Treg Immunotherapy in Crohn's Disease (TRIBUTE)

A Double-blind, Placebo Controlled, First Into Human Clinical Trial of T Regulatory Cells (TR004) for Inflammatory Bowel Disease Using (ex Vivo) Treg Expansion

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.

Study Overview

• Status: Unknown
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: TR004 (Treg immunotherapy); Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Graham Lord, Professor; Phone Number: +44 20 7188 3053; Email: TRIBUTE@gstt.nhs.uk
• Study Contact Backup: Name: Peter Irving, Dr; Phone Number: +44 20 7188 2499; Email: TRIBUTE@gstt.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immediate ATIMP (AP); Patients randomised to AP will receive Treg immunotherapy (TR004) infusion at Week 0 and Placebo infusion at Week 8.	Drug: TR004 (Treg immunotherapy); Administered Intravenously (IV); Other Names: Autologous regulatory T cells (Tregs) expanded in vitro; Other: Placebo; Administered Intravenously (IV)
Experimental: Delayed ATIMP (PA); Patients randomised to PA will receive Placebo infusion at Week 0 and Treg immunotherapy (TR004) infusion at Week 8.	Drug: TR004 (Treg immunotherapy); Administered Intravenously (IV); Other Names: Autologous regulatory T cells (Tregs) expanded in vitro; Other: Placebo; Administered Intravenously (IV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of dose limiting toxicities (DLTs)	Pre-defined safety events occurring 5 weeks post-infusions	Two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13
Determination of Maximum Tolerated Dose (MTD)	Defined as the dose associated with a target DLT rate of 25% occurring within 5 weeks post-infusions	Two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Activity Score (CDAI / PRO-2) calculated by evaluation of patient's diary completion and colonoscopy findings	Measurement of clinical response	CDAI / PRO-2 scores will be calculated at Week 0, Week 5, Week 8, Week 13, Week 16 and Week 21
Biomarkers analysis (CRP, FCP) measured by blood test and stool sample analysis	Measurement of clinical response	CRP and FCP will be measured throughout the study, from Week 0 to Week 21
Mucosal Healing Score (CDEIS / SES-CD) calculated by evaluation of colonoscopy findings	Measurement of clinical response	CDEIS / SES-CD scores will be calculated at Week 8 and Week 16

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To inform on the 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	Comparison of baseline CDAI value with values at Week 8 and Week 16, across all dose levels
Analysis of lymphocyte populations circulating in blood as well as localised in the intestinal lamina propria	Measurement of Immunological Response by analysis of translational research samples collected at specific time points. The baseline value will be compared to values obtained at subsequent time points, in order to measure the overall immunological response.	Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21
Cytokine levels in blood and in intestinal lamina propria	Measurement of Immunological Response by analysis of translational research samples collected at specific time points. The baseline value will be compared to values obtained at subsequent time points, in order to measure the overall immunological response.	Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21
Comparison of circulating and localised cells to determine differences and similarities	Measurement of Immunological Response by analysis of translational research samples collected at specific time points. The baseline value will be compared to values obtained at subsequent time points, in order to measure the overall immunological response.	Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21
Levels of circulating regulatory T cells labelled with Deuterium in blood	Measurement of Immunological Response by analysis of translational research samples collected at specific time points. The baseline value will be compared to values obtained at subsequent time points, in order to measure the overall immunological response.	Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21
Microbiome analysis from stool sample	Measurement of Immunological Response by analysis of translational research samples collected at specific time points. The baseline value will be compared to values obtained at subsequent time points, in order to measure the overall immunological response.	Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Imperial College London; Medical Research Council; Guy's and St Thomas' NHS Foundation Trust; St. George's Hospital, London; Miltenyi biotech
• Investigators: Study Director: Graham Lord, Professor, King's College London

Publications and helpful links

General Publications

• Canavan JB, Scotta C, Vossenkamper A, Goldberg R, Elder MJ, Shoval I, Marks E, Stolarczyk E, Lo JW, Powell N, Fazekasova H, Irving PM, Sanderson JD, Howard JK, Yagel S, Afzali B, MacDonald TT, Hernandez-Fuentes MP, Shpigel NY, Lombardi G, Lord GM. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease. Gut. 2016 Apr;65(4):584-94. doi: 10.1136/gutjnl-2014-306919. Epub 2015 Feb 24.
• Goldberg R, Scotta C, Cooper D, Nissim-Eliraz E, Nir E, Tasker S, Irving PM, Sanderson J, Lavender P, Ibrahim F, Corcoran J, Prevost T, Shpigel NY, Marelli-Berg F, Lombardi G, Lord GM. Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-alpha. Gastroenterology. 2019 May;156(6):1775-1787. doi: 10.1053/j.gastro.2019.01.025. Epub 2019 Jan 30.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2018
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): September 1, 2021

Study Registration Dates

• First Submitted: April 13, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: June 12, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease
• Other Study ID Numbers: TRIBUTE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No