Study design
This was a randomised, double-blind, parallel-group, placebo-controlled, multicentre, Phase III study with 1 : 1 randomisation to either intravenous iron or placebo. All patients were treated according to protocol and received double-blind intravenous iron therapy or placebo. All patients were followed for 6 months from date of operation. As the active and placebo infusion fluids cannot be matched in appearance, unblinded study personnel not otherwise involved in the study or in patient management were responsible for investigational drug administration. PREVENTT is reported in accordance with Consolidated Standards of Reporting Trials (URL: www.consort-statement.org/).
Aim
This study aimed to assess whether or not giving a single dose of intravenous iron to patients with anaemia prior to major abdominal surgery reduced the need for transfusion or the likelihood of death in the perioperative period. In addition, the effect of the intervention on postoperative complications, hospital stay, re-admission to hospital and quality-of-life outcomes was assessed.
Important changes to methods
The initial working protocol included an additional hospital visit for patients for assessment before their operation. This additional visit was not acceptable to patients, with failure to recruit patients in the first 4 months of the trial. In a protocol amendment, the timing of the preoperative assessments was changed such that these took place at the patient’s admission for their operation, avoiding the need for any additional visits to the hospital for the purpose of the trial. The amended trial protocol was relaunched at the start of 2014.
After this, there were only four further protocol amendments during the course of the trial, including reducing the timeline to surgery from 14 days to 10 days, revising the description for major surgery, adjusting the diagnosis of anaemia in line with the World Health Organization’s definitions (120 g/l for women and 130 g/l for men), and removing the need for preoperative liver function testing and updates as a result of revised Medicines and Healthcare products Regulatory Agency guidelines (see Appendix 1).
Participants
Inclusion criteria
Patients who met the following criteria at the start of treatment were eligible for the study:
Aged at least 18 years and providing signed written informed consent.
Undergoing elective major open abdominal surgery
benign or malignant disease
undergoing major surgery, defined as an operation of anticipated duration > 1 hour.
screening Hb level of ≥ 90 g/l (9.0 g/dl) but ≤ 120 g/l (12.0 g/dl) in women or 130 g/l (13.0 g/dl) in men within 4 weeks of randomisation.
Randomisation and administration of study infusion a minimum of 10 days and maximum of 42 days before the planned operation.
Women of childbearing potential had a negative pregnancy test (within last 7 days) and agreed to use effective form of contraception until 6 weeks post treatment.
Laboratory data used for the determination of eligibility at the baseline visit were not older than 4 weeks.
Exclusion criteria
Patients who, at the start of treatment, met any of the following criteria were not eligible for the study:
Undergoing laparoscopic surgery.
Body weight < 50 kg.
Known history of acquired iron overload, or family history of haemochromatosis or thalassaemia or TSAT > 50%.
Known reason for anaemia (e.g. untreated vitamin B12 or folate deficiency or haemoglobinopathy).
Known hypersensitivity to ferric carboxymaltose (Ferinject®; Vifor Pharma UK Limited, Staines-upon-Thames, UK) or its excipients.
Temperature > 37.5 °C or patient on non-prophylactic antibiotics.
Known chronic liver disease.
If clinically indicated for the patient to have liver function tests (LFTs) as part of pre-assessment for surgery and at this screening, alanine transaminase or aspartate transaminase was above three times the upper limit of the normal range.
Received erythropoietin or intravenous iron therapy in the previous 12 weeks.
Immunosuppressive therapy (for organ transplantation) or renal dialysis (current or planned) within the next 12 months.
Severe asthma or severe allergy (requiring hospitalisation within the last 12 months).
Unfit for elective surgery.
Pregnant or lactating.
Unable to fully comprehend and/or perform study procedures in the investigator’s opinion.
Patient involvement in another investigational medicinal product (IMP) trial within the previous 4 weeks, prior to randomisation. Involvement in another IMP trial, following randomisation, that may impact on the results of the PREVENTT trial.
Setting
Forty-six hospitals in the UK participated: University College London Hospitals NHS Foundation Trust; Royal Free London NHS Foundation Trust; Royal Cornwall Hospitals NHS Trust; Royal Devon and Exeter NHS Foundation Trust; Royal Marsden NHS Foundation Trust; The Hillingdon Hospitals NHS Foundation Trust; Swansea Bay University Health Board – Morriston Hospital; York Teaching Hospital NHS Foundation Trust; Dorset County Hospital NHS Foundation Trust; Maidstone and Tunbridge Wells NHS Trust; Newcastle Hospitals – Freeman Hospital; Southmead Hospital Bristol; The Royal London Hospital – Barts Health NHS Trust; Sheffield Teaching Hospital – Northern General Hospital; University Hospital Southampton NHS Foundation Trust; University Hospital of North Staffordshire NHS Trust; University Hospitals Bristol NHS Foundation Trust; Royal Sussex County Hospital; St James’s University Hospital; Guy’s and St Thomas’ NHS Foundation Trust; Central Manchester University Hospitals NHS Foundation Trust; Blackpool Teaching Hospitals; West Suffolk NHS Foundation Trust; Royal Surrey County Hospital; Wythenshawe Hospital; James Cook University Hospital; Broomfield Hospital – Mid Essex Hospital Trust; Royal Liverpool and Broadgreen University Hospitals NHS Trust; Salford Royal NHS Foundation Trust; The County Hospital, Wye Valley NHS Trust; Northampton General Hospital; Imperial College Healthcare NHS Trust; John Radcliffe Hospital – Oxford University Hospitals; Queen’s Medical Centre, Nottingham University Hospitals NHS Trust; Aintree University Hospital NHS Foundation Trust; Queen Elizabeth Hospital, NHS Gateshead; Royal Infirmary of Edinburgh; The Pennine Acute Hospitals; Norfolk and Norwich University Hospital; Peterborough and Stamford Hospitals; Russells Hall Hospital, Dudley; King’s College Hospital; Liverpool Women’s NHS Foundation Trust; Basildon University Hospital; Countess of Chester Hospital; Hinchinbrook Hospital – North West Anglia Foundation Trust; and Cheltenham and Gloucester Hospital, Gloucestershire Hospitals NHS Foundation Trust.
Randomisation
Randomisation was by a secure web-based service through the Clinical Trials Unit (CTU) at the London School of Hygiene & Tropical Medicine (LSHTM), provided by Sealed Envelope (London, UK). Randomisation used minimisation, taking into account baseline Hb level (< 100 g/l or ≥ 100 g/l), age (< 70 or ≥ 70 years), centre and operation type (major/major+/complex). Patients were randomised to receive either active treatment (intravenous iron as ferric carboxymaltose 1000 mg) or placebo. The web-based database allocated the participant a unique trial identification number and their identification details were entered onto the trial patient identification log < 100 g/l or ≥ 100 g/l kept in the investigator site file. Once this number was assigned to a patient, it was not reused, even in the case of participant withdrawal from the study.
Randomisation was performed at the trial sites by the unblinded member of staff who was delegated this responsibility by the principal investigator (PI) only, as evidenced by documentation in the delegation log. Each unblinded member of staff was trained in the use of the web-based randomisation service at the site initiation visit, and was then provided with their own individual password and personal identification number (PIN) to access the service.
The blinded staff did not have access to the randomisation system, and, therefore, remained blinded to the treatment allocated.
Blinding and unblinding
Blinding
The iron carboxymaltose solution is dark brown in appearance; blinding was obtained by shielding the patients from seeing the preparation of the study drug, and having the unblinded study personnel who were not involved in any study assessments (efficacy or safety) as those responsible for preparing and administering the study treatment. This unblinded member of staff was present throughout administration of the trial drug. Patient shielding was achieved by preparing and administering the study drug behind a screen or curtain. The drug was shielded from vision (light protection bags) and administered through black tubing.
The unblinded member of staff disposed of the administration kit in a concealed way. All patients were monitored during the trial drug administration as per normal clinical practice; any AEs were documented.
Unblinding
The blinding of patients or other medical staff could be broken for valid medical or safety reasons (e.g. in the case of a severe AE, when it is necessary for a treating health-care professional to know which treatment the patient has received).
Incidents of unblinding were recorded in the randomisation system, and reports on unblinding were sent to the sponsor and the Data Safety and Monitoring Committee (DSMC).
Interventions
Patients who conformed to all eligibility criteria and provided written informed consent were randomised to receive either intravenous iron or placebo 10–42 days before the planned date of their surgery, as described in Randomisation.
Administration of the IMP was carried out in a hospital in line with local protocols. The study medication was administered to patients by the unblinded member of staff. An intravenous line was sited for drug administration Following this, it was advised that the skin along the donor vein be wiped using an iodine swab to help maintain the blinding. The patient was shielded from seeing preparation of the study drug, drug administration, disconnection and removal of the intravenous line, as described above. Patients were monitored for AEs or signs of hypersensitivity during and for at least 30 minutes following the administration of the treatment.
In the intravenous iron group, 1000 mg of ferric carboxymaltose (Ferinject) was administered as an intravenous infusion (100 ml n/saline) over a minimum of 15 minutes using a black infusion kit.
In the placebo group, normal saline was administered as an intravenous infusion (100 ml n/saline) over a minimum of 15 minutes using a black infusion kit.
Adverse events occurring in connection with the administration of study medication were recorded. In the event of a patient having an allergic reaction or signs of intolerance during study drug administration, the investigator managed this in accordance with local protocol and submitted a completed serious adverse event (SAE) form to LSHTM within 24 hours of the event.
Data management
Confidentiality
All data were handled in accordance with the UK Data Protection Act 1998 and 2018.
The case report forms (CRFs) did not bear the patient’s name or other personal identifiable data. The patient’s date of birth and trial identification number were used for identification.
Data collection tools and source document identification
Trial data were collected electronically at each participating centre and transferred electronically to a secure server at the CTU at LSHTM, via a secure web-based system. Data collection and entry was carried out by trained investigators or research nurses at each site. Designated investigator staff entered the information required by the protocol onto the electronic case report forms (eCRFs) from the source documents. The following were used as source documents:
Medical notes.
Drug charts.
Anaesthetic records.
Electronic hospital systems for laboratory results.
Patient diaries.
Validated questionnaires (patients completed paper copies and these were considered source documents. Delegated members of staff transcribed the data into the eCRFs).
Details of all study staff involved in data processing were contained in the site-specific delegation log for each centre. Copies of these are held in the PREVENTT trial master file, which is held by the CTU at LSHTM.
It was the responsibility of each local investigator to ensure the accuracy of all data entered in the CRFs. The delegation log identified all those personnel with responsibilities for data collection and handling, including those who had access to the trial database.
Data handling and analysis
The PREVENTT database application was built on the popular open source web platform commonly referred to as LAMP (Linux, Apache, MySQL and PHP). It was hosted on a centralised application server at LSHTM and was accessed by users through a normal web browser [e.g. Internet Explorer (Microsoft Corporation, Redmond, WA, USA) or Firefox (Mozilla Corporation, Mountain View, CA, USA)]. Online forms (eCRFs) with built-in validation checks were used by investigators or research nurses at participating centres to enter data. The system was blinded so that treatment groups were not revealed to users of the database application.
Data were extracted from the system by exporting the database tables as CSV (comma-separated values) text files or other suitable format. Analyses were conducted by the trial statistician in a statistical package (such as Stata® version 15.0; StataCorp LP, College Station, TX, USA) after importing the database tables. For unblinded analyses, these files were combined with the CSV file exported from the unblinded randomisation system.
Electronic case report form requirements
Data were entered at each local site using an electronic data capture system and managed by the data manager at the LSHTM CTU. The data analysis was performed by the trial statistician based at LSHTM CTU.
Electronic data were monitored by central statistical monitoring and by site visits as outlined in a monitoring standard operating procedure (SOP). Control checks were programmed into the system and the electronic data capture system automatically flagged erroneous data points using range checks and validators (e.g. when date of death occurs before date of birth), as well as entered data points that were likely to be inaccurate or the result of a typing error (e.g. blood pressure of 80/120 instead of 120/80). The eCRF was also set up so that data could not be missed out or left blank. Any changes made to the electronic data were tracked to maintain an audit trail.
Patients completed the health-related quality-of-life (HRQoL) questionnaires at their hospital assessment visits. If patients did not attend these appointments, then blinded research staff were responsible for contacting them and encouraging them to complete these questionnaires and the patient diaries.
The data were transmitted securely from each local site to the LSTHM CTU, via password- or PIN-protected online data entry over an encrypted internet connection (Secure Sockets Layer). This transfer was in accordance with the Data Protection Acts 1998 and 2018, the University College London Information Security Policy and the Trust Information Governance Policy.
Monitoring and site visits
The conduct of the study was supervised by specifically trained monitors from the LSHTM CTU. A trial-specific monitoring plan was established following a risk assessment and full details are available in the PREVENTT Monitoring SOP. The trial was monitored according to this agreed plan.
Baseline assessment
Baseline assessments were planned to coincide with the routine hospital schedule such as outpatient, endoscopy or pre-assessment clinic attendance. The ‘baseline assessments’, including laboratory tests for the purposes of the PREVENTT trial, were the same as those for routine clinical care in pre assessment before major surgery, so as to follow routine clinical practice and surgical/anaesthetic pathways where possible. For convenience, patients could undergo ‘baseline’ assessments, randomisation and trial drug administrations at the same attendance.
Assessments included the following:
checking conformance with inclusion/exclusion criteria, including laboratory tests taken within the prior 4 weeks [full blood count (FBC), urea and electrolytes (UE), LFT where clinically indicated as part of pre assessment, iron studies, estimated glomerular filtration rate (eGFR), CRP, thyroid function tests, vitamin B12 and folate].
documentation of past medical history
vital signs (blood pressure, pulse rate, body weight, height and temperature)
12-lead ECG (electrocardiography)
additional blood samples for central laboratory analysis (FBC, iron studies, TSAT and total iron binding capacity)
HRQoL questionnaires
documentation of health resources used (HRU); patient diary issued.
Follow-up
Patients were initially followed up during their stay in hospital, up to discharge.
Follow-up assessments
The Post-Operative Morbidity Survey (POMS) was administered on days 3, 5, 7 and 14 after surgery, if the patient remained in hospital.
Documentation of postoperative complications [using the Clavien–Dindo (CD) system].
Transfusion of blood and blood components.
FBC, UE, eGFR and CRP (if collected as part of routine care).
On discharge, hand-out of documentation of HRU diaries.
Patients were subsequently followed up at 8 weeks (± 2 weeks) and 6 months (± 1 month) after their operation. If the operation did not take place, the follow-up visit was calculated from the planned surgery date. The following assessments were carried out at each follow-up visit.
Follow-up visit 1 [8 weeks (± 2 weeks) after operation]
Documentation of hospital admissions.
Transfusion of blood and blood components.
Vital signs (blood pressure, pulse rate, body weight).
FBC, UE, eGFR and CRP.
HRQoL questionnaires.
Documentation of HRU; diary collected and reissued.
Follow-up visit 2 [6 months (± 1 month) after operation]
Documentation of hospital admissions.
Transfusion of blood and blood components.
Vital signs (blood pressure, pulse rate, body weight).
FBC, UE, eGFR and CRP.
HRQoL questionnaires.
Collection of documentation of HRU; patient diary collected.
Safety assessments
Definitions
An AE was defined as any untoward medical occurrence in a patient or clinical trial patient to whom a medicinal product was administered, but not necessarily having a causal relationship with this treatment.
An adverse reaction (AR) was defined as any untoward and unintended response in a patient to an IMP that is related to any dose administered to that patient. This includes medication errors and uses outside protocol (including misuse and abuse of product).
An unexpected AR was defined as an AR the nature and severity of which is not consistent with the information about the medicinal product set out:
in the case of a product with a marketing authorisation, in the summary of product characteristics (SmPC) for that product
in the case of any other IMP, in the investigator’s brochure relating to the trial in question.
An important medical event was defined as an event that may jeopardise the subject or may require an intervention to prevent one of the above characteristics or consequences. Such events should also be considered ‘serious’.
Recording and reporting adverse events
All AEs were recorded in the medical records following consent. Any AEs that occurred within 30 days of the trial treatment were noted in the CRF, recorded in an AE form and reported to the LSHTM CTU. All AEs were recorded with clinical symptoms and accompanied with a simple (brief) description of the event, including dates. All AEs were reported to the sponsor at least once per year.
Assessment of adverse events
Each AE was assessed for causality, expectedness and seriousness.
Causality was defined as follows:
Suspected – there was at least some evidence to suggest a causal relationship (e.g. the event occurred within a reasonable time after administration of the trial medication).
Not suspected – there was little or no evidence to suggest there was a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant treatments).
Expectedness is defined as follows:
Expected – an AE that was classed as serious in nature and that is consistent with the information about ferric carboxymaltose listed in the SmPC.
Unexpected – an AE that was classed in nature as serious and that is not consistent with the information about ferric carboxymaltose listed in the SmPC.
The reference document to be used to assess expectedness against the IMP is the SmPC, which can be found at https://beta.medicines.org.uk/emc/ (accessed 1 October 2020), under Ferinject. The protocol will be used as the reference document to assess disease-related and/or procedural expected events.
Seriousness is defined as an AE or AR that:
results in death
is life-threatening
requires hospitalisation or prolongation of existing hospitalisation
results in persistent or significant disability or incapacity
consists of a congenital anomaly or birth defect.
Patient and public involvement
The Trial Steering Committee (TSC) comprised two lay members; one had ulcerative colitis and had undergone two major open laparotomies with a total colectomy and ileorectal anastomosis, and the other had several gynaecological procedures cumulating in a total abdominal hysterectomy. The lay members attended TSC meetings as full, voting members and contributed to the protocol; specifically, they prioritised the secondary end-point selection and also reviewed the patient information sheet, patient poster and diaries. The lay members were also very helpful in advising the Project Management Group (PMG) about how to approach patients for recruitment into the trial.
Definition of the end of the trial
The end of the study is defined as the date at which the last patient completed their last study visit.
