Clinical trial NCT03000296: Autologous Unselected Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease
Official title: Autologous Unselected Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Crohn's Disease
Inflammatory Bowel Diseases
Gastroenteritis
Keywords: autologous
lymphoablation
hematopoetic stem cell transplant
immune system
Bone marrow transplant
Lead sponsor: Beneficência Portuguesa de São Paulo
Sponsor class: OTHER
First posted: 2016-12-22
Enrollment: 50
Sex: ALL
Minimum age (years): 14
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study evaluates the safety and clinical benefits of a therapeutic approach using the cyclophosphamide (Cy) + thymoglobulin® (ATG) + granulocyte colony-stimulating factor (G-CSF) conditioning regimen followed by autologous hematopoietic stem cell transplantation (HSCT) rescue in the treatment of refractory Crohn's disease. Adverse events, and clinical and endoscopic conditions will be assessed at different short and long-term time points.

Detailed description: Crohn's disease (CD) is a chronic, refractory inflammatory bowel disease that affects the entire digestive tract associated with intestinal and extra intestinal manifestations or other autoimmune diseases. Conventional therapy for Crohn's disease includes anti-inflammatory, immunosuppressant and/or biologic drugs/corticosteroids. This treatment benefits the majority of patients. 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.

Hematopoietic stem cell transplantation (HSCT) has been proposed to cause lymphoablation and reset of the immune system as an alternative strategy to induce long-term disease control in this high-risk population.

This study enrolled Crohn's disease patients not responsive to conventional therapy.

Initially safety and the clinical outcome will be evaluated. The selected patients will be admitted to the bone marrow transplant (BMT) unit for the mobilization regimen using cyclophosphamide (Cy - 60 mg/kg) and G-CSF (10 mcg/kg/day) from the 5th day after Cy administration until harvesting progenitor cells from peripheral blood by leukapheresis.

After seven days of rest, the conditioning regimen consists of Cy (200 mg/kg total dose for four days), rabbit antithymocyte globulin (6.5 mg/kg total dose for four days) and methylprednisolone (500 mg/day).

The clinical course of patients with refractory Crohn´s disease will be evaluated to determine the efficacy of HSCT as a therapeutic tool including the adverse aspects of the procedure, clinical outcome and quality of life.

Eligibility criteria: Inclusion Criteria:

1. Age between 14 and 50 years (patients aged 50 - 70 can participate at the principal investigators discretion).
2. Confirmed diagnosis of active Crohn's disease:

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

     \*Crohn's Disease Activity Index (CDAI) \> 150, and ii) Two of the following:
   * Harvey Bradshaw Index \> 4
   * Endoscopic evidence of active disease confirmed by histology
   * Clear evidence of active small bowel Crohn's disease on computed tomography (CT) or magnetic resonance (MR) enterography.
3. Unsatisfactory course despite immunosuppressive agents (usually azathioprine, methotrexate and two biologic agents (normally infliximab, adalimumab and/or certolizumab) in addition to corticosteroids. Patients should have relapsing and refractory disease 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. Informed consent:

   * Prepared to undergo additional study procedures as per trial schedule
   * 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

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

Primary outcomes:
measure: Safety of unselected autologous HSCT in refractory Crohn´s disease patients
timeFrame: 12 months
Secondary outcomes:
measure: Crohn´s Disease Activity Index (CDAI)
timeFrame: 12 months
measure: CRAIG Crohn´s Severity Score (CSS)
timeFrame: 12 months
measure: Inflammatory Bowel Disease Questionnaire (IBDQ)
timeFrame: 24 months
measure: Short Form-36 Health Survey (SF-36)
timeFrame: 24 months
measure: Simple Endoscopic Activity Score (SES)
timeFrame: 24 months
measure: Crohn's Disease Endoscopic Index of Severity (CDEIS)
timeFrame: 24 months
measure: Rutgeerts endoscopic score
timeFrame: 24 months
measure: Harvey & Bradshaw Index (HBI)
timeFrame: 24 months
Other outcomes:
Locations:
city: Sao Jose do Rio Preto
country: Brazil
facility: Beneficencia Portuguesa
state: SP
Study officials:
affiliation: Beneficencia Portuguesa
name: Milton A Ruiz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: