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Trial registered on ANZCTR


Registration number
ACTRN12618001128280
Ethics application status
Approved
Date submitted
29/06/2018
Date registered
10/07/2018
Date last updated
29/07/2019
Date data sharing statement initially provided
29/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Is methotrexate better than placebo in the treatment of early ectopic pregnancies?
Scientific title
Methotrexate versus placebo in early tubal ectopic pregnancies: a double-blinded randomised trial
Secondary ID [1] 295365 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ectopic pregnancy 308592 0
Condition category
Condition code
Reproductive Health and Childbirth 307569 307569 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To study treatment with systemic methotrexate (MTX) in a single dose intramuscular regimen (50mg/m^2 based on patient body surface area) in patients with ectopic pregnancy (EP) and increasing/plateauing serum hCG concentrations, with regards to treatment success, complications and length of follow-up. The primary hypothesis is that single-dose MTX is more effective than a placebo in patients with an early tubal EPs and rising or plateauing hCG. Since the intervention is administered by a clinically-trained nurse, there are no concerns with intervention adherence. In the traditional single dose MTX protocols, additional doses may be required if the EP is not resolving. In this study, multiple doses of MTX or placebo may be administered, which is one of the secondary outcomes.
Intervention code [1] 301687 0
Treatment: Drugs
Comparator / control treatment
Placebo, in this case, will be an intramuscular injection of normal saline. In traditional protocols, if an EP is not resolving after a single dose of MTX, as demonstrated by an inappropriately declining hCG, more doses of medication are administered. Since we do not know whether an EP could resolve following a period of plateauing hCG, expectant management may still be appropriate. As such, the patients allocated to the placebo group could receive up to 4 doses of placebo if the hCG is plateauing on hCG blood tests. Placebo will not be given if the hCG is increasing by more than 15% or the patient demonstrates signs of EP rupture or haemodynamic instability.
Control group
Placebo

Outcomes
Primary outcome [1] 306519 0
The primary outcome measure is an uneventful decline of serum hCG to an undetectable level (< 5 IU/L) by the initial intervention strategy, i.e. single dose systemic MTX or placebo. In the context of this study, uneventful means the patient does not experience any complication such as ruptured EP or requirement of subsequent doses of medication. It means that the EP resolves after the first and only injection, whether that be MTX or placebo.
Timepoint [1] 306519 0
All patients will attend for a serum hCG measurement on day 4. Provided patients are haemodynamically stable, they will attend for another blood test on day 7. If a decline in serum hCG > 15% between days 4 - 7 is observed, weekly blood tests will be scheduled until undetectable hCG levels.
Secondary outcome [1] 348760 0
(Re)interventions (additional MTX injections or surgical procedures),
Timepoint [1] 348760 0
Any point in the timeline from diagnosis to resolution of EP.
Secondary outcome [2] 348844 0
Treatment complications including intra-abdominal bleeding necessitating blood transfusion, emergency surgeries,
Timepoint [2] 348844 0
Any point in the timeline from diagnosis to resolution of EP.
Secondary outcome [3] 348845 0
Time to failure of initial therapy,
Timepoint [3] 348845 0
Time between initial diagnosis and requirement of another treatment options (e.g. MTX in the case of those receiving placebo or surgery).

If serum hCG levels increase or decrease < 15% between days 4 - 7, a second dose of MTX 50mg/m^2/Placebo IM will be given and that day will be redefined as the new day 1, following which the above protocol is followed. If at any point in the weekly blood test monitoring, there is a < 15% hCG decline, another dose of MTX/Placebo is given to a maximum of 4 doses in total, at which point if successful resolution is still not ensured, routine unblinding will occur and this will permit informed consent on proceeding with surgery or MTX management (in the setting of placebo randomised patients). If three weekly values are similar, we give an additional dose of MTX 50 mg/m^2/Placebo IM. If any increase in serum hCG > 15% between days 4 - 7 or at any subsequent follow-up, unblinding will occur and again, patients will be counselled on next steps: MTX or surgery
Secondary outcome [4] 348846 0
Time to resolution of pregnancy.
Timepoint [4] 348846 0
Time between initial diagnosis and resolution of pregnancy (i.e. hCG < 5 IU/ml)

Eligibility
Key inclusion criteria
Haemodynamically stable patients, with a visible tubal EP on transvaginal ultrasound (an ectopic gestational sac with or without the embryo, or an ectopic mass) and serum hCG concentrations rising after 48 hours observation and below 1500 IU/L are eligible for the trial. This hCG cut-off level is based on previous uncontrolled and controlled studies on single dose MTX. We have adopted inclusion criteria widely used in studies on MTX17. Using these criteria, we estimate approximately 24% of all EPs will be eligible for entry in the trial. Patients of all ages will be considered eligible.
Minimum age
13 Years
Maximum age
60 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with declining hCG, a viable EP (embryonic cardiac activity on ultrasound), severe abdominal pain and/or peritonism, haemodynamic instability, evidence of significant haemoperitoneum on scan (> 300ml, blood above the uterine fundus and/or in the Morison's pouch) or contraindications to MTX (leukopaenia, thrombocytopaenia, or elevated serum liver enzymes or creatinine) are not included.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be achieved by central randomisation by list held in the Cancer Care Pharmacy. The list will not be in the possession of any study physicians. allocation involves contacting the holder of the allocation schedule who is at the Cancer Care Pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be assigned on an individual basis to an injection of MTX or a placebo of normal saline 0.9%. Patients will remain in the same allocation as noted in the above Follow Up section.

Randomisation will be performed using blocks, stratified by centre. Treatment codes lists for each centre will be exported and sent to the pharmacy. The randomisation list will be kept in the pharmacy. The pharmacist responsible for reviewing the randomisation list will be unblinded. This is necessary in order to blind the clinicians providing the aftercare and serum hCG follow up of recruited patients. The fact that the pharmacists will not be blinded will not impact negatively on the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data analysis will be performed according to the intention to treat principle. Outcome measures will be compared by calculating relative risks and their 95% confidence intervals. Where appropriate, results will be given as mean values with 95% confidence intervals or medians with a range. Comparisons will be undertaken using 2-sample t-tests or Mann-Whitney U Test as appropriate. For the time to event outcomes, Kaplan-Meier curves will be used to summarise the data, and comparisons will be made using a log-rank test.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
76
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11276 0
Nepean Hospital - Kingswood
Recruitment hospital [2] 11277 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 23162 0
2747 - Kingswood
Recruitment postcode(s) [2] 23163 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 299958 0
Hospital
Name [1] 299958 0
Nepean Hospital, Nepean Blue Mountains Local Health District
Country [1] 299958 0
Australia
Primary sponsor type
Hospital
Name
Nepean Hospital
Address
Nepean Hospital
Derby Street
Kingswood
2747
NSW
Country
Australia
Secondary sponsor category [1] 299338 0
None
Name [1] 299338 0
Address [1] 299338 0
Country [1] 299338 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300821 0
Nepean Blue Mountains Local Health District Human Research Ethics Committee
Ethics committee address [1] 300821 0
Nepean Hospital
Derby St
Kingswood
2747
NSW
Ethics committee country [1] 300821 0
Australia
Date submitted for ethics approval [1] 300821 0
01/01/2018
Approval date [1] 300821 0
11/07/2018
Ethics approval number [1] 300821 0
Ethics committee name [2] 301112 0
Nepean Blue Mountains Local Health District Human Research Ethics Committee
Ethics committee address [2] 301112 0
Derby Street
Kingswood
NSW 2747
Ethics committee country [2] 301112 0
Australia
Date submitted for ethics approval [2] 301112 0
30/01/2018
Approval date [2] 301112 0
11/07/2018
Ethics approval number [2] 301112 0
HREC/1/NEPEAN/18

Summary
Brief summary
Tubal ectopic pregnancies (EPs) are diagnosed earlier in their natural history due to transvaginal ultrasound (TVS) technology. There is no evidence that methotrexate (MTX) is necessary for all these early EPs, as many may resolve spontaneously in the absence of any treatment. Two recent randomised controlled trials demonstrate the safety of expectant management for patients with early EPs. In these studies, patients were randomised and treated with MTX or placebo on the day of diagnosis. By monitoring them expectantly without therapy for 48 hours following diagnosis, it is possible to identify patients with declining hCG levels, representing a subset of patients with spontaneous resolution of the EP. As such, the aim of this study is to verify if MTX is more effective than the placebo in patients with tubal EP and rising/plateauing serum hCG (< 1500 IU/L) levels at a 48-hour mark following definitive diagnosis.

Our goal is to study treatment with systemic MTX in a single dose intramuscular regimen in patients with EP and increasing/plateauing serum hCG concentrations, with regards to treatment success, complications and length of follow-up. The primary hypothesis is that single-dose MTX is more effective than a placebo in patients with an early tubal EPs and rising or plateauing hCG.
Trial website
Trial related presentations / publications
Public notes
Biochemical resolution of the pregnancy was chosen as the primary outcome because it is the more accurate measure of successful treatment. We did not choose the need for a second injection because the optimal dose of MTX is still unknown. The absence of indication for surgical intervention could be considered a more relevant outcome clinically, but we believe this is more prone to be biased by the individual decision of the surgeon. Biochemical resolution of the pregnancy has been used as a primary outcome measure by other studies on EP.

Contacts
Principal investigator
Name 84926 0
A/Prof George Condous
Address 84926 0
Nepean Clinical School, Nepean Hospital
62 Derby St
Kingswood
2747
NSW
Country 84926 0
Australia
Phone 84926 0
+61 2 4734 4777
Fax 84926 0
+61 2 4734 4887
Email 84926 0
[email protected]
Contact person for public queries
Name 84927 0
Mathew Leonardi
Address 84927 0
Nepean Clinical School, Nepean Hospital
62 Derby St
Kingswood
2747
NSW
Country 84927 0
Australia
Phone 84927 0
+61 2 4734 4777
Fax 84927 0
+61 2 4734 4887
Email 84927 0
[email protected]
Contact person for scientific queries
Name 84928 0
Mathew Leonardi
Address 84928 0
Nepean Clinical School, Nepean Hospital
62 Derby St
Kingswood
2747
NSW
Country 84928 0
Australia
Phone 84928 0
+61 2 4734 4777
Fax 84928 0
+61 2 4734 4887
Email 84928 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3556Study protocolIshwari Casikar, Chuan Lu, Shannon Reid, Tommaso Bignardi, Max Mongelli, Alastair Morris, Richard Wild and George Condous, “Methotrexate vs Placebo in Early Tubal Ectopic Pregnancy: A Multi- Centre Double-Blind Randomised Trial”, Reviews on Recent Clinical Trials (2012) 7: 238. https://doi.org/10.2174/157488712802281321  



Results publications and other study-related documents

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