Complete Response Rate - 6 Months	80 percentage of participants Interval 52.0 to 96.0	—

SECONDARY outcome

Timeframe: Up to 6 months

Complete Response is the percentage of individuals achieving complete disease regression as defined by no evidence of microscopic viable hyperplasia or carcinoma on endometrial biopsy in complex atypical hyperplasia and Grade 1 endometrial adenocarcinoma groups. The group are based on the initial treatment assignment and not on the treatment eventually received.

Outcome measures

Outcome measures
Measure	Whole Group n=10 Participants Subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma.	Grade 1 Endometrial Adenocarcinoma n=5 Participants Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Complete Response Rate by Group	100 percentage of participants Interval 72.0 to 100.0	40 percentage of participants Interval 5.0 to 85.0

SECONDARY outcome

Timeframe: Up to 12 months

Complete Response is the percentage of participants achieving complete disease regression as defined by no evidence of microscopic viable hyperplasia or carcinoma on endometrial biopsy.

Outcome measures

Outcome measures
Measure	Whole Group n=11 Participants Subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma.	Grade 1 Endometrial Adenocarcinoma n=5 Participants Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Percent Complete Response Rate-12 Months	100 percentage of participants Interval 74.0 to 100.0	60 percentage of participants Interval 23.0 to 88.0

SECONDARY outcome

Timeframe: 12 months

Population: Subjects who are with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma, started the study treatment.

Patients adhered to at least 80% of the scheduled doses throughout the prescribed treatment period. Subjects who achieved a biopsy-proven complete response stopped the treatment early but were still considered adherent to the treatment.

Outcome measures

Outcome measures
Measure	Whole Group n=11 Participants Subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma.	Grade 1 Endometrial Adenocarcinoma n=7 Participants Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Adherence of Treatment	10 Participants	7 Participants

SECONDARY outcome

Timeframe: Up to 12 months

Population: Subjects who are with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma, started the study treatment

All treatment-attributed adverse events (definite, possible, and probable) with grade information are reported based on The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CTCAE is a descriptive terminology that can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Outcome measures

Outcome measures
Measure	Whole Group n=12 Participants Subjects with complex atypical hyperplasia or Grade 1 endometrial adenocarcinoma.	Grade 1 Endometrial Adenocarcinoma n=8 Participants Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Treatment Attributed Adverse Events Insomnia Grade1	0 Participants	1 Participants
Treatment Attributed Adverse Events Reproductive system and breast disorders - Other, specify Grade1	1 Participants	0 Participants
Treatment Attributed Adverse Events Abdominal pain Grade1	0 Participants	1 Participants
Treatment Attributed Adverse Events Abdominal pain Grade 2	0 Participants	1 Participants
Treatment Attributed Adverse Events Alanine aminotransferase increased Grade1	2 Participants	1 Participants
Treatment Attributed Adverse Events Alanine aminotransferase increased Grade 2	0 Participants	1 Participants
Treatment Attributed Adverse Events Anorexia Grade1	2 Participants	1 Participants
Treatment Attributed Adverse Events Anxiety Grade2	1 Participants	1 Participants
Treatment Attributed Adverse Events Aspartate aminotransferase increased Grade1	2 Participants	1 Participants
Treatment Attributed Adverse Events Aspartate aminotransferase increased Grade2	0 Participants	1 Participants
Treatment Attributed Adverse Events Blood and lymphatic system disorders - Other, specify Grade1	2 Participants	1 Participants
Treatment Attributed Adverse Events Blood and lymphatic system disorders - Other, specify Grade2	0 Participants	1 Participants
Treatment Attributed Adverse Events Diarrhea Grade 1	4 Participants	3 Participants
Treatment Attributed Adverse Events Diarrhea Grade 2	2 Participants	1 Participants
Treatment Attributed Adverse Events Diarrhea Grade 3	1 Participants	0 Participants
Treatment Attributed Adverse Events Dizziness Grade 2	1 Participants	1 Participants
Treatment Attributed Adverse Events Headache Grade1	1 Participants	0 Participants
Treatment Attributed Adverse Events Headache Grade2	1 Participants	0 Participants
Treatment Attributed Adverse Events Fatigue Grade1	0 Participants	1 Participants
Treatment Attributed Adverse Events Nausea Grade1	8 Participants	4 Participants
Treatment Attributed Adverse Events Nausea Grade2	2 Participants	0 Participants
Treatment Attributed Adverse Events Stomach pain Grade1	0 Participants	1 Participants
Treatment Attributed Adverse Events Vaginal hemorrhage Grade1	1 Participants	0 Participants
Treatment Attributed Adverse Events Vaginal discharge Grade1	0 Participants	1 Participants
Treatment Attributed Adverse Events Vomiting Grade 3	1 Participants	0 Participants

Adverse Events

Complex Atypical Hyperplasia

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Grade 1 Endometrial Adenocarcinoma

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Complex Atypical Hyperplasia n=12 participants at risk Subjects with biopsy-proven complex atypical hyperplasia	Grade 1 Endometrial Adenocarcinoma n=8 participants at risk Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Renal and urinary disorders Renal calculi	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.

Other adverse events

Additional Information

Lauren Higgins

University of North Carolina Lineberger Comprehensive Cancer Center

Phone: 919- 966-4432

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Complex Atypical Hyperplasia n=12 participants at risk Subjects with biopsy-proven complex atypical hyperplasia	Grade 1 Endometrial Adenocarcinoma n=8 participants at risk Subjects with biopsy-proven Grade 1 endometrial adenocarcinoma
Blood and lymphatic system disorders Blood and lymphatic system disorders - Other, specify	16.7% 2/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	25.0% 2/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Abdominal pain	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	25.0% 2/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Diarrhea	58.3% 7/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	50.0% 4/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Dyspepsia	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Nausea	83.3% 10/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	50.0% 4/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Stomach pain	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Gastrointestinal disorders Vomiting	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
General disorders Chills	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
General disorders Fatigue	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Hepatobiliary disorders Portal hypertension	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Infections and infestations Rhinitis infective	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Infections and infestations Upper respiratory infection	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Infections and infestations Urinary tract infection	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Injury, poisoning and procedural complications Wound complication	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Investigations Alanine aminotransferase increased	16.7% 2/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	25.0% 2/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Investigations Aspartate aminotransferase increased	16.7% 2/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	25.0% 2/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Investigations Creatinine increased	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Metabolism and nutrition disorders Anorexia	16.7% 2/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Metabolism and nutrition disorders Hyperglycemia	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Metabolism and nutrition disorders Hyperuricemia	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Metabolism and nutrition disorders Hypoglycemia	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Metabolism and nutrition disorders Obesity	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Nervous system disorders Dizziness	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Nervous system disorders Headache	16.7% 2/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Psychiatric disorders Anxiety	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Psychiatric disorders Depression	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Psychiatric disorders Insomnia	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	37.5% 3/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Renal and urinary disorders Renal calculi	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Reproductive system and breast disorders Reproductive system and breast disorders - Other, specify	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Reproductive system and breast disorders Uterine hemorrhage	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Reproductive system and breast disorders Vaginal hemorrhage	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Reproductive system and breast disorders Vaginal pain	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Respiratory, thoracic and mediastinal disorders Sleep apnea	8.3% 1/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	0.00% 0/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Respiratory, thoracic and mediastinal disorders Sore throat	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Skin and subcutaneous tissue disorders Skin ulceration	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.
Reproductive system and breast disorders Vaginal discharge	0.00% 0/12 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.	12.5% 1/8 • Up to 13 months Adverse events were collected from day one of the study drug administration to 30 days after completion of treatment. Any hospital admission was graded as a serious adverse event per protocol.