ACTorNOT: Optimal Treatment for Women With a Persisting Pregnancy of Unknown Location

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02152696
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Augusta University (Other), Penn State University (Other), University of California, San Francisco (Other), University of North Carolina (Other), University of Oklahoma (Other), University of Pennsylvania (Other)
• Enrollment: 255
• Locations: 17
• Arms: 3
• Actual Duration (Months): 60.8
• Patients Per Site: 15
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a randomized controlled trial to compare three currently available management strategies for women with a persisting pregnancy of unknown location (PPUL), which makes them at-risk for ectopic pregnancy. We will recruit hemodynamically stable women with a confirmed PPUL to be randomized to one of three strategies: 1) Uterine evacuation followed by methotrexate (MTX) for some (those that have evidence of a non visualized ectopic pregnancy) 2) Empiric treatment with MTX for all 3) Expectant management. Randomization will be 1:1:1 into these three arms. After randomization, they will be followed and treated clinically as is indicated by the progression of their condition. Primary outcome measures: uneventful decline of hCG to 5 IU/mL.

Condition or Disease	Intervention/Treatment	Phase
Persistent Pregnancy of Unknown Location; Ectopic Pregnancy	Drug: Methotrexate; Procedure: Uterine Evacuation; Other: Expectant Management	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Optimal Treatment for Women With a Persisting Pregnancy of Unknown Location - a Randomized Clinical Trial of Women at Risk for an Ectopic Pregnancy: Active Treatment Versus No Treatment
• Actual Study Start Date: Jul 25, 2014
• Actual Primary Completion Date: Aug 1, 2019
• Actual Study Completion Date: Aug 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Expectant Management Subjects will have their PPUL expectantly managed using serum hCG monitoring.	Other: Expectant Management; Pregnancy will be expectantly managed using serum hcg monitoring
Active Comparator: Uterine evacuation with MTX for some Subjects will undergo a uterine evacuation. If hCG levels do not sufficiently decrease after the uterine evacuation, the subject will be treated with methotrexate. If hCG levels do sufficiently decrease after the uterine evacuation, no further treatment is required.	Drug: Methotrexate; Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.; Procedure: Uterine Evacuation; Uterine evacuation or dilation and curettage. At the clinician's discretion, this can be performed using local anesthesia, sedation or general anesthesia and can use a manual or electrical evacuation.
Active Comparator: Empiric treatment with MTX for all Subjects will be treated with methotrexate, receiving one dose on day 0 and a subsequent dose on day 4. Additional doses will be administered as needed based on hCG levels.	Drug: Methotrexate; Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Uneventful Clinical Resolution of a Pregnancy of Unknown Location Without Change From the Initial Management Strategy [6 weeks from randomization]

   The primary outcome measure in each of each 3 treatment arm is the uneventful clinical resolution of a PPUL without change in treatment from the initial management strategy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female with a persisting pregnancy of unknown location:

• A pregnancy of unknown location is defined as a pregnancy in a woman with a positive pregnancy test but no definitive signs of pregnancy in the uterus or adnexa on ultrasound imaging. A definitive sign of gestation includes ultrasound visualization of a gestational sac with a yolk sac (with or without an embryo) in the uterus or in the adnexa. Ultrasound must be performed within 7 days prior to randomization.

• Persistence of hCG is defined as at least 2 serial hCG values (over 2-14 days), showing < 15% rise per day, or < 50% fall between the first and last value.

• Patient is hemodynamically stable, hemoglobin >10 mg/dL

• Greater than or 18 years of age

Exclusion Criteria:

• Hemodynamically unstable in need of acute treatment

• Most recent hCG > 5000 mIU/mL

• Patient obtaining care in relation to a recently completed pregnancy (delivery, spontaneous or elective abortion)

• Diagnosis of gestational trophoblastic disease

• Subject unwilling or unable to comply with study procedures

• Known hypersensitivity to MTX

• Presence of clinical contraindications for treatment with MTX

• Prior medical or surgical management of this gestation

• Subject unwilling to accept a blood transfusion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94115
2	Denver Health	Denver	Colorado	United States	80204
3	Yale University	New Haven	Connecticut	United States	06520
4	University of South Florida	Tampa	Florida	United States	33606
5	Augusta University	Augusta	Georgia	United States	30912
6	Northwestern University	Chicago	Illinois	United States	60611
7	University Of Illinois at Chicago	Chicago	Illinois	United States	60612
8	Wayne State University	Southfield	Michigan	United States	48034
9	Washington University	Saint Louis	Missouri	United States	63108
10	University of Rochester	Rochester	New York	United States	14642
11	University of North Carolina	Chapel Hill	North Carolina	United States	27599
12	Carolinas Medical Center - Women's Institute	Charlotte	North Carolina	United States	28204
13	Duke University	Durham	North Carolina	United States	27708
14	University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
15	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
16	Greenville Health System	Greenville	South Carolina	United States	29605
17	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• Yale University
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Augusta University
• Penn State University
• University of California, San Francisco
• University of North Carolina
• University of Oklahoma
• University of Pennsylvania

Investigators

• Study Director: Esther Eisenberg, MD MPH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Study Chair: Nanette Santoro, MD, University of Colorado, Denver
• Principal Investigator: Kurt Barnhart, MD MSCE, University of Pennsylvania
• Study Director: Michael Diamond, MD, Augusta University
• Study Director: Richard Legro, MD, Penn State University
• Study Director: Marcelle Cedars, MD, University of California, San Francisco
• Study Director: Anne Steiner, MD MPH, University of North Carolina
• Study Director: Karl Hansen, MD PhD, University of Oklahoma
• Study Director: Christos Coutifaris, MD PhD, University of Pennsylvania
• Study Director: Heping Zhang, PhD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 9, 2019

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02152696
• Other Study ID Numbers: 2000023590; 2U10HD055925-06
• First Posted: Jun 2, 2014
• Last Update Posted: Dec 8, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Pregnancy, Ectopic; Cardiac Complexes, Premature; Methotrexate

Study Results

Participant Flow

Arm/Group Title	Expectant Management	Uterine Evacuation With MTX for Some	Empiric Treatment With MTX for All
Arm/Group Description	Subjects will have their PPUL expectantly managed using serum hCG monitoring. Expectant Management: Pregnancy will be expectantly managed using serum hcg monitoring	Subjects will undergo a uterine evacuation. If hCG levels do not sufficiently decrease after the uterine evacuation, the subject will be treated with methotrexate. If hCG levels do sufficiently decrease after the uterine evacuation, no further treatment is required. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels. Uterine Evacuation: Uterine evacuation or dilation and curettage. At the clinician's discretion, this can be performed using local anesthesia, sedation or general anesthesia and can use a manual or electrical evacuation.	Subjects will be treated with methotrexate, receiving one dose on day 0 and a subsequent dose on day 4. Additional doses will be administered as needed based on hCG levels. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.
Period Title: Overall Study
STARTED	86	87	82
COMPLETED	86	86	81
NOT COMPLETED	0	1	1

Baseline Characteristics

Arm/Group Title	Expectant Management	Uterine Evacuation With MTX for Some	Empiric Treatment With MTX for All	Total
Arm/Group Description	Subjects will have their PPUL expectantly managed using serum hCG monitoring. Expectant Management: Pregnancy will be expectantly managed using serum hcg monitoring	Subjects will undergo a uterine evacuation. If hCG levels do not sufficiently decrease after the uterine evacuation, the subject will be treated with methotrexate. If hCG levels do sufficiently decrease after the uterine evacuation, no further treatment is required. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels. Uterine Evacuation: Uterine evacuation or dilation and curettage. At the clinician's discretion, this can be performed using local anesthesia, sedation or general anesthesia and can use a manual or electrical evacuation.	Subjects will be treated with methotrexate, receiving one dose on day 0 and a subsequent dose on day 4. Additional doses will be administered as needed based on hCG levels. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.	Total of all reporting groups
Overall Participants	86	87	82	255
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.1 (5.6)	31.2 (5.9)	31.5 (5.7)	31.6 (5.7)
Sex: Female, Male (Count of Participants)
Female	86 100%	87 100%	82 100%	255 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 3.5%	8 9.2%	6 7.3%	17 6.7%
Not Hispanic or Latino	80 93%	75 86.2%	74 90.2%	229 89.8%
Unknown or Not Reported	3 3.5%	4 4.6%	2 2.4%	9 3.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 3.5%	10 11.5%	4 4.9%	17 6.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	37 43%	33 37.9%	32 39%	102 40%
White	41 47.7%	40 46%	39 47.6%	120 47.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	5 5.8%	4 4.6%	7 8.5%	16 6.3%
Region of Enrollment (Count of Participants)
United States	86 100%	87 100%	82 100%	255 100%
Estimated gestational age - week (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	6.4 (1.8)	6.9 (1.9)	6.7 (2.0)	6.7 (1.9)
First hCG value at screening (mIU/ml) (mIU/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/ml]	661.2 (688.6)	561.9 (702.5)	633.3 (695.8)	618.3 (694.2)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Uneventful Clinical Resolution of a Pregnancy of Unknown Location Without Change From the Initial Management Strategy
Description	The primary outcome measure in each of each 3 treatment arm is the uneventful clinical resolution of a PPUL without change in treatment from the initial management strategy.
Time Frame	6 weeks from randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Expectant Management	Uterine Evacuation With MTX for Some	Empiric Treatment With MTX for All
Arm/Group Description	Subjects will have their PPUL expectantly managed using serum hCG monitoring. Expectant Management: Pregnancy will be expectantly managed using serum hcg monitoring	Subjects will undergo a uterine evacuation. If hCG levels do not sufficiently decrease after the uterine evacuation, the subject will be treated with methotrexate. If hCG levels do sufficiently decrease after the uterine evacuation, no further treatment is required. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels. Uterine Evacuation: Uterine evacuation or dilation and curettage. At the clinician's discretion, this can be performed using local anesthesia, sedation or general anesthesia and can use a manual or electrical evacuation.	Subjects will be treated with methotrexate, receiving one dose on day 0 and a subsequent dose on day 4. Additional doses will be administered as needed based on hCG levels. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.
Measure Participants	86	87	82
Count of Participants [Participants]	31 36%	42 48.3%	45 54.9%

Adverse Events

Time Frame	The period of time over which the adverse events were collected is: from the initiation of the study procedures to the end of the study treatment follow-up, which is about an average of 42 days following the last administration of study treatment.
Arm/Group Title	Expectant Management		Uterine Evacuation With MTX for Some		Empiric Treatment With MTX for All
Arm/Group Description	Subjects will have their PPUL expectantly managed using serum hCG monitoring. Expectant Management: Pregnancy will be expectantly managed using serum hcg monitoring		Subjects will undergo a uterine evacuation. If hCG levels do not sufficiently decrease after the uterine evacuation, the subject will be treated with methotrexate. If hCG levels do sufficiently decrease after the uterine evacuation, no further treatment is required. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels. Uterine Evacuation: Uterine evacuation or dilation and curettage. At the clinician's discretion, this can be performed using local anesthesia, sedation or general anesthesia and can use a manual or electrical evacuation.		Subjects will be treated with methotrexate, receiving one dose on day 0 and a subsequent dose on day 4. Additional doses will be administered as needed based on hCG levels. Methotrexate: Two Dose Protocol: The patient will receive the first dose of MTX 50mg/m2 on treatment day 0. She will receive a second dose of MTX 50mg/m2 on treatment day 4 and a serum hCG level will be drawn. Subsequent doses of MTX will be administered based on hCG levels.
All Cause Mortality
	Expectant Management		Uterine Evacuation With MTX for Some		Empiric Treatment With MTX for All
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/86 (0%)		0/87 (0%)		0/82 (0%)
Serious Adverse Events
	Expectant Management		Uterine Evacuation With MTX for Some		Empiric Treatment With MTX for All
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/86 (2.3%)		2/87 (2.3%)		0/82 (0%)
Pregnancy, puerperium and perinatal conditions
Hospitalization	0/86 (0%)	0	1/87 (1.1%)	1	0/82 (0%)	0
Salpingectomy	2/86 (2.3%)		0/87 (0%)	0	0/82 (0%)	0
Right ruptured ectopic pregnancy	0/86 (0%)	0	1/87 (1.1%)	1	0/82 (0%)	0
Other (Not Including Serious) Adverse Events
	Expectant Management		Uterine Evacuation With MTX for Some		Empiric Treatment With MTX for All
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/86 (51.2%)		53/87 (60.9%)		46/82 (56.1%)
Gastrointestinal disorders
Nausea	22/86 (25.6%)	22	32/87 (36.8%)	32	31/82 (37.8%)	31
Vomiting	2/86 (2.3%)	2	11/87 (12.6%)	11	10/82 (12.2%)	10
Loss of Appetite	25/86 (29.1%)	25	28/87 (32.2%)	28	23/82 (28%)	23
Mouth Sores	5/86 (5.8%)	5	6/87 (6.9%)	6	6/82 (7.3%)	6
Diarrhea	9/86 (10.5%)	9	21/87 (24.1%)	21	13/82 (15.9%)	13
General disorders
One or more adverse event	44/86 (51.2%)	44	53/87 (60.9%)	53	46/82 (56.1%)	46
Heart Burn/Indigestion	7/86 (8.1%)	7	12/87 (13.8%)	12	5/82 (6.1%)	5
Hair Loss	4/86 (4.7%)	4	9/87 (10.3%)	9	6/82 (7.3%)	6
Fatigue	38/86 (44.2%)	38	38/87 (43.7%)	38	36/82 (43.9%)	36
Dizziness or weakness	18/86 (20.9%)	18	27/87 (31%)	27	17/82 (20.7%)	17
Shoulder or back pain	14/86 (16.3%)	14	18/87 (20.7%)	18	12/82 (14.6%)	12
Persistent dry cough	3/86 (3.5%)	3	5/87 (5.7%)	5	5/82 (6.1%)	5
Any Other Side Effects	6/86 (7%)	6	4/87 (4.6%)	4	3/82 (3.7%)	3
Nervous system disorders
Headaches	31/86 (36%)	31	25/87 (28.7%)	25	27/82 (32.9%)	27
Reproductive system and breast disorders
Pelvic Pain	37/86 (43%)	37	42/87 (48.3%)	42	38/82 (46.3%)	38
Surgical and medical procedures
Vaginal bleeding	38/86 (44.2%)	38	46/87 (52.9%)	46	39/82 (47.6%)	39

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.