Optimal treatment for women with a persisting pregnancy of unknown location, a randomized controlled trial: The ACT-or-NOT trial

Barnhart, Kurt T.; Sammel, Mary D.; Stephenson, Mary D.; Robins, Jared C.; Hansen, Karl R.; Youssef, Wahid A; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

doi:10.1016/j.cct.2018.09.009

Cited by 10 publications

(10 citation statements)

References 18 publications

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“…24 Ruptured ectopic pregnancy was not chosen as a primary outcome because it was considered unethical to refrain from additional treatment until rupture in the face of progression of disease. 12…”

Section: Discussionmentioning

confidence: 99%

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Barnhart

Hansen

Stephenson

et al. 2021

JAMA

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IMPORTANCEWomen with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities.OBJECTIVE To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. DESIGN, SETTING, AND PARTICIPANTS This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019).INTERVENTIONS Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). MAIN OUTCOMES AND MEASURESThe primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of −12%. RESULTS Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, −8.4% to ϱ]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%).CONCLUSIONS AND RELEVANCE Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results.

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Section: Discussionmentioning

confidence: 99%

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Barnhart

Hansen

Stephenson

et al. 2021

JAMA

Self Cite

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“…The definition of a persistent pregnancy of unknown location included no definitive ultrasound evidence of intrauterine or extrauterine gestation and a plateau in hCG, defined as <30%, <50%, <75%, or <100% in 2, 3, 4, or 7 days, respectively. 3 Here, 2 clinicians confirmed eligibility into the trial. Serial hCG levels from the participant were compared with levels used to assess the viability of a pregnancy.…”

Section: Methodsmentioning

confidence: 98%

“…Illustration of hCG rise for clinical trial study participant (in black) compared with first percentile rise (in red) and hCG from a subset of women with viable gestation and initial hCG of <1500 mIU/mL (in gray). Adapted from Barnhart et al 3…”

Section: Serial Hcg Levelsmentioning

confidence: 99%

Declaring a gestation nonviable: when 99% certainty is not enough

Barnhart

Senapati

Sammel

2021

American Journal of Obstetrics and Gynecology

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“…Randomized clinical trials (RCTs) remain the gold standard for understanding the effect of a treatment or other intervention relative to placebo or standard of care. [1][2][3] To make the trial more efficient and ethical, confirmatory adaptive designs become more widely acceptable and popular to allow flexible interim modifications in the ongoing trials using unblinded data without compromising the type I error rate. [4][5][6] An appealing branch is the response adaptive randomization (RAR) design, where the chance of a newly enrolled subject being assigned to a treatment arm varies over the course of the trial based on accumulating outcome data for subjects previously enrolled.…”

Section: Introductionmentioning

confidence: 99%

A practical response adaptive block randomization (RABR) design with analytic type I error protection

Zhan

Geng

Zhang

et al. 2021

Statistics in Medicine

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ical, and pragmatic perspectives in the sense that subjects are more likely to be randomized to better performing treatment groups based on accumulating data. However, applications of RAR in confirmatory drug clinical trials with multiple active arms are limited largely due to its complexity, and lack of control of randomization ratios to different treatment groups. To address the aforementioned issues, we propose a Response Adaptive Block Randomization (RABR) design allowing arbitrarily prespecified randomization ratios for the control and high-performing groups to meet clinical trial objectives. We show the validity of the conventional unweighted test in RABR with a controlled type I error rate based on the weighted combination test for sample size adaptive design invoking no large sample approximation. The advantages of the proposed RABR in terms of robustly reaching target final sample size to meet regulatory requirements and increasing statistical power as compared with the popular Doubly Adaptive Biased Coin Design are demonstrated by statistical simulations and a practical clinical trial design example.

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Optimal treatment for women with a persisting pregnancy of unknown location, a randomized controlled trial: The ACT-or-NOT trial

Abstract: This multicenter randomized controlled trial will provide guidance for evidence-based management for women who have persisting pregnancy of unknown location.

Cited by 10 publications

References 18 publications

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Declaring a gestation nonviable: when 99% certainty is not enough

A practical response adaptive block randomization (RABR) design with analytic type I error protection

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