Plain English Summary
Background and study aims
Infection following miscarriage surgery is a problem affecting over 33 million pregnancies each year. A majority of women will have their miscarriage managed with surgery to empty the womb. Infection can occur following this surgery and this is a particular problem in low income countries. In some low income countries the rates of infection following miscarriage surgery are as high as 30%. These infections can result in death, serious illness or long-term health problems. Currently international and national medical guidelines do not recommend antibiotics to be given routinely in miscarriage surgery, because there is no evidence that tells us that this works. If antibiotics are given just before the procedure of miscarriage surgery this may reduce the chance of infection occurring. The aim of this study is to test this in four low income countries.
Who can participate?
Women who have suffered a miscarriage and are scheduled to have their miscarriage managed surgically, through an operation to empty their uterus.
What does the study involve?
Participants are offered either a single dose of prophylactic antibiotics (doxycycline and metronidazole) or an identical looking dummy pill (placebo), to be taken by mouth before the surgery. Participants are followed for 2 weeks after surgery to see if there is any difference in the rate of women developing pelvic infection. If any women show signs of infection they are given full treatment as soon as it is detected. The study also assess whether using antibiotics before surgery is cost effective.
What are the possible benefits and risks of participating?
Those women taking part in the study may benefit by having their health followed very carefully after the surgery. The study team also facilitate these women receiving prompt treatment if there are any problems. Even if participants do not benefit personally they study may help improve care for women in the future. Risks of taking part include the small risk of side effects from doxycycline or metronidazole, but these medications have been selected because they have a low risk of serious side effects such as allergy.
Where is the study run from?
The study is being managed and sponsored by the University of Birmingham (UK). The study sites are:
1. Malawi: Queen Elizabeth Central Hospital, Zomba Central Hospital and Kamuzu Central Hospital
2. Uganda: Mbale Regional Referral Hospital and Soroti Regional Referral Hospital
3. Tanzania: St Francis Hospital, Mwananyamala Hospital and Bagamoyo District Hospital
4. Pakistan: Aga Khan University Main Hospital, Hyderabad Hospital, Garden Hospital, Kharader Hospital and Karimabad Hospital
When is the study starting and how long is it expected to run for?
September 2013 to May 2017
Who is funding the study?
The Medical Research Council, the Wellcome Trust and the Department for International Development (UK)
Who is the main contact?
Dr David Lissauer
d.m.lissauer@bham.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Prof Arri Coomarasamy
ORCID ID
Contact details
School of Clinical and Experimental Medicine
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Type
Scientific
Additional contact
Dr David Lissauer
ORCID ID
Contact details
School of Clinical and Experimental Medicine
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
RG_12-048
Study information
Scientific title
Effectiveness of antibiotic prophylaxis during surgical evacuation of the uterus for miscarriage management in low income countries: a multinational, randomised, double-blind placebo-controlled trial
Acronym
AIMS
Study hypothesis
To test the hypothesis that in women having miscarriage surgery, pre-surgery prophylactic antibiotics (oral doxycycline 400 mg and oral metronidazole 400 mg) reduces the risk of pelvic infection within 14 days of surgery.
Ethics approval
1. UK - Liverpool Ethics, 10/04/2013, protocol 13.15
2. Malawi - College of Medicine Research Ethics Committee, 11/10/2013, P.06/13/1393
3. Pakistan - Aga Khan University Research Ethics Committee, 11/11/2013, 2756-obs-erc-13
4. Pakistan - Drugs Regulatory Authority of Pakistan, 16/09/2014, F.6-1/2013
5. Tanzania - IHI IRB, 30/08/2013, IHI/IRB/no.25-2013
6. Tanzania - NIMRI, 01/11/2013, NIMRlHQ/R.8aJVol. IX/1652
7. Tanzania - TDFA, 04/08/2014, TFDAI4/CTR/001/03
8. Uganda - UNCST, 28/05/2014, HS 1400
9. Uganda - NDA, 06/12/2013, 347/ESR/NDA/DID-06/2013
Study design
Randomised double-blind placebo-controlled multi-national study with economic evaluation
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Prevention
Patient information sheet
http://www.aimstrial.org/patientinfo.aspx?lang=1
Condition
Infection, miscarriage, sepsis, antibiotic prophylaxis
Intervention
1. Doxycycline 400 mg oral and Metronidazole 400 mg oral, taken approximately 2 hours before the scheduled time of surgery
2. Placebo tablets of identical appearance and weight
Both the woman and health worker will not know which type of tablets they have been given. Participants are followed for 2 weeks after surgery to see if there is any difference in the rate of women developing pelvic infection. If any women show signs of infection they will be given full treatment as soon as it is detected. The study will also determine whether using antibiotics before surgery is cost effective.
Intervention type
Drug
Phase
Not Applicable
Drug names
Doxycycline, metronidazole
Primary outcome measure
Current primary outcome measures as of 27/01/2017:
Pelvic infection within 14* days of surgery, defined as two or more of:
1. Purulent vaginal discharge - on vaginal examination
2. Pyrexia >38.0°C - using a standardised tympanic thermometer
3. Tenderness on clinical examination
4. A white cell count >12x109/l , with no other recognised cause of infection
5. Or one of the above features, with the clinically identified need (following clinical assessment) to administer antibiotics for the treatment of presumed pelvic infection.
*In cases where participants do not return for follow up within this period, follow up until 28 days will be acceptable
Previous primary outcome measures:
Pelvic infection within 14 days of surgery, defined as two or more of:
1. Purulent vaginal discharge
2. Pyrexia >38.0°C
3. Uterine tenderness on examination and d) a white cell count >15x10^9 /l, with no other recognised cause of infection
Secondary outcome measures
Current secondary outcome measures as of 27/01/2017:
1. Secondary outcome measures:
Assessed at the follow-up appointment with a clinical assessment, history taking and reviewing available patient medical records:
1.1. Overall antibiotic use
1.2. Each component of the primary outcome
1.3. Death
1.4. Hospital admission
1.5. Unplanned consultations
1.6. Blood transfusion
1.7. Vomiting
1.8. Diarrhoea
1.9. Adverse events
1.10. Anaphylaxis and allergy
1.11. Duration of clinical symptoms (pain, additional analgesia, vaginal bleeding)
1.12. Days before return to usual daily activities
2. Outcomes for exploratory analyses:
2.1. Surgical complications
2.2. Full microbiological information, antibiotic sensitivities and any evidence of drug resistance will be collected where available
3. Resource use outcomes:
Resource use data will be prospectively collected to estimate the costs associated with the additional use of antibiotics in all participating centres in both arms of the trial. The main resources to be monitored include:
3.1. Additional staff time for explanation and dispensing of the medication
3.2. Type and grade of the health professional caring for each woman
3.3. Inpatient admissions and consultations (planned and unplanned)
3.4. Outpatient and emergency admissions and consultations
3.5. Unplanned further surgical interventions (e.g. curettage)
3.6. Additional investigation costs (e.g. ultrasounds)
3.7. Consumables (e.g. medication)
3.8. Resources used to manage surgery and treatment related complications (e.g. bleeding requiring transfusion)
Previous secondary outcome measures:
1. Secondary measures:
1.1. Death
1.2. Hospital admission
1.3. Unplanned consultations
1.4. Antibiotic use for presumed diagnosis of pelvic infection
1.5. Blood transfusion
1.6. Vomiting
1.7. Diarrhoea
1.8. Adverse events
1.9. Anaphylaxis and allergy
1.10. Duration of clinical symptoms (pain, additional analgesia, vaginal bleeding, days before return to usual daily activities)
2. Outcomes for exploratory analyses:
2.1. Surgical complications
2.2. Full microbiological information, antibiotic sensitivities and any evidence of drug resistance will be collected where available
3. Resource use outcomes: The main resources to be monitored include:
3.1. Additional staff time for explanation and dispensing of the medication
3.2. Type and grade of the health professional caring for each woman
3.3. Inpatient admissions and consultations (planned and unplanned)
3.4. Outpatient and emergency admissions and consultations
3.5. Unplanned further surgical interventions (e.g. curettage)
3.6. Additional investigation costs (e.g. ultrasounds)
3.7. Consumables (e.g. medication)
3.8. Resources used to manage surgery and treatment related complications (e.g. bleeding requiring transfusion)
Overall trial start date
01/09/2013
Overall trial end date
16/05/2017
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Women with a spontaneous miscarriage (under 22 weeks gestation)
2. Women undergoing surgical evacuation of the uterus (by manual vacuum aspiration, suction curettage or sharp curettage)
3. Willing and able to give informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
3400
Total final enrolment
3412
Participant exclusion criteria
1. Induced abortion of pregnancy
2. Septic miscarriage or evidence of infection
3. Allergy to either of the antibiotics
4. Current antibiotic use, or antibiotic use in the 7 days preceding surgical evacuation
5. Current febrile illness (temperature < 38oC)
7. Other contraindication to doxycycline or metronidazole use
8. Patient with condition requiring immediate care e.g. severe haemorrhage
9. Age less than 16 years
Recruitment start date
02/06/2014
Recruitment end date
26/04/2017
Locations
Countries of recruitment
Malawi, Pakistan, Tanzania, Uganda
Trial participating centre
Queen Elizabeth Central Hospital
-
Malawi
Trial participating centre
Zomba Central Hospital
-
Malawi
Trial participating centre
Kamuzu Central Hospital
-
Malawi
Trial participating centre
Mbale Regional Referral Hospital
-
Uganda
Trial participating centre
Soroti Regional Referral Hospital
-
Uganda
Trial participating centre
St Francis Hospital
-
Tanzania
Trial participating centre
Mwananyamala Hospital
-
Tanzania
Trial participating centre
Bagamoyo District Hospital
-
Tanzania
Trial participating centre
Aga Khan University Main Hospital
-
Pakistan
Trial participating centre
Hyderabad Hospital
-
Pakistan
Trial participating centre
Garden Hospital
-
Pakistan
Trial participating centre
Kharader Hospital
-
Pakistan
Trial participating centre
Karimabad Hospital
-
Pakistan
Funders
Funder type
Government
Funder name
Joint Global Health Trials Scheme
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Medical Research Council (UK), grant ref: MR/J009792/1
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Funder name
Wellcome Trust (UK), grant ref: 099943
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Funder name
Department for International Development (DfID) (UK)
Alternative name(s)
Department for International Development, UK, DFID
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Publication is planned in a high-impact peer reviewed journal within one year after the overall trial end date.
IPD sharing plan
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.
Intention to publish date
Participant level data
Other
Basic results (scientific)
Publication list
1. 2018 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/29685179
2. 2019 results in https://www.ncbi.nlm.nih.gov/pubmed/30865795 (added 14/03/2019)
3. 2018 systematic review in https://www.ncbi.nlm.nih.gov/pubmed/29739349