Autologous Transplant Targeted Against Crohn's (ATTAC)

• ClinicalTrials.gov Identifier: NCT04154735
• Recruitment Status: Withdrawn
• First Posted: November 6, 2019
• Last Update Posted: November 8, 2019
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

Tracking Information

• First Submitted Date: March 8, 2019
• First Posted Date: November 6, 2019
• Last Update Posted Date: November 8, 2019
• Estimated Study Start Date: November 2019
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 6, 2019)

• Treatment-related mortality [ Time Frame: 3 years ]
  Treatment-related mortality
• Overall survival [ Time Frame: 3 years ]
  Survival of participants
• Clinical remission [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Change of Crohn's Disease Activity Index CDAI ≤ 150, Harvey-Bradshaw Index (HBI) ≤4, may be on immune suppressive drugs
• Complete remission [ Time Frame: 1 year, 2 years, 3 years ]
  Change of Clinical, endoscopic, and histologic remission on no immune modulating drugs

Original Primary Outcome Measures (submitted: November 4, 2019)

• Treatment-related mortality [ Time Frame: 3 years ]
  Treatment-related mortality
• Overall survival [ Time Frame: 3 years ]
  Survival of participants
• Clinical remission [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Change of CDAI ≤ 150, Harvey-Bradshaw Index (HBI) ≤4, may be on immune suppressive drugs
• Complete remission [ Time Frame: 1 year, 2 years, 3 years ]
  Change of Clinical, endoscopic, and histologic remission on no immune modulating drugs

Current Secondary Outcome Measures (submitted: November 6, 2019)

• Craig's Crohn's Severity Index [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in the severity of Crohn's Disease according to the Craig's Crohn's Severity Index (CDAI)
• Endoscopic severity scales [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Simple Endoscopic Score for Crohn's Disease (SES-CD)
• Histologic remission on colonoscopy with biopsy [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  No evidence of disease on biopsy
• Endoscopic remission [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  No evidence of disease on colonoscopy
• Drug-free clinical remission [ Time Frame: 1 year, 2 years, 3 years ]
  Crohn's Disease Activity Index (CDAI ≤ 150),Harvey Bradshaw Index HBI ≤4, no immune suppressive drugs
• Relapse-free survival [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Relapse is defined as Crohn's Disease Activity Index CDAI >150, Harvey Bradshaw Index HBI >4, and restarting or increasing immune based medication(s)
• Stool markers [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in fecal calprotectin and fecal lactoferrin
• Quality of life short form Survey (SF-36) [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in quality of life, measured by 36-Item Short Form Survey (SF-36) The evaluation of the results was done by attributing scores to each question, which were then transformed into a scale ranging from 0 to 100, where 0 corresponds to the worst quality of life and 100 to the best.
• Inflammatory Bowel Disease Questionnaire [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Inflammatory Bowel Disease Questionnaire (IBDQ) Total IBDQ score ranges from 32 to 224. A higher score indicates better quality of life.
• Crohn's Disease Endoscopic Index of Severity (CDEIS) [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Crohn's Disease Endoscopic Index of Severity (CDEIS)

Original Secondary Outcome Measures (submitted: November 4, 2019)

• Craig's Crohn's Severity Index [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in the severity of Crohn's Disease according to the Craig's Crohn's Severity Index (CDAI)
• Endoscopic severity scales [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Simple Endoscopic Score for Crohn's Disease (SES-CD)
• Histologic remission on colonoscopy with biopsy [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  No evidence of disease on biopsy
• Endoscopic remission [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  No evidence of disease on colonoscopy
• Drug-free clinical remission [ Time Frame: 1 year, 2 years, 3 years ]
  CDAI ≤ 150, HBI ≤4, no immune suppressive drugs
• Relapse-free survival [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Relapse is defined as CDAI >150, HBI >4, and restarting or increasing immune based medication(s)
• Stool markers [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in fecal calprotectin and fecal lactoferrin
• Quality of life by SF-36 [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement in quality of life, measured by SF-36
• Inflammatory Bowel Disease Questionnaire [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Inflammatory Bowel Disease Questionnaire (IBDQ)
• Crohn's Disease Endoscopic Index of Severity (CDEIS) [ Time Frame: 6 months, 1 year, 2 years, 3 years ]
  Improvement on the Crohn's Disease Endoscopic Index of Severity (CDEIS)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Autologous Transplant Targeted Against Crohn's
• Official Title: Autologous Hematopoietic Stem Cell Transplant for Crohn's Disease
• Brief Summary: This study is a new Phase II trial to assess the toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) utilizing a new non-myeloablative conditioning regimen in patients with high-risk Crohn's disease (CD). The regimen will include low-dose immunosuppressive therapy and a targeted antibiotic for six to twelve months post-HSCT.
• Detailed Description: The autologous hematopoietic stem cell transplantation (HSCT) in this study utilizes a new non-myeloablative conditioning regimen in patients with high-risk Crohn's disease (CD). The regimen includes two types of chemotherapy (cyclophosphamide and fludarabine) as well as alemtuzumab. The regimen will include low-dose immunosuppressive therapy with tacrolimus (Prograf) for one year post-HSCT in attempt to prevent relapse and improve long-term remission. Patients will also receive rifaximin (Xifaxan) for six months post-HSCT to target abnormal intestinal microbiota that may trigger intestinal inflammation. The ability of these experimental treatments to stop relapses and progression (worsening) of Crohn's disease will be assessed.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Crohn's Disease

Intervention

• Drug: Fludarabine
  A chemotherapy medication commonly used in the treatment of leukemia and lymphoma
• Drug: Cyclophosphamide
  A medication used as chemotherapy and to suppress the immune system
  Other Name: Cytoxan
• Drug: Mesna
  A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
  Other Name: Mesnex
• Drug: Alemtuzumab
  A protein that kills the immune cells that are thought to be causing Crohn's; it is commonly used in the treatment of leukemia and lymphoma
  Other Names:

  • Lemtrada
  • Campath
• Drug: G-CSF
  A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
  Other Names:

  • Neupogen
  • Filgrastim
  • Granix
  • Zarxio
• Drug: Rifaximin
  An antibiotic used to treat irritable bowel syndrome and relapsing C. difficile infection; it inhibits DNA-dependent RNA polymerase
  Other Name: Xifaxan
• Drug: Tacrolimus
  A medication which suppresses the immune system and inhibits T-lymphocytes; commonly used to lower the risk of organ rejection following transplant
  Other Names:

  • Prograf
  • Envarsus XR
  • Stargraf XL

Study Arms

Experimental: Hematopoietic Stem Cell Transplantation

Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with fludarabine, cyclophosphamide, mesna, and alemtuzumab. Granulocyte-colony stimulating factor (G-CSF) will be administered post-transplant until engraftment. Rifaximin and tacrolimus will be administered for 6 and 12 months, respectively, beginning one day before the infusion of stem cells.

Interventions:

• Drug: Fludarabine
• Drug: Cyclophosphamide
• Drug: Mesna
• Drug: Alemtuzumab
• Drug: G-CSF
• Drug: Rifaximin
• Drug: Tacrolimus

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: November 4, 2019): 0
• Original Actual Enrollment: Same as current
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age 18 years and less than age 50 years at the time of pre-transplant evaluation
2. Ability to give informed consent

3. An established clinical diagnosis of severe Crohn's Disease* that has failed therapy with prednisone or budesonide (Entocort) and either a or b below:

   1. At least two anti-tumor necrosis factor (TNF) drugs (e.g., infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia))

   2. One anti-TNF drug as above and either vedolizumab (Entyvio) or ustekinumab (Stelara)

      • Severe Crohn's Disease is defined as a CDAI (see Appendix A) of 250 to 400 or a Craig's Crohn's Severity Index (CCSI, see Appendix B) that is > 17.

Exclusion Criteria:

1. Uncontrolled diabetes mellitus or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment
2. Prior history of malignancy (except localized basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix). Other malignancies for which the patient is judged to be cured by local surgical therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis
3. Positive pregnancy test, inability to pursue effective means of birth control, or failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
4. HIV positive
5. Hepatitis B or C positive
6. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible
7. Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter or history of coronary artery disease or congestive heart failure
8. Left ventricular ejection fraction (LVEF) <50%
9. Forced vital capacity (FVC) <60% of predicted after bronchodilator therapy (if necessary) or diffusing capacity of the lungs for carbon monoxide (DLCO) hemoglobin corrected <60 % predicted
10. Serum creatinine >2 mg/dl
11. 24-hour urine creatinine clearance <90
12. Liver transaminases >2x of normal limits, or bilirubin >2 mg/dl unless due to Crohn's Disease
13. Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1500/ul
14. Failure to collect at least 2 x10^6 cluster of differentiation 34 (CD34+) cells/kg
15. Any active infection
16. Known hypersensitivity to mouse, rabbit, or E. coli derived proteins
17. Short Bowel Syndrome defined as intestinal dysfunction with the presence of significant malabsorption of both macronutrients and micronutrients or when gastrointestinal function is inadequate to maintain nutrient and hydration status without intravenous or enteral supplementation.
18. History of anorexia nervosa (serum albumin ≤ 20 g/L, body mass index ≤ 18)
19. Patients presenting with intestinal perforation or toxic megacolon or a problem that will require urgent surgery. The presence of intestinal stomas, strictures, or fistulae does not exclude the patient from study.
20. Unable or unwilling to stop using and/or smoking tobacco products
21. Abnormal peripheral blood cytogenetics

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 49 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04154735
• Other Study ID Numbers: DIAD.ATTAC.2018
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Richard Burt, MD, Northwestern University
• Original Responsible Party: Same as current
• Current Study Sponsor: Northwestern University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard Burt, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: January 2019