Stem Cell Transplantation in Crohn's Disease

Официальное название

Autologous Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Mesna
  Stem Cell Mobilization: Infused according to institutional guidelines; Post-PBSC Infusion Conditioning: Mesna provided with Cytoxan according to institutional protocol.
• Препарат Cyclophosphamide
  Stem Cell Mobilization: Cyclophosphamide (CY) infused intravenously over 1 hour: 50 mg/kg (25 mg/kg/day on 2 consecutive days)
• Препарат Filgrastim
  Stem Cell Mobilization: Filgrastim (G-CSF) 10 mcg/kg SC will start 5 days after the last dose of CY and will end the day before the last leukapheresis; Post-PBSC Infusion Conditioning: Filgrastim administered intravenously 5 mcg/kg IV starting day + 5, continue until ANC of \>1000/μL
• Процедура Apheresis catheter placement
  Subjects will require placement of an Apheresis catheter by Intervention Radiologists on the day of collection of stem cells.
• Процедура Leukapheresis
  Leukapheresis will be performed on a continuous flow separator machine according to institutional guidelines to target 3-8 x 10\^6 CD34+ cells/kg body weight.
• Препарат Fludarabine
  Preparative/Conditioning Regime Fludarabine given as 30 mg/m2 per dose x 4 days, beginning on day -6.
• Препарат Methylprednisolone
  Preparative/Conditioning Regime r-ATG pre-medication according to institutional guidelines
• Препарат Diphenhydramine
  Preparative/Conditioning Regime r-ATG premedication according to institutional guidelines
• Препарат Acetaminophen
  Preparative/Conditioning Regime r-ATG premedication according to institutional guidlines
• Препарат anti-thymocyte globulin (rabbit)
  Preparative/Conditioning Regime r-ATG administered intravenously: 2.5 mg/kg/dose IV over 6 hours on specified days (day -6,-4,-2); ); total 3 doses=7.5 mg/kg.

Первичные конечные точки

• Change in mucosal healing [Срок оценки: Change from pre-HSCT (baseline) to 6 months and 12 months post HSCT]
• Change in erythrocyte sedimentation rate (SED rate) [Срок оценки: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT]
• Change in fecal calprotectin concentration [Срок оценки: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT]
• Change in C reactive protein (CRP) [Срок оценки: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT]
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Срок оценки: Up to 24 months post HSCT]
• Incidence of HSCT Related Complications [Срок оценки: Up to 24 months post HSCT]
• Change in clinical measures of sustained remission [Срок оценки: Up to 24 months post HSCT]

Вторичные конечные точки (4)

• Change in quality of life [Срок оценки: 0, 2, 4, 6, 12 and 24 months post HSCT]
• Change in school and work productivity [Срок оценки: 0, 2, 4, 6, 12 and 24 months post HSCT]
• Change in thymopoiesis after HSCT [Срок оценки: 0, 2, 4, 6, 12 and 24 months post HSCT]
• Change in T-cell repertoire after HSCT using spectratyping [Срок оценки: 0, 2, 4, 6, 12 and 24 months post HSCT]

Критерии участия

Критерии включения

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

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

i) PCDAI > 30, and ii) Two of the following:

• elevated CRP
• endoscopic evidence of active disease confirmed by histology
• clear evidence of active small bowel Crohn's disease on CT or MR enterography.
• 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.
• Current problems unsuitable for surgery or patient at risk for developing short bowel syndrome.
• Accepted by a majority of the members of the combined IBD Center as an appropriate candidate (see Selection description below).
• Informed consent

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

Критерии исключения

• Pregnancy or unwillingness to use adequate contraception during the study, in women of childbearing age. Unwillingness of using appropriate contraceptive measures in males.
• 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 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.
• any infection with HIV, HTLV-1 or 2, hepatitis viruses, or any other infection the investigators consider a contraindication to participation.
• other chronic disease causing significant organ failure.
• Infection or risk thereof:

• Current clinical relevant abscess or significant active infection.
• 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.
• History of tuberculosis or at current increased risk of tuberculosis
• Quantiferon Gold test result or other investigations that the investigators regard as evidence of active tuberculosis.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Cedars-Sinai Medical Center — Los Angeles

Идентификаторы

NCT: NCT04224558 · Pro00051458

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗