Treg Immunotherapy in Crohn's Disease

Study Purpose

Crohn's Disease (CD) is a condition that causes inflammation of the digestive system or gut. Crohn's can affect any part of the gut, though the most common area affected is the end of the ileum (the last part of the small intestine), or the colon. Crohn's is a chronic condition. This means that it is ongoing and life-long, although patients may have periods of good health (remission), as well as times when symptoms are more active (relapses or flare-ups). Current available therapies frequently fail to maintain long-term remission and may be complicated by significant side effects. There is an unmet medical need for novel therapies. Cellular therapies are emerging as potentially attractive therapeutic strategies. The TRIBUTE trial will use autologous regulatory T cells (Tregs) expanded in vitro. It is hoped that the administration of this treatment to patients with active CD will change the immune responses in the gut and reduce bowel wall inflammation.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 80 Years
Gender All
More Inclusion & Exclusion Criteria

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. 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: 1. Hb > 100g/L and WBC > 3.5 x 109/L and Plt > 100 x 109/L. 2. Creatinine < 1.5x ULN. 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.

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 109/L or Plt < 100 x 109/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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03185000
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

King's College London
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Graham Lord, Professor
Principal Investigator Affiliation King's College London
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

OtherOtherOtherOtherOtherOther
Overall Status Not yet recruiting
Countries
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Crohn Disease
Study Website: View Trial Website
Additional Details

The TRIBUTE trial is looking at a new type of treatment for Crohn's Disease (CD), called regulatory T-cells (Tregs) immunotherapy. Regulatory T-cells are naturally produced by the immune system. These cells have a powerful immunosuppressive action; they prevent auto-immune diseases by suppressing the over-active response that the immune system mounts against the body in these diseases. In addition it is thought that in patients with active CD, other immune cells in the gut are resistant to the normal controlling action of Tregs. Finally, we have found that Tregs that are isolated from patients and then are grown in the laboratory are more suppressive than Tregs freshly isolated from patients' blood. Treg immunotherapy, TR004, will be unique to each patient. White blood cells will be extracted from their blood via leukapheresis. These cells will form the starting material to manufacture TR004 by expansion in a GMP accredited laboratory following a validated manufacturing process. It will take between 20 and 45 days to produce enough cells for the immunotherapy treatment. The trial aims to recruit a total of 24 patients diagnosed with moderate to severe CD. Men and women aged over 18 years who did not tolerate or did not respond to at least 2 standard treatments for the condition will be eligible to participate. TRIBUTE is a double-blind, placebo controlled, crossover, First Into Human clinical trial of a single dose of TR004, with an adaptive Continual Reassessment Method (CRM) dose finding design. In stage 1 of the study, the maximum tolerated dose (MTD) will be determined from an initial cohort of 16 patients. In the second stage, 8 further patients will be added to allow a minimum effective dose (MED) to be determined from all patients. 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 and the other will first receive placebo at the same dose as each other and in each period. There will be 3 dose levels for TR004: 0.5

  • - 1.0 million TR004/kg, 3.0 - 5.0 million TR004/kg and 8.0 - 10.0 million TR004/kg.
The first pair on the trial will be dosed at 0.5
  • - 1.0 million TR004/kg.
Dose levels for subsequent pairs will be allocated by the CRM algorithm program. DSMB members will oversee the decision making process and make the final decision on the next dose level. Participants may be involved in the study for up to 14 months, from screening to safety follow-up at Week 52. Eligible participants will receive two infusions eight weeks apart, one at Week 0 and one at Week 8. One infusion will be the TR004 infusion, the other one will be a placebo infusion. Patients will have a number of blood tests over the course of the trial. This will allow the doctors to monitor how safe TR004 is and how the body reacts to it. Other tests, including vital signs such as blood pressure, heart rate and temperature, stool testing, and colonoscopy/biopsy will also be 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 will fill out questionnaires and diaries to monitor their progress over the course of the trial. There are currently no known benefits to the participants in taking part in the study. While it is hoped that the treatment will reduce bowel inflammation, this may not happen. 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. During leukapheresis and on infusion days cannulas will be inserted in participant's veins. The cannula insertion may cause pain, bruising, or, on rare occasions, infection. Some people find the leukapheresis uncomfortable due to having to stay in the same position for 2-3 hours. Blood calcium level may fall during the procedure and this can cause numbness and tingling in hands and feet and around the mouth. Patients can also feel cold, dizzy or sick. A colonoscopy poses few risks. Rarely, complications of a colonoscopy may include:
  • - Reaction to the sedative used during the test.
  • - Bleeding from the site where the tissue sample (biopsy) is taken.
  • - A tear in the colon or rectum wall (perforation).
The risk of this is less than 1 in 1,000. This is the first time this particular expanded Tregs treatment will be tested in human so there may be potential unknown risks that could be 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 transfusion symptoms include a red, itchy skin rash, swelling of the hands, arms, feet, ankles and legs, dizziness and headaches. Less common symptoms include high temperature, chills and shivering. The TRIBUTE study will be set-up and run at Guy's and St Thomas NHS Foundation Trust, London. It will be the only UK centre recruiting participants into the study although patients may be referred from other hospitals in order to take part in the trial.

Arms & Interventions

Arms

Experimental: Immediate ATIMP (AP)

Patients randomised to AP will receive Treg immunotherapy (TR004) infusion at Week 0 and Placebo infusion at Week 8.

Experimental: Delayed ATIMP (PA)

Patients randomised to PA will receive Placebo infusion at Week 0 and Treg immunotherapy (TR004) infusion at Week 8.

Interventions

Drug: - TR004 (Treg immunotherapy)

Administered Intravenously (IV)

Other: - Placebo

Administered Intravenously (IV)

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Graham Lord, Professor

TRIBUTE@gstt.nhs.uk

+44 20 7188 3053

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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