Autologous Transplant Targeted Against Crohn's (ATTAC)

Autologous Hematopoietic Stem Cell Transplant for Crohn's Disease

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.

Study Overview

• Status: Withdrawn
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: G-CSF; Drug: Mesna; Drug: Fludarabine; Drug: Alemtuzumab; Drug: Rifaximin; Drug: Tacrolimus

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
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Cyclophosphamide; A medication used as chemotherapy and to suppress the immune system; Other Names: Cytoxan; Drug: G-CSF; A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream; Other Names: Filgrastim; Neupogen; Zarxio; Granix; Drug: Mesna; A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder; Other Names: Mesnex; Drug: Fludarabine; A chemotherapy medication commonly used in the treatment of leukemia and lymphoma; 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: Campath; Lemtrada; Drug: Rifaximin; An antibiotic used to treat irritable bowel syndrome and relapsing C. difficile infection; it inhibits DNA-dependent RNA polymerase; Other Names: 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Craig's Crohn's Severity Index	Improvement in the severity of Crohn's Disease according to the Craig's Crohn's Severity Index (CDAI)	6 months, 1 year, 2 years, 3 years
Endoscopic severity scales	Improvement on the Simple Endoscopic Score for Crohn's Disease (SES-CD)	6 months, 1 year, 2 years, 3 years
Histologic remission on colonoscopy with biopsy	No evidence of disease on biopsy	6 months, 1 year, 2 years, 3 years
Endoscopic remission	No evidence of disease on colonoscopy	6 months, 1 year, 2 years, 3 years
Drug-free clinical remission	Crohn's Disease Activity Index (CDAI ≤ 150),Harvey Bradshaw Index HBI ≤4, no immune suppressive drugs	1 year, 2 years, 3 years
Relapse-free survival	Relapse is defined as Crohn's Disease Activity Index CDAI >150, Harvey Bradshaw Index HBI >4, and restarting or increasing immune based medication(s)	6 months, 1 year, 2 years, 3 years
Stool markers	Improvement in fecal calprotectin and fecal lactoferrin	6 months, 1 year, 2 years, 3 years
Quality of life short form Survey (SF-36)	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.	6 months, 1 year, 2 years, 3 years
Inflammatory Bowel Disease Questionnaire	Improvement on the Inflammatory Bowel Disease Questionnaire (IBDQ) Total IBDQ score ranges from 32 to 224. A higher score indicates better quality of life.	6 months, 1 year, 2 years, 3 years
Crohn's Disease Endoscopic Index of Severity (CDEIS)	Improvement on the Crohn's Disease Endoscopic Index of Severity (CDEIS)	6 months, 1 year, 2 years, 3 years

Collaborators and Investigators

• Sponsor: Northwestern University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 1, 2019
• Primary Completion (ANTICIPATED): March 1, 2023
• Study Completion (ANTICIPATED): March 1, 2024

Study Registration Dates

• First Submitted: March 8, 2019
• First Submitted That Met QC Criteria: November 4, 2019
• First Posted (ACTUAL): November 6, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 8, 2019
• Last Update Submitted That Met QC Criteria: November 6, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Hematopoietic Stem Cell Transplant; Autologous Stem Cell Transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Calcineurin Inhibitors; Cyclophosphamide; Rifaximin; Fludarabine; Tacrolimus; Alemtuzumab
• Other Study ID Numbers: DIAD.ATTAC.2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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