Clinical trial NCT04224558: Stem Cell Transplantation in Crohn's Disease
Official title: Autologous Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Crohn Disease
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
First posted: 2020-01-13
Enrollment: 15
Sex: ALL
Minimum age (years): 13
Maximum age (years): 28
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Unfortunately, some patients with Crohn's disease (CD) fail to respond to the best clinical treatments and some only experience temporary benefit. For severe Crohn's disease, there is an experimental treatment called "high dose immunoablation" followed by autologous hematopoietic stem cell transplantation (HSCT). This study removes over active lymphocytes (immunoablation) and replaces them using blood stem cells that have been taken from the patient's own body. The aim of the study is to reset or reprogram the patient's immune system to its state prior to diagnosis.

Detailed description: The treatment of Crohn's disease has proven to be quite efficacious in the majority of patients with the timely use of combination therapies for remission induction (corticosteroids and/or biologics) and maintenance of disease control (immunosuppressives and/or biologics). However, a proportion of patients fail to achieve complete and long term disease control and often require multiple intestinal surgeries with a risk of developing short bowel syndrome. Lymphoablation followed by hematopoietic stem cell transplantation to rescue the immune system has been proposed as an alternative strategy to induce long term disease control in this high-risk population. It has been demonstrated that despite the potential toxicity and morbidity associated with the procedure, the benefit-risk ratio is favorable. Hence, the investigators propose to offer HSCT to selected CD patients and to study mechanisms of reducing T cell autoreactivity which will hopefully lead to more focused therapeutic approaches in the future.

This is an open-label, non-randomized, non-blinded, prospective study in therapeutic refractory Crohn's patients, failing conventional therapy.

The primary objective is to evaluate the safety and potential clinical benefit of lymphoablation followed by autologous HSCT rescue in therapy refractory CD. Death (transplant-related mortality, TRM) and severe toxicity (≥ grade 3 toxicity; NCI Toxicity Criteria version 4.0) within the first 6 months after HSCT will be monitored to meet this end-point.

SECONDARY OBJECTIVES

1. To evaluate the incidence of HSCT related complications, i.e. viral reactivations (CMV, Adenovirus, EBV, BK virus) or fungal infections.
2. To evaluate the impact of HSCT on quality of life and school productivity.
3. To elucidate the underlying mechanism involved in the observed benefit of HSCT on CD.

First, the safety will be evaluated by the amount of related adverse events. All adverse events will be recorded in a standardized way and their relationship to the study protocol will be assessed at various short and long term time points.

Second, to determine clinical benefit, the percentage of patients in sustained disease remission at 0, 2, 4, 6, 12 and 24 months post HSCT will be determined. Sustained disease remission is defined as a Crohn's Disease Activity Index (CDAI) \< 150 without the use of corticosteroids. In addition, mucosal healing will be assessed during ileocolonoscopy at 6 and 12 months following HSCT using the CD endoscopic index (SES).

SECONDARY ENDPOINTS

- Change in Crohn's disease endoscopic index after 6 and 12 months.

Eligibility criteria: Inclusion Criteria:

1. Aged 13-28 years are eligible
2. Confirmed diagnosis of active Crohn's disease:

   1. Diagnosis of Crohn's disease based on typical radiological appearances and / or typical histology at least 6 months prior to screening.
   2. Active disease at the time of registration to the trial, defined as

   i) PCDAI \> 30, and ii) Two of the following:
   1. elevated CRP
   2. endoscopic evidence of active disease confirmed by histology
   3. clear evidence of active small bowel Crohn's disease on CT or MR enterography.
3. Unsatisfactory course despite 3 immunosuppressive agents (usually azathioprine, methotrexate and infliximab, adalimumab and/or certolizumab) in addition to corticosteroids. Patients should have relapsing disease (i.e. 1 exacerbation/year) despite thiopurines, methotrexate and/or infliximab/adalimumab/certolizumab maintenance therapy or clear demonstration of intolerance / toxicity to these drugs.
4. Current problems unsuitable for surgery or patient at risk for developing short bowel syndrome.
5. Accepted by a majority of the members of the combined IBD Center as an appropriate candidate (see Selection description below).
6. Informed consent

   1. Prepared to undergo additional study procedures as per trial schedule
   2. Patient has undergone intensive counseling about risks

Exclusion Criteria:

1. Pregnancy or unwillingness to use adequate contraception during the study, in women of childbearing age. Unwillingness of using appropriate contraceptive measures in males.
2. Concomitant severe disease

   1. renal: creatinine clearance \< 30 mL/min (measured or estimated)
   2. cardiac: clinical evidence of refractory congestive heart failure; left ventricular ejection fraction \< 40% by cardiac echo; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences as evaluated by an experienced echo cardiographer
   3. pulmonary: diffusion capacity \<40%
   4. psychiatric disorders including active drug or alcohol abuse
   5. concurrent or recent history of malignant disease (excluding non-melanoma skin cancer)
   6. uncontrolled hypertension, defined as resting systolic blood pressure ≥ 140 and/or resting diastolic pressure ≥ 90 despite at least 2 anti-hypertensive agents.
   7. any infection with HIV, HTLV-1 or 2, hepatitis viruses, or any other infection the investigators consider a contraindication to participation.
   8. other chronic disease causing significant organ failure.
3. Infection or risk thereof:

   1. Current clinical relevant abscess or significant active infection.
   2. Perianal fistula without free drainage. Perianal fistulas is not an exclusion provided there is natural free drainage or a seton suture(s) have been placed.
   3. History of tuberculosis or at current increased risk of tuberculosis
   4. Quantiferon Gold test result or other investigations that the investigators regard as evidence of active tuberculosis.
   5. Abnormal chest X-ray (CXR) consistent with active infection or neoplasm.

6) Significant malnutrition: Body Mass Index (BMI) ≤ 18, serum albumin \< 20 g/l.

7) Previous poor compliance. 8) Concurrent enrollment in any other protocol using an investigational drug or hematopoietic growth factor up to four weeks before study entry.

Primary outcomes:
measure: Change in mucosal healing
timeFrame: Change from pre-HSCT (baseline) to 6 months and 12 months post HSCT
measure: Change in erythrocyte sedimentation rate (SED rate)
timeFrame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT
measure: Change in fecal calprotectin concentration
timeFrame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT
measure: Change in C reactive protein (CRP)
timeFrame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Up to 24 months post HSCT
measure: Incidence of HSCT Related Complications
timeFrame: Up to 24 months post HSCT
measure: Change in clinical measures of sustained remission
timeFrame: Up to 24 months post HSCT
Secondary outcomes:
measure: Change in quality of life
timeFrame: 0, 2, 4, 6, 12 and 24 months post HSCT
measure: Change in school and work productivity
timeFrame: 0, 2, 4, 6, 12 and 24 months post HSCT
measure: Change in thymopoiesis after HSCT
timeFrame: 0, 2, 4, 6, 12 and 24 months post HSCT
measure: Change in T-cell repertoire after HSCT using spectratyping
timeFrame: 0, 2, 4, 6, 12 and 24 months post HSCT
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: David Ziring, MD
role: PRINCIPAL_INVESTIGATOR
References: