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Treg Immunotherapy in Crohn's Disease (TRIBUTE)

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ClinicalTrials.gov Identifier: NCT03185000
Recruitment Status : Not yet recruiting
First Posted : June 14, 2017
Last Update Posted : June 14, 2017
Sponsor:
Collaborators:
Guy's and St Thomas' NHS Foundation Trust
Medical Research Council
Imperial College London
St. George's Hospital, London
Miltenyi biotech
Information provided by (Responsible Party):
King's College London

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Crohn Disease Drug: TR004 (Treg immunotherapy) Other: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Placebo Controlled, First Into Human Clinical Trial of T Regulatory Cells (TR004) for Inflammatory Bowel Disease Using (ex Vivo) Treg Expansion
Estimated Study Start Date : February 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease

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 Name: 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 Name: Autologous regulatory T cells (Tregs) expanded in vitro

Other: Placebo
Administered Intravenously (IV)




Primary Outcome Measures :
  1. Rate of dose limiting toxicities (DLTs) [ Time Frame: Two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13 ]
    Pre-defined safety events occurring 5 weeks post-infusions

  2. Determination of Maximum Tolerated Dose (MTD) [ Time Frame: Two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13 ]
    Defined as the dose associated with a target DLT rate of 25% occurring within 5 weeks post-infusions


Secondary Outcome Measures :
  1. Disease Activity Score (CDAI / PRO-2) calculated by evaluation of patient's diary completion and colonoscopy findings [ Time Frame: CDAI / PRO-2 scores will be calculated at Week 0, Week 5, Week 8, Week 13, Week 16 and Week 21 ]
    Measurement of clinical response

  2. Biomarkers analysis (CRP, FCP) measured by blood test and stool sample analysis [ Time Frame: CRP and FCP will be measured throughout the study, from Week 0 to Week 21 ]
    Measurement of clinical response

  3. Mucosal Healing Score (CDEIS / SES-CD) calculated by evaluation of colonoscopy findings [ Time Frame: CDEIS / SES-CD scores will be calculated at Week 8 and Week 16 ]
    Measurement of clinical response


Other Outcome Measures:
  1. To inform on the Minimum Effective Dose (MED) of TR004 [ Time Frame: Comparison of baseline CDAI value with values at Week 8 and Week 16, across all dose levels ]
    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. Analysis of lymphocyte populations circulating in blood as well as localised in the intestinal lamina propria [ Time Frame: Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 ]

    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.


  3. Cytokine levels in blood and in intestinal lamina propria [ Time Frame: Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 ]

    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.


  4. Comparison of circulating and localised cells to determine differences and similarities [ Time Frame: Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 ]

    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.


  5. Levels of circulating regulatory T cells labelled with Deuterium in blood [ Time Frame: Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 ]

    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.


  6. Microbiome analysis from stool sample [ Time Frame: Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21 ]

    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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03185000


Contacts
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Contact: Graham Lord, Professor +44 20 7188 3053 TRIBUTE@gstt.nhs.uk
Contact: Peter Irving, Dr +44 20 7188 2499 TRIBUTE@gstt.nhs.uk

Sponsors and Collaborators
King's College London
Guy's and St Thomas' NHS Foundation Trust
Medical Research Council
Imperial College London
St. George's Hospital, London
Miltenyi biotech
Investigators
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Study Director: Graham Lord, Professor King's College London
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: King's College London
ClinicalTrials.gov Identifier: NCT03185000    
Other Study ID Numbers: TRIBUTE
First Posted: June 14, 2017    Key Record Dates
Last Update Posted: June 14, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases