Management of Pregnancies of Unknown Location (PUL)
Primary Purpose
Pregnancy, Ectopic, Pregnancy, High Risk, Pregnancy Early
Status
Active
Phase
Not Applicable
Locations
Sweden
Study Type
Interventional
Intervention
Risk classification of PUL by M4
Risk classification of PUL by NICE
Sponsored by
About this trial
This is an interventional diagnostic trial for Pregnancy, Ectopic
Eligibility Criteria
Inclusion Criteria:
- Patients with a PUL
- Patients with mild or no symptoms
- Patients willing to be randomized
- First hCG value <10,000 IU/L
- Patients with an interval between two hCG measurements of 44-56 h
Exclusion Criteria:
- Hemodynamically unstable patients
- Hemoperitoneum
- Patients not managed as outpatients during the course of the initial two hCG measurements
- Non-understanding of the oral or written study information
Sites / Locations
- Södra Älvsborgs Sjukhus
- Sahlgrenska University Hospital
- Skaraborgs sjukhus Skövde
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
M4
NICE
Arm Description
High risk classification if the chance of the PUL being an EP ≥5 %; a calculation based on the average value of the two hCG and the ratio of these two hCG (0 h/48 h). Otherwise a low risk classification is made and a predicted outcome of either an IUP or failed PUL is presented.
High risk classification if the change in rising hCG levels ≤ 63 % or the change in declining hCG ≤ 50 %. If these cut-offs are exceeded the PUL is classified as low risk and predicted to be either an IUP or failed PUL depending on rising or declining hCG levels.
Outcomes
Primary Outcome Measures
Sensitivity
EPs (percent) correctly classified as high risk of being an EP among PULs
Specificity
IUPs and failed PULs (percent) correctly classified as low risk of being an EP among PULs
Secondary Outcome Measures
HAD (Hospital and anxiety scale)
Scoring (Depression and anxiety):
0-7=Normal Borderline abnormal=8-10 11-21=Abnormal
Follow up visits (efficacy)
Number of hCG and TVS performed overall and within each final outcome (EP, IUP, and failed PUL)
Adverse events
Number of treatment related adverse events as assessed by EMA (European medicines agency)
Deviation from PUL management protocol
Number of unplanned visits, initiated by the physician or the patient
Treatment of ectopic pregnancy
Surgical (laparoscopic salpingotomy/salpingectomy), medical (MTX) or expectant management. Number of ruptured EPs.
The Short Form (36) Health Survey
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section.Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Sensitivity (M6)
EPs (%) correctly classified as high risk of being an EP among PULs
Specificity (M6)
IUPs and failed PULs (%) correctly classified as low risk of being an EP among PULs
Specificity, optimal cut-off
Optimal cut-off in hCG decline (percent) between two measurements to correctly classify IUPs and failed PULs as low risk of being an EP among PULs with declining hCG levels.
Sensitivity, optimal cut-off
Optimal cut-off in hCG decline (percent) between two measurements to correctly classify an EP as high risk among PULs with declining hCG levels.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03461835
Brief Title
Management of Pregnancies of Unknown Location (PUL)
Official Title
- a Randomized Control Trial of Two hCG- Based Decision Support Models
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 22, 2018 (Actual)
Primary Completion Date
March 31, 2023 (Actual)
Study Completion Date
March 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Göteborg University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
In a randomized multicenter trial the investigators want to compare the ability of two hCG-based models in correctly classifying EPs as high risk among PULs and correctly classifying IUPs and failed PULs as low risk after two hCG measurements.
After the classification of PULs into high or low risk of EP, the clinical management will be the same within each risk group (high and low) regardless of randomization group (which model classified the patients). The clinical management will be according to the management protocol published in a NICE guideline.
Detailed Description
Pregnancy of unknown location (PUL) is a term used to describe a situation where there is no evidence of a gestation either intra-or extrauterine on transvaginal sonography (TVS) in women seeking medical attention for various reasons in early pregnancy. The principal tool in PUL management besides TVS is the interpretation of the change in serial serum human chorionic gonadotropin (hCG) levels. A recent meta-analysis concluded that there is not enough evidence to recommend a specific strategy using hCG when managing PULs. In a NICE (National Institute of health and care excellence) guideline however women with a PUL acceptable for outpatient surveillance, where the rate of change in rising hCG levels surpassing 63 % in 48 hours (h) highly likely represents an IUP and the patient is triaged to a TVS after one week. Those with a decline in hCG levels of more than 50 % are predicted to be failed PULs and a urinary pregnancy test (UPT) after two weeks is appropriate. If the rate of change in hCG levels fail to meet these cut-offs a re-visit within 24 h is warranted in order to possibly diagnose an EP and suitable treatment selected. In a previous study; an hCG based logistic regression model, M4 classified 70 % of all PULs as low risk of being an EP, hence qualifying for a reduced follow-up while correctly identifying 88 % of EPs. A study from Sahlgrenska University hospital (SU) evaluated the M4 model with similar results, where also the cut-offs by NICE similarly identified 86 % of EPs but to a lesser extent correctly classified low risk PULs. Another finding in the study was that EPs identified by M4 mainly depicted rising hCG levels opposed to the NICE model identifying mainly EPs with declining hCG levels which could have clinical consequences since EPs with rising hCG levels more often seem to necessitate laparoscopic surgery and maybe a postponed diagnosis could be deleterious in these cases. Hence, the M4 model potentially would be better than the NICE cut-offs for PUL management. None of these findings however have been evaluated in a randomized controlled trial (RCT). An updated version of M4 named M6 was first published 2016 and has not been externally validated. Neither has prior cut-offs of declining hCG levels currently used to define a failed PUL.
The handling of these women is often lengthy with a high level of uncertainty before a final diagnosis can be made. The psychological morbidity in this group is largely unknown, while well acknowledged in women following miscarriage, were up to 41% self-reporting clinically significant levels of anxiety and 36% reporting depression within 1 month. In a recent study 24 % (CI 21-28) and 11 % (8-14) respectively of women with either a miscarriage or ectopic pregnancy experienced moderate or severe anxiety and depression according to the Hospital Anxiety Depression Scale (HADS), compared to 13 % (7-21) and 2 % (1-8) in a control group without complications in early pregnancy. We aim to determine the presence and severity of psychological distress and quality of life among women with a pregnancy of unknown location.
A secondary objective is to test following hypothesis: Women with an early normal pregnancy starting as a pregnancy of unknown location have twice as high probability of having HADS-scores above or equal to eight on both subscales, than women with an early normal pregnancy.
We calculated that we would need 121 women in each group to reach a power of 80 % to detect an absolute difference of 15 percentage points after one week, with a 15 % incidence of HADS anxiety score ≥ 8 among control subjects and 30 % among IUP starting as a PUL at a two-sided alpha level of 0.05 (20). For protection against that 10 % of patients will be lost to follow-up a total of 130 women are included in each group. In a second calculation based on using HADS as a continuous scale, 94 women would need to be included in each group to detect an absolute two points difference on the anxiety subscale of the HADS assuming a mean score of 6.0 and a standard deviation of 3.4 in control subjects, at a significance level 0.05 and power 0.80. This minimally important difference is based on mean scores on the HADS anxiety subscale reported for women in early pregnancy in prior studies (20-22). We plan to include a total of 210 women with a 1:1 ratio to account for an expected 10 % loss to follow-up.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnancy, Ectopic, Pregnancy, High Risk, Pregnancy Early
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1200 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
M4
Arm Type
Active Comparator
Arm Description
High risk classification if the chance of the PUL being an EP ≥5 %; a calculation based on the average value of the two hCG and the ratio of these two hCG (0 h/48 h). Otherwise a low risk classification is made and a predicted outcome of either an IUP or failed PUL is presented.
Arm Title
NICE
Arm Type
Active Comparator
Arm Description
High risk classification if the change in rising hCG levels ≤ 63 % or the change in declining hCG ≤ 50 %. If these cut-offs are exceeded the PUL is classified as low risk and predicted to be either an IUP or failed PUL depending on rising or declining hCG levels.
Intervention Type
Diagnostic Test
Intervention Name(s)
Risk classification of PUL by M4
Intervention Description
High or low risk of being an ectopic pregnancy
Intervention Type
Diagnostic Test
Intervention Name(s)
Risk classification of PUL by NICE
Intervention Description
High or low risk of being an ectopic pregnancy
Primary Outcome Measure Information:
Title
Sensitivity
Description
EPs (percent) correctly classified as high risk of being an EP among PULs
Time Frame
1 month
Title
Specificity
Description
IUPs and failed PULs (percent) correctly classified as low risk of being an EP among PULs
Time Frame
1 month
Secondary Outcome Measure Information:
Title
HAD (Hospital and anxiety scale)
Description
Scoring (Depression and anxiety):
0-7=Normal Borderline abnormal=8-10 11-21=Abnormal
Time Frame
1 month
Title
Follow up visits (efficacy)
Description
Number of hCG and TVS performed overall and within each final outcome (EP, IUP, and failed PUL)
Time Frame
1 month
Title
Adverse events
Description
Number of treatment related adverse events as assessed by EMA (European medicines agency)
Time Frame
1 month
Title
Deviation from PUL management protocol
Description
Number of unplanned visits, initiated by the physician or the patient
Time Frame
1 month
Title
Treatment of ectopic pregnancy
Description
Surgical (laparoscopic salpingotomy/salpingectomy), medical (MTX) or expectant management. Number of ruptured EPs.
Time Frame
1 month
Title
The Short Form (36) Health Survey
Description
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section.Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Time Frame
1 month
Title
Sensitivity (M6)
Description
EPs (%) correctly classified as high risk of being an EP among PULs
Time Frame
1 month
Title
Specificity (M6)
Description
IUPs and failed PULs (%) correctly classified as low risk of being an EP among PULs
Time Frame
1 month
Title
Specificity, optimal cut-off
Description
Optimal cut-off in hCG decline (percent) between two measurements to correctly classify IUPs and failed PULs as low risk of being an EP among PULs with declining hCG levels.
Time Frame
1 month
Title
Sensitivity, optimal cut-off
Description
Optimal cut-off in hCG decline (percent) between two measurements to correctly classify an EP as high risk among PULs with declining hCG levels.
Time Frame
1 month
10. Eligibility
Sex
Female
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with a PUL
Patients with mild or no symptoms
Patients willing to be randomized
First hCG value <10,000 IU/L
Patients with an interval between two hCG measurements of 44-56 h
Exclusion Criteria:
Hemodynamically unstable patients
Hemoperitoneum
Patients not managed as outpatients during the course of the initial two hCG measurements
Non-understanding of the oral or written study information
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annika Strandell, Ass.prof.
Organizational Affiliation
Göteborg University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Södra Älvsborgs Sjukhus
City
Borås
ZIP/Postal Code
501 82
Country
Sweden
Facility Name
Sahlgrenska University Hospital
City
Göteborg
ZIP/Postal Code
413 45
Country
Sweden
Facility Name
Skaraborgs sjukhus Skövde
City
Skövde
ZIP/Postal Code
541 85
Country
Sweden
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
20947073
Citation
Barnhart K, van Mello NM, Bourne T, Kirk E, Van Calster B, Bottomley C, Chung K, Condous G, Goldstein S, Hajenius PJ, Mol BW, Molinaro T, O'Flynn O'Brien KL, Husicka R, Sammel M, Timmerman D. Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril. 2011 Mar 1;95(3):857-66. doi: 10.1016/j.fertnstert.2010.09.006. Epub 2010 Oct 14.
Results Reference
background
PubMed Identifier
22956411
Citation
van Mello NM, Mol F, Opmeer BC, Ankum WM, Barnhart K, Coomarasamy A, Mol BW, van der Veen F, Hajenius PJ. Diagnostic value of serum hCG on the outcome of pregnancy of unknown location: a systematic review and meta-analysis. Hum Reprod Update. 2012 Nov-Dec;18(6):603-17. doi: 10.1093/humupd/dms035. Epub 2012 Sep 6.
Results Reference
background
PubMed Identifier
23638497
Citation
National Collaborating Centre for Women's and Children's Health (UK). Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management in Early Pregnancy of Ectopic Pregnancy and Miscarriage. London: RCOG Press; 2012 Dec. Available from http://www.ncbi.nlm.nih.gov/books/NBK132775/
Results Reference
background
PubMed Identifier
23293216
Citation
Van Calster B, Abdallah Y, Guha S, Kirk E, Van Hoorde K, Condous G, Preisler J, Hoo W, Stalder C, Bottomley C, Timmerman D, Bourne T. Rationalizing the management of pregnancies of unknown location: temporal and external validation of a risk prediction model on 1962 pregnancies. Hum Reprod. 2013 Mar;28(3):609-16. doi: 10.1093/humrep/des440. Epub 2013 Jan 4.
Results Reference
background
PubMed Identifier
27580995
Citation
Fistouris J, Bergh C, Strandell A. Classification of pregnancies of unknown location according to four different hCG-based protocols. Hum Reprod. 2016 Oct;31(10):2203-11. doi: 10.1093/humrep/dew202. Epub 2016 Aug 31.
Results Reference
background
PubMed Identifier
23303651
Citation
Mavrelos D, Nicks H, Jamil A, Hoo W, Jauniaux E, Jurkovic D. Efficacy and safety of a clinical protocol for expectant management of selected women diagnosed with a tubal ectopic pregnancy. Ultrasound Obstet Gynecol. 2013 Jul;42(1):102-7. doi: 10.1002/uog.12401. Epub 2013 May 27.
Results Reference
background
PubMed Identifier
27165655
Citation
Bobdiwala S, Guha S, Van Calster B, Ayim F, Mitchell-Jones N, Al-Memar M, Mitchell H, Stalder C, Bottomley C, Kothari A, Timmerman D, Bourne T. The clinical performance of the M4 decision support model to triage women with a pregnancy of unknown location as at low or high risk of complications. Hum Reprod. 2016 Jul;31(7):1425-35. doi: 10.1093/humrep/dew105. Epub 2016 May 10.
Results Reference
background
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Management of Pregnancies of Unknown Location (PUL)
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