Plain English Summary
Background and study aims
Inflammatory bowel disease (IBD) is a term used to describe conditions which cause long-term inflammation (swelling) in the gut. The two main forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). Crohn’s disease can affect any part of the gut, but is most commonly at the end of the ileum (the last part of the small intestine) or the colon (the large intestine). Crohn's disease is a long-term (chronic) condition. There is currently no cure, and so the main aim of treatment is to reduce the symptoms (remission) and prevent the disease from “flaring up” and becoming active again. The TRIBUTE trial is looking at a new type of treatment for Crohn’s Disease called regulatory T-cells (Tregs) immunotherapy. Regulatory T-cells are naturally produced by the immune system to modulate the immune system and prevent autoimmune disease (where the immune system mistakenly attacks the body's own healthy tissue). Treg immunotherapy will be unique to each patient. White blood cells will be extracted from their blood using a process in which blood is removed from the body and passed through a filter to remove white blood cells (including Tregs) before being returned to the body. These cells will be used to create the Treg immunotherapy. The aim of this study is to assess the safety and effectiveness of regulatory T-cells (Tregs) immunotherapy in patients with crohn's disease.
Who can participate?
Adults who have been diagnosed with moderate to severe crohn's disease who did not tolerate or respond to at least 2 standard treatments.
What does the study involve?
Participants are randomly allocated to receive two treatments spaced eight weeks apart in a random order. The first treatment involves receiving an infusion (drip) of Treg immunotherapy, and the second involves an infusion of a placebo (dummy drug). After both treatments, participants attend regular follow-up at which blood samples are taken to monitor how safe the treatment is and how the body reacts to Treg immunotherapy.Other tests, including vital signs such as blood pressure, heart rate and temperature, stool testing, and colonoscopy (a test that allows the inner lining of your large intestine to be viewed) are also performed for this purpose and participants will have regular check-ups by the trial team. Scans such as CT scans, MRI scans or ultrasounds may be performed prior to starting the trial and participants fill out questionnaires and diaries to monitor their progress over the course of the trial.
What are the possible benefits and risks of participating?
There are currently no known benefits to the participants in taking part in the study, however it is hoped that the treatment will reduce bowel inflammation. Participants may not directly benefit from taking part in this study but the information gained from their participation may help to improve the treatments available to other people with Crohn’s Disease. During the blood tests participants may experience discomfort and there is a risk of bleeding and bruising around the puncture site but this is very rarely serious. The anticipated risks of Treg administration are similar to those of a blood transfusion. The potential risks are likely to be lower because the cells infused will be the patient’s own cells rather than cells from a blood donor. Common side effects may include a red, itchy skin rash, swelling of the hands, arms, feet, ankles and legs, dizziness and headaches. Less common side effects include high temperature, chills and shivering.
Where is the study run from?
1. Guy’s Hospital (UK)
2. St Thomas' Hospital (UK)
When is the study starting and how long is it expected to run for?
April 2016 to September 2021
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
1. Professor Graham Lord (scientific)
2. Dr Peter Irving (public)
Prof Graham Lord
Department of Experimental Immunobiology
Division of Transplantation Immunology and Mucosal Biology
5th floor Tower Wing
Great Maze Pond
Dr Peter Irving
Department of Gastroenterology
St Thomas’ Hospital
Westminster Bridge Road
A double-blind, placebo controlled, First Into Human clinical trial of T regulatory cells (TR004) for Inflammatory Bowel Disease Using (ex vivo) Treg Expansion
Tregs will “reset” the balance of the immune system and thus provide a treatment for patients with moderate to severe Crohn’s Disease.
Not provided at time of registration
Double-blind placebo-controlled randomised crossover trial
Primary study design
Secondary study design
Randomised cross over trial
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet.
Patients will be block randomised in a two-period crossover design to the order in which they receive both TR004 and placebo. In each successive pair of subjects, one will first receive TR004 (autologous GMP- expanded regulatory T cells) and the other will first receive placebo at the same dose as each other and in each period. Eligible patients will receive a single dose of TR004 and a single dose of placebo, either at Week 0 or Week 8, depending on randomisation allocation.
Patients randomised to AP will receive TR004 at Week 0 and Placebo at Week 8.
Patients allocated to PA will receive Placebo at Week 0 and TR004 at Week 8.
There will be 3 dose levels for TR004: 0.5 – 1.0 x 10^6 TR004/kg, 3.0 – 5.0 x 10^6 TR004/kg and 8.0 – 10.0 x 10^6 TR004/kg.
The first pair on the trial will be dosed at 0.5 – 1.0 x 10^6 TR004/kg. Dose levels for subsequent pairs will be allocated by the CRM algorithm program. The information will be reviewed during the DSMB meetings in order to agree the dose level for the next pairs. Both TR004 and Placebo will be administered intravenously over 30 minutes maximum.
On dosing days, patients will be closely monitored. Blood tests and vital signs will be taken at specific time points throughout the day. At Week 8, patients will also have a colonoscopy and biopsy. Patients will be discharged from hospital the day after dosing, unless there are any safety concerns.
Patients will then attend outpatient follow-up visits at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 and 52 (safety FUP). During these visits, patients will be reviewed by a doctor who will examine them and asks questions about how they have been feeling, any events/reactions they may want to report or any changes in their regular medications. Clinical and research blood tests will be taken to monitor safety following the infusions as well as a potential response to treatment. Blood pressure, heart rate, oxygen saturation, temperature and weight will be measured to monitor safety. Stool samples will be collected in order to measure inflammation markers and any potential changes from baseline. Patients will complete quality of life questionnaires in order to identify potential changes from baseline. At Week 16, patients will also have a colonoscopy and biopsy.
TR004 (autologous GMP- expanded regulatory T cells)
Primary outcome measures
1. Rate of dose limiting toxicities (DLTs) occurring 5 weeks post-infusions – two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13
2. Determination of Maximum Tolerated Dose (MTD), defined as the dose associated with a target DLT rate of 25%, is assessed by recording the rate of DLTs occurring between W0 and W5 and between W8 and W13
Secondary outcome measures
Clinical Response is assessed at baseline, 8 and 16 weeks by measuring:
1. Disease Activity Score (CDAI / PRO-2) calculated by evaluation of the parameters reported on the patient's diary and colonoscopy findings
2. Biomarkers analysis (CRP, FCP) measured by blood test and stool sample analysis
3. Mucosal Healing Score (CDEIS / SES-CD) calculated by evaluation of colonoscopy findings
1. Minimum Effective Dose (MED) of TR004, defined as the dose at which at least 1 patient out of 6 patients treated at the same dose level has demonstrated a within-patient efficacy response set out as being a reduction in CDAI of at least 100 points over 8 weeks from TR004 infusion
2. Immunological Response is assessed at Week 1, 2, 3, 5, 9, 10, 11, 13, 16 and 21 by measuring:
2.1. Lymphocyte populations circulating in blood as well as localised in the intestinal lamina propria, as measured by analysis of translational research blood samples
2.2. Cytokine levels in blood and in intestinal lamina propria, as measured by analysis of translational research blood samples
2.3. Differences and similarities in circulating and localised cells, as measured by analysis of translational research blood samples
2.4. Levels of circulating regulatory T cells labelled with Deuterium in blood, as measured by analysis of translational research blood samples
2.5. Microbiome is assessed using stool samples
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Able and willing to provide written informed consent and able to comply with the protocol requirements
2. Male or female aged between 18 and 80 (inclusive) years of age
3. A diagnosis of Crohn’s disease (CD) established ≥3 months prior to consent by standard clinical, radiological, endoscopic and histological criteria
4. Documented moderate-to-severe CD with a Crohn’s Disease Activity Index (CDAI) 220 within 3 months of screening
5. Active CD (mucosal inflammation) including ulceration, as assessed by colonoscopy at screening
6. Failure to tolerate or to respond to at least 2 prior lines of standard CD medication intended to induce or maintain remission, as determined by the referring gastroenterologist. Examples of such medications include, but are not limited to, azathioprine, mercaptopurine, methotrexate or anti-tumour necrosis factor antibody therapy. This does not include steroids and 5-ASA medications
7. Stable doses of concomitant medications, as defined in Section 5.6
8. Normal or non-clinically significant electrocardiogram (ECG), as assessed by the Investigator at screening
9. Negative stool test for Clostridium difficile and faecal culture for standard pathogens at screening. For non-pathogenic organism, inclusion will be at the discretion of the Principal Investigator (PI)
10. Negative serology for HIV, Hepatitis B (cAb and sAg), Hepatitis C, HTLV and Syphilis at screening
11. Subject is judged by the principal investigator to be in otherwise good health based upon the results of all screening investigations in combination with medical history and physical examination
12. Clinical Blood Tests prior to dosing, assessed on Day-1 at Week 0 and Week 8:
12.1. Hb > 100g/L and WBC > 3.5 x 10^9/L and Plt > 100 x 10^9/L
12.2. Creatinine < 1.5x ULN
12.3. Total bilirubin ≤ 34 µmol/L and ALT ≤ 2x ULN and GGT ≤ 2xULN. Elevated unconjugated bilirubin related to Gilbert’s syndrome is allowed
13. Negative urine pregnancy test for female of childbearing potential prior to dosing, assessed on Day-1 at Week 0 and Week 8
Target number of participants
24 (Stage 1: 16 patients, Stage 2: 8 patients)
Participant exclusion criteria
1. A diagnosis of ulcerative colitis or IBD-unclassified
2. CD treatment-naïve patients, defined as patients who have never received or have refused standard CD treatment
3. History of clinically significant drug or alcohol abuse in the last 12 months
4. Any history of major immune deficiency disorder, except Crohn’s disease
5. Patients with a history of pulmonary embolism or deep vein thrombosis. Current or recent history (within 1 year prior to screening) of major organ or system failure or condition, acute or chronic that in the opinion of the investigator should preclude enrollment, except Crohn’s disease
6. History of intestinal resection or intra-abdominal surgery within 6 months prior to visit 1 (screening)
7. Requirement for immediate or imminent surgical, endoscopic or radiological intervention for indications including (but not limited to) toxic megacolon, obstruction, massive haemorrhage, perforation, sepsis, or intra-abdominal or perianal abscess
8. Patients with ileostomy or colostomy
9. Patients with short bowel syndrome (less than 1.5m of small bowel)
10. Complication of Crohn’s disease such as strictures/stenosis, penetrating disease, or any other manifestation that might require surgery. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to screening and/or during the screening period
11. Patients who are currently using anticoagulants including but not limited to warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban (note that anti-platelet agents such as aspirin up to 325mg daily or clopidogrel are permitted)
12. Current medically significant infection i.e. infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to screening or oral anti-infectives for non-Crohn’s disease related infections within 14 days prior to screening visit
13. Subject with an active systemic viral infection or any active viral infection that based on the investigator’s clinical assessment makes the subject unsuitable for the study
14. History of tuberculosis (TB), unless there is documented evidence of completion of a full course of anti-TB treatment prior to screening. For patients with latent TB, as defined by a physician specialised in TB, they must have received prophylactic treatment for 4 weeks minimum prior to dosing
15. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident (within 6 months of screening) and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study
16. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in any biopsy performed during the screening endoscopy or endoscopy performed within 45 days of baseline unless this is deemed to be a sporadic adenoma and has been completely removed
17. Significant laboratory abnormalities:
Hb < 100g/L or WBC < 3.5 x 10^9/L or Plt < 100 x 10^9/L
Creatinine > 1.5x ULN
Total bilirubin ≥ 34 µmol/L or ALT ≥ 2x ULN or GGT ≥ 2xULN. Elevated unconjugated bilirubin related to Gilbert’s syndrome is allowed
18. Anti-TNF,vedolizumab or ustekinumab therapy within 8 weeks of study treatment initiation. Exposure to cyclosporine or tacrolimus within 2 weeks of anticipated study date of consent
19. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during the course of the study
20. Received another investigational drug within 60 days of anticipated study date of consent or 5 half lives whichever is greater
21. Subject who previously received stem cell transplantation
22. Current evidence of dysplasia or history of malignancy within the last 5 years (except successfully treated squamous cell or basal cell carcinoma, without metastases or localised carcinoma in situ of the cervix)
23. Pregnant and lactating patients (females of childbearing potential must have a negative dipstick pregnancy test at study entry)
24. Female patients of childbearing potential (i.e. not post-menopausal or surgically sterilised) who are not willing to use effective methods of contraception (included but not limited to hormonal contraception, Intrauterine devices, sexual abstinence, vasectomised partner) to prevent pregnancy or abstain from heterosexual activity for the duration of the trial up to W21 visit
25. Male patients who are not willing to use an effective method of contraception (included but not limited to use of condom, vasectomy, sexual abstinence) for the duration of the study up to W21 visit, when engaging in sexual activity with a female of childbearing potential
26. Allergy to any component / excipients used for the manufacture of TR004
27. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study
28. Inability to comply with the study protocol
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
Great Maze Pond
Trial participating centre
St Thomas Hospital
Westminster Bridge Road
King's College London
King’s Health Partners Clinical Trial Office
Great Maze Pond
Guy's and St Thomas NHS Foundation Trust (GSTFT)
Great Maze pond
Medical Research Council
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
It is intended that the results of the trial will be submitted for publication in peer-reviewed scientific journals. Results will also be reported and disseminated at International conferences.
IPD Sharing plan:
The current data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
Participant level data
To be made available at a later date
Results - basic reporting