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

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

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.

Study Overview

• Status: Completed
• Conditions: Ectopic Pregnancy; Persistent Pregnancy of Unknown Location
• Intervention / Treatment: Other: Expectant Management; Drug: Methotrexate; Procedure: Uterine Evacuation

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • University of California San Francisco
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Michigan
    • Southfield, Michigan, United States, 48034
      • Wayne State University
  • Missouri
    • Saint Louis, Missouri, United States, 63108
      • Washington University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Medical Center - Women's Institute
    • Durham, North Carolina, United States, 27708
      • Duke University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Uneventful Clinical Resolution of a Pregnancy of Unknown Location Without Change From the Initial Management Strategy	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.	6 weeks from randomization

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Barnhart KT, Hansen KR, Stephenson MD, Usadi R, Steiner AZ, Cedars MI, Jungheim ES, Hoeger KM, Krawetz SA, Mills B, Alston M, Coutifaris C, Senapati S, Sonalkar S, Diamond MP, Wild RA, Rosen M, Sammel MD, Santoro N, Eisenberg E, Huang H, Zhang H; Reproductive Medicine Network. Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial. JAMA. 2021 Aug 3;326(5):390-400. doi: 10.1001/jama.2021.10767.

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2014
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 19, 2019

Study Registration Dates

• First Submitted: May 28, 2014
• First Submitted That Met QC Criteria: May 28, 2014
• First Posted (Estimate): June 2, 2014

Study Record Updates

• Last Update Posted (Actual): December 8, 2020
• Last Update Submitted That Met QC Criteria: November 18, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Pregnancy Complications; Pregnancy, Ectopic; Cardiac Complexes, Premature; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: 2000023590; 2U10HD055925-06 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD will be shared with other researchers through the NICHD DASH system. It will be available 6 months after publication of the primary results.