Treg Immunotherapy in Crohn's Disease
Avainsanat
Abstrakti
Kuvaus
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.
Päivämäärät
Viimeksi vahvistettu: | 03/31/2017 |
Ensimmäinen lähetys: | 04/12/2017 |
Arvioitu ilmoittautuminen lähetetty: | 06/11/2017 |
Ensimmäinen lähetetty: | 06/13/2017 |
Viimeisin päivitys lähetetty: | 06/11/2017 |
Viimeisin päivitys lähetetty: | 06/13/2017 |
Todellinen opintojen alkamispäivä: | 01/31/2018 |
Arvioitu ensisijainen valmistumispäivä: | 08/31/2020 |
Arvioitu tutkimuksen valmistumispäivä: | 08/31/2021 |
Ehto tai tauti
Interventio / hoito
Drug: TR004 (Treg immunotherapy)
Other: Placebo
Vaihe
Varren ryhmät
Varsi | Interventio / hoito |
---|---|
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. |
Kelpoisuusehdot
Tutkimukseen soveltuvat iät | 18 Years Vastaanottaja 18 Years |
Sukupuolet, jotka ovat kelpoisia tutkimukseen | All |
Hyväksyy terveelliset vapaaehtoiset | Joo |
Kriteeri | 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 |
Tulokset
Ensisijaiset tulosmittaukset
1. Rate of dose limiting toxicities (DLTs) [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) [Two periods will be assessed, from Week 0 to Week 5 and from Week 8 to Week 13]
Toissijaiset tulosmittaukset
1. Disease Activity Score (CDAI / PRO-2) calculated by evaluation of patient's diary completion and colonoscopy findings [CDAI / PRO-2 scores will be calculated at Week 0, Week 5, Week 8, Week 13, Week 16 and Week 21]
2. Biomarkers analysis (CRP, FCP) measured by blood test and stool sample analysis [CRP and FCP will be measured throughout the study, from Week 0 to Week 21]
3. Mucosal Healing Score (CDEIS / SES-CD) calculated by evaluation of colonoscopy findings [CDEIS / SES-CD scores will be calculated at Week 8 and Week 16]
Muut lopputulokset
1. To inform on the Minimum Effective Dose (MED) of TR004 [Comparison of baseline CDAI value with values at Week 8 and Week 16, across all dose levels]
2. Analysis of lymphocyte populations circulating in blood as well as localised in the intestinal lamina propria [Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21]
3. Cytokine levels in blood and in intestinal lamina propria [Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21]
4. Comparison of circulating and localised cells to determine differences and similarities [Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21]
5. Levels of circulating regulatory T cells labelled with Deuterium in blood [Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21]
6. Microbiome analysis from stool sample [Translational research samples will be collected at Week 1, 2, 3, 5, 9, 10, 11, 13, 16, 21]