A Randomized Controlled Trial Evaluating the Efficacy of a Combination of Tofacitinib and Fecal Microbiota Transplantation (FMT) versus Tofacitinib and Sham Transplantation in Inducing Remission in Patients with Moderate to Severe Ulcerative Colitis
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- 1.Clinical remission at 8 weeks defined as SCCAI less than or equal to 2 and rectal bleeding sub score of 0
研究概览
简要总结
Ulcerative Colitis is a chronicimmune-mediated inflammatory disorder of the colorectum with bimodal agedistribution with anincidence peak in the 2nd or 3rd decades and followed bysecond peak between 50 and 80 years of age. It usually presents with bloody diarrhea,urgency and anemia. It causes continuous mucosal inflammation extending fromthe rectum to the proximal colon. Pathogenesisinvolves inappropriate mucosal immunologic response to gut microbiota and otherenvironmental factors in a genetically predisposedindividual. At present treatment is directedto dysregulated immune response and is limited by moderate efficacy, sideeffects (infections and malignancy) and cost, especially in developingcountries, where the disease burden of IBD is rising.
Corticosteroids are used in moderate tosevere acute flare ups; however, their use should be restricted to no more than2-3 months due to risk of serious side-effects. Moreover, a subset of patientseither do not respond to steroids and require step- up therapy or are unable totaper off steroids. Other treatment options in patients with moderate to severeulcerative colitis include either ciclosporin /tacrolimus, TNF antagonists orcolectomy.
Tofacitinib, an oral,small-molecule Janus kinase inhibitor has been shown to have potential efficacy as induction and maintenance therapy for ulcerative colitis. Its usage appears attractive due to its rapid onsetof action, rapid clearance, predictable pharmacokinetics and lack ofimmunogenicity, decreased susceptibility to colonic loss, widespreadavailability, and lower costs compared with other therapies.
The diversity of compositionof intestinal microbiota is lower in UC patients as it contains less numbers ofFirmicutes (Clostridium clusters XIVa and IV) and Bacteroidetes. Althoughno cause or effect relationship has yet been established, modulation of gutmicrobiota is associated with improved outcomes in ulcerative colitis indifferent RCTs. Fecal microbiota transplantation (FMT) defined asinfusion of Fecal suspension from ahealthy individual into the gastrointestinal tract of an individual with GIdisease carries a diverse population of microbiota and their metabolites hasshown good success rates in randomized control trials in patients with UC whofailed conventional agents. Fecal microbiota transplantation has alsodemonstrated short-term as well as long-term safety in patients withClostridioides difficile colitis and ulcerative colitis, even in patients onimmunosuppression.
However, no approach till date has evaluated the efficacy of acombination of microbial manipulation and immunosuppression in causingremission in patients with moderate to severe ulcerative colitis.
Hence, inthis RCT, we hypothesise that a combination of two strategies- Tofacitinib (bytargeting the immune response) and FMT (by modulating gut microbiota) couldlead to superior outcomes in moderate to severe UC patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Permuted block randomization, fixed
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •Patients with moderate to severe (as defined by SCCAI score >6) endoscopically active UC (UCEIS >1) 2)Patients giving written informed consent 3)Patients who are steroid dependent or refractory 4)Patients who are thiopurine failure or intolerant 5)Anti-TNF naïve or experienced (intolerant or non-responder) but last dose ≥2 months back 6)Anti-integrin naïve or experienced (intolerant or non-responder) but last dose ≥2 months back 7)Concomitant therapy allowed- a.Topical steroid and topical 5-ASA therapy (if stable for last 2 weeks) b.Oral corticosteroids (Prednisone equivalent up to 20 mg/day; budesonide up to 9 mg/day.
- •Stable dose for at least 2 weeks prior to baseline period.
- •Budesonide tapering 3mg every 3weekly and prednisolone tapering 5mg every 2 weekly), c.Patients on stable doses of 5-ASA (5-amino salicylic acid) for past 4 weeks 8)Women of childbearing age should agree to avoid conception during the study period.
排除标准
- •Age <18 years, >65 years 2)Patients with acute severe ulcerative colitis 3)Clinical signs of fulminant colitis or toxic megacolon 4)Indeterminate, ischemic, infectious or Crohn’s colitis 5)UC limited to distal 15 cm of colon 6)Received no treatment for UC in past i.e., treatment-naïve 7)Patients who are steroid naïve 8)If subject have received the following therapy- a.Intravenous corticosteroids within 2 weeks prior to baseline b.Anti-TNF therapy (e.g., infliximab, adalimumab, or certolizumab) within 8 weeks prior to baseline 9)Pregnancy and lactation 10)Concomitant Clostridioides Difficile infection 11)Severe comorbid medical illness a.Cardiac: NYHA II or higher congestive heart failure b.Renal: Creatine clearance (Cockcroft Gault formula) <40 ml/min c.Severe hepatic impairment d.Malignancies or a history of malignancies e.Significant trauma or major surgery within 4 weeks f.History of bowel surgery within 6 months 12)Contraindication to Tofacitinib including a.Severe hepatic impairment: b.Hepatitis B, C c.Active TB d.H/O DVT or thrombotic disorder.
结局指标
主要结局
1.Clinical remission at 8 weeks defined as SCCAI less than or equal to 2 and rectal bleeding sub score of 0
时间窗: 8 weeks
2.Endoscopic remission at 8 weeks defined as UCEIS less than or equal to 1
时间窗: 8 weeks
次要结局
- 1.Clinical response at 8 weeks defined as decline in SCCAI by greater than or equal to 3 points.(2.Endoscopic response at 8 weeks defined as decline in UCEIS by 2 points)