Condition category
Digestive System
Date applied
15/05/2008
Date assigned
16/05/2008
Last edited
07/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Ulcerative colitis is a long-term condition where the colon and rectum become inflamed, causing diarrhoea and abdominal pain. It often leads to frequent and long inpatients stays and emergency colectomy (surgery to remove the colon), and is therefore a major burden on patients and NHS resources. Recent studies have reported that two new drugs, infliximab and ciclosporin, are often effective at treating steroid-resistant ulcerative colitis in the short term, but there is a lack of evidence in the longer-term. The aim of this study is to compare the clinical and cost effectiveness of infliximab and ciclosporin in acute severe steroid-resistant ulcerative colitis.

Who can participate?
Patients aged 18 and over with steroid-resistant ulcerative colitis (i.e., does not respond to steroid treatment)

What does the study involve?
Participants are randomly allocated to be treated with either infliximab or ciclosporin. All participants are then followed up for two years (and using routine records for a further eight years) to assess quality of life, death rates, colectomy rates, severe illness, NHS and patient borne costs, and patient views of these treatments.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Swansea University (UK)

When is the study starting and how long is it expected to run for?
September 2008 to August 2014

Who is funding the study?
NIHR Health Technology Assessment Programme - HTA (UK)

Who is the main contact?
Dr Anne Seagrove
a.c.seagrove@swansea.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Anne Seagrove

ORCID ID

Contact details

School of Medicine
Swansea University
Singleton Park
Swansea
SA2 8PP
United Kingdom
+44 (0)1792 513411
a.c.seagrove@swansea.ac.uk

Type

Scientific

Additional contact

Prof John G Williams

ORCID ID

Contact details

School of Medicine
Swansea University
Singleton Park
Swansea
SA2 8PP
United Kingdom
+44 (0)1792 513401
j.g.williams@swansea.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

HTA 06/78/03; NRES: 08/MRE09/42

Study information

Scientific title

Comparison of infliximab and ciclosporin in steroid resistant ulcerative colitis: a randomised controlled trial

Acronym

CONSTRUCT

Study hypothesis

To determine the clinical and cost effectiveness of infliximab and ciclosporin in acute severe steroid resistant ulcerative colitis.

More details can be found at: http://www.nets.nihr.ac.uk/projects/hta/067803
Protocol can be found at: http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0005/51476/PRO-06-78-03.pdf

Ethics approval

Research Ethics Committee (REC) for Wales, July 2008, ref: 08/MRE09/42

Study design

Two-arm pragmatic multi-centre randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet.

Condition

Acute severe steroid resistant ulcerative colitis

Intervention

Current interventions as of 22/10/2012:
Infliximab:
Infliximab as 5mg/kg intravenous infusion over a 2 hour period, at baseline and at 2 and 6 weeks after the first infusion, in accordance with local prescribing guidelines and policies.
Ciclosporin:
IV ciclosporin (2 mg/kg/day) by continuous infusion for up to 7 days (aiming for trough levels 100 – 200 ng/ml) followed by oral ciclosporin (5.5 mg/kg/day in two divided doses) for up to 12 weeks. Whole blood ciclosporin levels measured according to local practice ideally 48 hours after oral therapy and then approximately every two weeks.
For both treatments:
Azathioprine or 6-mercaptopurine should be started at therapeutically appropriate doses in both groups at week 4, at the discretion of the supervising consultant.
Steroids must be tapered to zero by week 12 in both groups in patients that remain well but should be re-escalated in patients that become symptomatic.
Septrin should be given as prophylaxis against Pneumocystis jiroveci (carinii) pneumonia in both groups, at the discretion of the supervising consultant.
After 12 weeks, treatment is at the discretion of the supervising consultant.

Previous interventions until 22/10/2012:
Patients will be randomised to either infliximab (Remicade®) or ciclosporin (Sandimmun®/ Neoral®).
Both infliximab and ciclosporin will be used in accordance with normal routes of administration, dosage, dosage regimen and treatment periods as detailed below. Relapse or failure to respond at any stage will prompt surgical referral.
Infliximab:
Infliximab (5 mg per kg as a single intravenous infusion) at time 0 and further doses at 2 and 6 weeks followed by infusions every 8 weeks up to 6 months. The addition/continuation of azathioprine or 6-mercaptopurine is necessary if tolerated (to reduce likelihood of antibody formation). Steroids will be tapered over a 3 month period.
Ciclosporin:
Intravenous ciclosporin (2 mg per kg) for 7 days (aiming for trough levels of 150-250 ng/ml) will be followed by oral ciclosporin (8 mg/kg) for 3 months while the effect of either azathioprine or 6-mercaptopurine is allowed (commenced on discharge). During that 3 month period, steroids are also tapered and Septrin® should be given to cover for pneumocystis carinii pneumonia.

Intervention type

Drug

Phase

Not Applicable

Drug names

infliximab, ciclosporin

Primary outcome measures

Current primary outcome measures as of 22/10/2012:
The primary outcome measure is quality-adjusted survival, weighted by scores on the disease-specific CCQ.

Previous primary outcome measures until 22/10/2012:
Quality of life, measured at 3, 6, 12 and 24 months with the following:
1. Disease specific questionnaire: UK-Inflammatory Bowel Disease Questionnaire (IBDQ)
2. Generic questionnaires: The 12-item short form health survey (SF-12) and EQ-5D

Secondary outcome measures

Current secondary outcome measures as of 22/10/2012:
1. Generic SF-12 and EQ-5D QoL questionnaires.
2. Emergency and planned colectomy; centres report all colectomies undertaken based on clinical judgement and patient agreement, both emergency and elective.
3. Mortality.
4. Re-admissions, including those for non-UC-specific causes.
5. Incidence of malignancies, subdivided between colorectal, other GI and other malignancies.
6. Incidence of serious infections during treatment, including bacterial infections, pneumonia, abscesses, and other serious infections.
7. Incidence of renal disorders during treatment.
8. Incidence of new symptoms during or attributable to treatment.
9. Incidence of adverse events, grouped as SUSARs, SARs, SAEs, ARs or AEs and including all relevant events described in 3. to 8. above.
10. Disease activity, measured by the criteria proposed by Truelove and Witts: to this end we seek to measure full blood count, inflammatory markers and albumin at baseline and three, six, 12, 18, 24, 30 and 36 months.
11. Quality of life, measured by the CCQ.
12. NHS costs, measured by a healthcare resource use questionnaire and hospital activity data; the economic analysis will combine these with quality adjusted survival.
13. Patient borne costs, including number of days off work and travel costs to healthcare; we shall report these separately from NHS costs because the main economic analysis takes the perspective of the NHS.
14. Patient views, of the alternative drugs elicited through 12 (10%) telephone interviews in each arm following discharge from hospital about three months and 12 months after randomisation.
15. Healthcare professional views about the drugs and their administration; a minimum of 8 clinicians and 4 nurses will be interviewed.

Previous secondary outcome measures until 22/10/2012:
1. Emergency and planned colectomy; colectomy may be undertaken based on clinical judgement and patient agreement. The incidence of emergency colectomy will be measured up to 2 years post-admission during the research data collection and up to 10 years during the clinical data collection and record linkage phase. Similarly, elective colectomy will be measured separately up to 2 years and 10 years follow-up.
2. Concomitant medical therapy; continuing steroid treatment, and/or the addition of azathioprine (or other immunosuppressive therapy) will be at the discretion of the attending team. Oral ciclosporin, or a second infusion of infliximab may be given. Data on treatment will be recorded by the patient after discharge up to 3 months after entry to the trial, and recorded at each hospital visit.
3. Mortality; which will be measured by case fatality and standardised mortality ratios up to 2 and 10 years follow-up.
4. Quality adjusted survival; to combine the effects of quality of life and mortality, will be measured up to 2 years follow-up and then modelled for lifetime Quality Adjusted Life Years
5. Disease activity; Full blood count, inflammatory markers and albumin will be measured at baseline and at 3, 6, 12 and 24 months.
6. Re-admissions; including for non-UC specific causes. Data will be collected for two years but monitored using routine data for a further eight years.
7. Total NHS costs; measured up to 2 years follow-up.
8. Patient borne costs; including number of days off work per year and travel costs for health care, up to 2 years follow-up. These will be reported separately from the NHS costs and will not be included in the cost utility estimates.
9. Patient views; elicited through telephone interviews, following discharge from hospital at approximately 2 to 3 and 6 to 8 months into follow-up. These will be conducted for 24 patients, 12 (5%) in each of the two trial arms.

Overall trial start date

01/09/2008

Overall trial end date

31/08/2014

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 22/10/2012:
1.1. Patients admitted acutely (ie an emergency admission) with severe colitis (as evidenced by eg a Mayo score of at least 2 on endoscopic finding) who fail to respond to approximately 2-5 days of intravenous hydrocortisone therapy, who also have either:
1.2. A histological diagnosis of ulcerative colitis in this episode
OR
1.3. A histological diagnosis of indeterminate colitis in this episode, where clinical judgement (based on macroscopic appearance, disease distribution or previous history) suggests a diagnosis of ulcerative colitis rather than Crohn’s disease
OR
1.4. Typical symptoms of ulcerative colitis but histology awaited
OR
1.5. A history of ulcerative colitis (previously confirmed histologically)

Previous inclusion criteria until 22/10/2012:
1. Patients with ulcerative colitis (UC) diagnosed on histological evidence
2. Inpatients with documented evidence of acute severe UC (based on sigmoidoscopic appearances and Truelove and Witts' criteria)
3. Continuing acute severe UC (according to Truelove and Witts criteria) after three days intravenous hydrocortisone

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

250 (125 in each arm)

Participant exclusion criteria

Current exclusion criteria as of 22/10/2012:
1. Patient aged under 18 years of age on admission
2. Patient with histological diagnosis inconsistent with ulcerative colitis (indeterminate colitis is not necessarily “inconsistent with ulcerative”-see inclusion criteria b)
3. Patient with enteric infection confirmed on stool microscopy or culture or histology (includes salmonella, shigella, clostridium difficile, campylobacter and CMV)
4. Patient from a vulnerable group
5. Patient unable to consent for themselves
6. Patient who are pregnant (as evidenced by +ve pregnancy test) or currently lactating
7. Women of child-bearing potential who are not prepared to use adequate contraception during treatment with infliximab and for 6 months afterwards in line with the Summary of Product Characteristics
8. Patient with current malignancy, excluding basal cell carcinoma
9. Patient with serious co-morbidities, including:
9.1. Immunodeficiency
9.2. Myocardial infarction (within last month)
9.3. Moderate or severe heart failure (NYHA class III or IV)
9.4. Acute stroke (within last month)
9.5. Respiratory failure
9.6. Renal failure
9.7. Hepatic failure
9.8. Active, or suspected active tuberculosis
9.9. Other severe infections (as determined by the investigator) such as sepsis, abscesses and opportunistic infections
10.1. Patient with a history of hypersensitivity to
10.2. Infliximab (Remicade)
10.3. Ciclosporin (Sandimmun and Neoral)
10.4. Polyethoxylated oils (Sandimmun Concentrate for IV Infusion)
11. Concomitant use of tacrolimus or rosuvastatin
12. Patients who do not speak English well enough to take part in the study, and for whom local translation services cannot be provided
13. Where clinical need determines the patient should undergo emergency colectomy without further medical treatment
14. Patients currently taking part in other clinical trials
15. Patients who have received treatment with either infliximab or ciclosporin in the three months before admission
16. Patient with contraindication(s) to treatment with Infliximab or Ciclosporin

Previous exclusion criteria until 22/10/2012:
1. Age under 18 years on the day of admission
2. Treatment with either infliximab or ciclosporin in the three months before admission
3. Positive stool microscopy or culture for enteric infection, including salmonella, shigella and Clostridium difficile
4. Pregnancy and lactation
5. Malignancy, excluding basal cell carcinoma
6. Other serious co-morbidities, including immunodeficiency, myocardial infarction, acute stroke, respiratory, renal or hepatic failure
7. Severe cognitive impairment
8. Patients unable to consent for themselves
9. Patients who do not speak English well enough to take part in the study
10. Where clinical need determines the patient should undergo emergency colectomy without further medical treatment
11. Patients currently taking part in other clinical trials
12. Patients from vulnerable groups with the exception of severe illness as this will be the reason for their acute admission and treatment

Recruitment start date

01/09/2008

Recruitment end date

31/08/2014

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Swansea University
Swansea
SA2 8PP
United Kingdom

Sponsor information

Organisation

Swansea University (UK)

Sponsor details

Singleton Park
Swansea
SA2 8PP
United Kingdom
+44 (0)1792 285412
c.d.jones@swansea.ac.uk

Sponsor type

University/education

Website

http://www.swan.ac.uk

Funders

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

01/04/2016

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2014 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/24785401
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27329657
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27595142

Publication citations

  1. Protocol

    Seagrove AC, Alam MF, Alrubaiy L, Cheung WY, Clement C, Cohen D, Grey M, Hilton M, Hutchings H, Morgan J, Rapport F, Roberts SE, Russell D, Russell I, Thomas L, Thorne K, Watkins A, Williams JG, Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT)., BMJ Open, 2014, 4, 4, e005091, doi: 10.1136/bmjopen-2014-005091.

  2. Results

    Williams JG, Alam MF, Alrubaiy L, Clement C, Cohen D, Grey M, Hilton M, Hutchings HA, Longo M, Morgan JM, Rapport FL, Seagrove AC, Watkins A, Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT), Health Technol Assess, 2016 , 20, 44, 1-320, doi: 10.3310/hta20440.

Additional files

Editorial Notes

07/09/2016: Publication reference added. 23/06/2016: Publication reference added. 19/04/2016: Plain English summary added. 22/10/2012: the following changes were made to the trial record: 1. The target number of participants was updated from 480 (240 in each arm) to 250 (125 in each arm). 2. The overall trial end date was updated from 31/08/2012 to 31/08/2014.