A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)

trial protocol

James May, Colin Duncan, Ben Mol, Siladitya Bhattacharya, Jane Daniels, Lee Middleton, Catherine Hewitt, Arri Coomarasamy, Davor Jurkovic, Tom Bourne, Cecilia Bottomley, Alexandra Peace-Gadsby, Ann Doust, Stephen Tong, Andrew W Horne (Corresponding Author)

Research output: Contribution to journalArticle

1 Downloads (Pure)

Abstract

BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.

METHODS AND ANALYSIS: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.

DISCUSSION: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.

TRIAL REGISTRATION: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

Original languageEnglish
Article number643
JournalTrials
Volume19
DOIs
Publication statusPublished - 20 Nov 2018

Fingerprint

Tubal Pregnancy
Ectopic Pregnancy
Clinical Protocols
Methotrexate
Randomized Controlled Trials
Placebos
Chorionic Gonadotropin
Therapeutics
Epidermal Growth Factor Receptor
Serum
Online Systems
Ambulatory Monitoring
Menstruation
gefitinib
Gynecology
Health Personnel
Registries
Emergencies

Keywords

  • Abortifacient Agents, Nonsteroidal/administration & dosage
  • Adolescent
  • Adult
  • Clinical Trials, Phase III as Topic
  • Double-Blind Method
  • Drug Therapy, Combination
  • ErbB Receptors/antagonists & inhibitors
  • Female
  • Gefitinib/administration & dosage
  • Humans
  • Methotrexate/administration & dosage
  • Middle Aged
  • Multicenter Studies as Topic
  • Pregnancy
  • Pregnancy, Tubal/diagnosis
  • Protein Kinase Inhibitors/administration & dosage
  • Randomized Controlled Trials as Topic
  • Time Factors
  • Treatment Outcome
  • United Kingdom
  • Young Adult

Cite this

A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3) : trial protocol. / May, James; Duncan, Colin; Mol, Ben; Bhattacharya, Siladitya; Daniels, Jane; Middleton, Lee; Hewitt, Catherine; Coomarasamy, Arri; Jurkovic, Davor; Bourne, Tom; Bottomley, Cecilia; Peace-Gadsby, Alexandra; Doust, Ann; Tong, Stephen; Horne, Andrew W (Corresponding Author).

In: Trials, Vol. 19, 643, 20.11.2018.

Research output: Contribution to journalArticle

May, J, Duncan, C, Mol, B, Bhattacharya, S, Daniels, J, Middleton, L, Hewitt, C, Coomarasamy, A, Jurkovic, D, Bourne, T, Bottomley, C, Peace-Gadsby, A, Doust, A, Tong, S & Horne, AW 2018, 'A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol', Trials, vol. 19, 643. https://doi.org/10.1186/s13063-018-3008-6
May, James ; Duncan, Colin ; Mol, Ben ; Bhattacharya, Siladitya ; Daniels, Jane ; Middleton, Lee ; Hewitt, Catherine ; Coomarasamy, Arri ; Jurkovic, Davor ; Bourne, Tom ; Bottomley, Cecilia ; Peace-Gadsby, Alexandra ; Doust, Ann ; Tong, Stephen ; Horne, Andrew W. / A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3) : trial protocol. In: Trials. 2018 ; Vol. 19.
@article{54d678a4fef14a77988fda78dad8d059,
title = "A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol",
abstract = "BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70{\%} of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.METHODS AND ANALYSIS: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.DISCUSSION: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.TRIAL REGISTRATION: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.",
keywords = "Abortifacient Agents, Nonsteroidal/administration & dosage, Adolescent, Adult, Clinical Trials, Phase III as Topic, Double-Blind Method, Drug Therapy, Combination, ErbB Receptors/antagonists & inhibitors, Female, Gefitinib/administration & dosage, Humans, Methotrexate/administration & dosage, Middle Aged, Multicenter Studies as Topic, Pregnancy, Pregnancy, Tubal/diagnosis, Protein Kinase Inhibitors/administration & dosage, Randomized Controlled Trials as Topic, Time Factors, Treatment Outcome, United Kingdom, Young Adult",
author = "James May and Colin Duncan and Ben Mol and Siladitya Bhattacharya and Jane Daniels and Lee Middleton and Catherine Hewitt and Arri Coomarasamy and Davor Jurkovic and Tom Bourne and Cecilia Bottomley and Alexandra Peace-Gadsby and Ann Doust and Stephen Tong and Horne, {Andrew W}",
year = "2018",
month = "11",
day = "20",
doi = "10.1186/s13063-018-3008-6",
language = "English",
volume = "19",
journal = "Trials",
issn = "1745-6215",
publisher = "BioMed Central",

}

TY - JOUR

T1 - A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)

T2 - trial protocol

AU - May, James

AU - Duncan, Colin

AU - Mol, Ben

AU - Bhattacharya, Siladitya

AU - Daniels, Jane

AU - Middleton, Lee

AU - Hewitt, Catherine

AU - Coomarasamy, Arri

AU - Jurkovic, Davor

AU - Bourne, Tom

AU - Bottomley, Cecilia

AU - Peace-Gadsby, Alexandra

AU - Doust, Ann

AU - Tong, Stephen

AU - Horne, Andrew W

PY - 2018/11/20

Y1 - 2018/11/20

N2 - BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.METHODS AND ANALYSIS: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.DISCUSSION: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.TRIAL REGISTRATION: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

AB - BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.METHODS AND ANALYSIS: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.DISCUSSION: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.TRIAL REGISTRATION: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

KW - Abortifacient Agents, Nonsteroidal/administration & dosage

KW - Adolescent

KW - Adult

KW - Clinical Trials, Phase III as Topic

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - ErbB Receptors/antagonists & inhibitors

KW - Female

KW - Gefitinib/administration & dosage

KW - Humans

KW - Methotrexate/administration & dosage

KW - Middle Aged

KW - Multicenter Studies as Topic

KW - Pregnancy

KW - Pregnancy, Tubal/diagnosis

KW - Protein Kinase Inhibitors/administration & dosage

KW - Randomized Controlled Trials as Topic

KW - Time Factors

KW - Treatment Outcome

KW - United Kingdom

KW - Young Adult

U2 - 10.1186/s13063-018-3008-6

DO - 10.1186/s13063-018-3008-6

M3 - Article

VL - 19

JO - Trials

JF - Trials

SN - 1745-6215

M1 - 643

ER -