Autologous Stem Cell Transplant for Refractory Crohn's Disease
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|ClinicalTrials.gov Identifier: NCT02676622|
Recruitment Status : Withdrawn (PI moved to a different institution.)
First Posted : February 8, 2016
Last Update Posted : February 3, 2017
Crohn's disease is an 'auto-immune' disorder of the gut. In this condition the body's own immune system is fighting its gut and causing inflammation and other symptoms. Patients who are refractory (not responding) to the medications usually used to control Crohn's disease (medicines like steroids, azathioprine, methotrexate, cyclophosphamide and antibodies like Infliximab), may consider being part of this study.
In this study, the investigators plan to wipe out (ablate) the 'faulty immune system' with medicines (immune-ablation) and then give back the patients own stored stem cells (that have been collected before) - a procedure called autologous (self) stem cell transplant (ASCT). Once the new immune system regrows again from the stem cells, it is hoped that the 'faulty' immune cells do not return again and do not fight the gut leading to remission from symptoms of Crohn's disease. The aim of this treatment therefore, is to reset or re-program the immune system, so that it does not fight the patient's own body.
Currently, there are very few trials and experience with this procedure in children and young adults. There have been a few studies that have shown benefit of ASCT procedure in adult patients. In some patients, the benefit lasted for 1-5 years; but 1 in 5 (20%) participants were not taking their medications for the Crohn's disease even 5 years after ASCT. Other 80% needed medications again, but in most cases with better disease control.
In order to potentially improve the long term outcomes of ASCT, the investigators are adding another medication (in addition to those used in adult studies) called IL-2 (Aldesleukin), which will be given as an every-other-day injection under the skin (subcutaneous) at very low doses for 6 weeks after the ASCT and can be taken at home. Low dose IL-2 is known to increase a type of immune cell called T-regulatory cells (Tregs) that make immune cells less reactive to self. Study doctors believe that increased population of Tregs after ASCT may lead to a better control of Crohn's disease- higher percentage of cures or disease control for a longer period of time compared to the previous adult trials.
Therefore, the goals of this study are-
- To see if ASCT can be used safely and can provide substantial benefit in young adults who have refractory Crohn's disease.
- To see if addition of IL-2 after the ASCT is safe and effective.
|Condition or disease||Intervention/treatment||Phase|
|Crohn's Disease||Drug: mobilization of stem cells to prepare for Leukapheresis Other: Leukapheresis- Collection of stem cells Drug: Preparative regimen 4-6 weeks after Leukapheresis Other: Stem Cell Transplant Drug: Low-dose IL-2 administration||Phase 2|
Crohn's Disease (CD) is an immunologically mediated chronic illness that has a relapsing and remitting course, most commonly presenting in the 2nd or 3rd decade and causing life long impairment of health and quality of life. Mainstay of clinical treatment for severe disease is combination of anti-inflammatory agents like 5-aminosalicyaltes and immunosuppressive medications like corticosteroids and newer anti-TNF antibodies like Infliximab. None of the drugs are, at present, curative and a relevant subset of patients are refractory to many of these pharmacologic approaches.
Immunoablative treatment followed by autologous stem cell rescue (Autologous HSCT) has been tried in this refractory group of patients with successful results. Autologous HSCT works in this auto-immune setting through the eradication of effector/memory T-cell clones due to a direct immuno-ablative effect of drugs used in the preparative regimen; by leading to an immune-reset- recovering clones of T- cells from the infused stem cells do not mount an auto-immune response and are tolerant to 'self' antigens and, by upregulation of T regulatory cells (Treg, CD4+CD25+FOXP3+ or CD8+ FOXP3+) via change in cytokine mileu during transplant. Increased population of Tregs restricts the activity of self reactive effector T-cells.
This pilot study is designed to gain on the success of previously published adult studies of autologous HSCT in refractory CD, with the aim to confirm the feasibility, safety and efficacy of HSCT and ultra low dose IL-2 when given post-HSCT in pediatric patients and young adults. IL-2 in very low doses has been shown to increase the proliferation of Treg lymphocytes and decrease inflammatory response. Hence, use of IL-2 post-transplant will result in significant and persistent increase in Treg population that may lead to more durable remissions after immunoablative therapy.
This pilot will focus on the 'safety' of this treatment in pediatric population.Since, this combination of immuno-ablative therapy followed by ultra low dose IL-2 has not been studied in children with CD, therefore transplant related mortality (TRM) and severe toxicity (> grade 3 toxicity by NCI criteria) will be monitored for 100 days post-transplant in all the patients and stopping rules will be enforced in case of excessive toxicity or TRM (>10%). Correlative studies will be performed at specific time points to assess the cytokine and inflammatory markers, immune-reconstitution and quantitative Treg cells; while clinical assessments will be done for 1 year post-HSCT for disease activity, steroid free remission period to evaluate the 'clinical efficacy' of this procedure.
The major aim of this pilot is to generate the preliminary safety and cytokine profile data to confirm the feasibility and benefit of autologous HSCT and IL-2 in children and young adults with refractory CD.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Pilot Study of Autologous Hematopoietic Stem Cell Transplantation With Post-Transplant Ultra Low-Dose IL-2 for Refractory Crohn's Disease|
|Study Start Date :||April 2013|
|Actual Primary Completion Date :||April 2013|
|Actual Study Completion Date :||April 2013|
Experimental: Stem-cell mobilization and Leukapheresis
Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY.
Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT
Drug: mobilization of stem cells to prepare for Leukapheresis
Cyclophosphomide 2 g/m2 x 2 consecutive days.
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 leukapharesis.
Other: Leukapheresis- Collection of stem cells
Placement of an Apheresis Catheter on the day of collection of stem cells.
Leukapheresis will be performed on a continuous flow separator machine to target 3-8 x 106 CD34+ cells/kg body weight.
Drug: Preparative regimen 4-6 weeks after Leukapheresis
Prior to starting medicines, a central venous line will be placed (arm or chest)
Cyclophosphamide iv: 50 mg/kg iv over 2 hours
Mesna iv (uro-protectant): 36 mg/kg iv over 12 hours
r-ATG (Thymoglobulin, Genzyme): 2.5 mg/kg/dose iv over 6 hours on days -3,-2,-1
Other: Stem Cell Transplant
Infusion of the(cryopreserved and thawed)peripheral blood stem cells (PBSC)occurs on Day 0.
Day +5: start Filgrastim (G-csf) subcutaneous injections
Hospitalization in isolation room for 4-5 weeks
Drug: Low-dose IL-2 administration
IL-2 Subcutaneous injections will start once ANC is > 500/µL and patient is afebrile (start IL-2 will be approximately day +20)for 6 weeks of treatment.
Once patient or parent has learnt the administration and patient is tolerating it well, then the rest of the treatment can be administered at home after discharge with weekly follow up visits.
Other Name: Aldesleukin
- The primary endpoint of the study is feasibility and safety of the autologous HSCT and low dose IL-2 post-HSCT, as evaluated by day +100 TRM (transplant related mortality) and incidence of severe toxicity. [ Time Frame: 1 year after transplant ]
- Secondary endpoints are evaluations of the effects of HSCT on clinical and laboratory manifestations of Crohn's Disease, i.e. frequency of and types of transplant related complications that were observed. [ Time Frame: 1 year after transplant ]Incidence of Infections: CMV reactivation and disease, adenovirus infection, BK virus reactivation, EBV PTLD and invasive fungal infections will be estimated and documented.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02676622
|Principal Investigator:||Sandeep Soni, MD||Nationwide Children's Hospital|