Stem Cell Transplantation in Crohn's Disease
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04224558|
Recruitment Status : Not yet recruiting
First Posted : January 13, 2020
Last Update Posted : January 13, 2020
|Condition or disease||Intervention/treatment||Phase|
|Crohn Disease||Drug: Mesna Drug: Cyclophosphamide Drug: Filgrastim Procedure: Apheresis catheter placement Procedure: Leukapheresis Drug: Fludarabine Drug: Methylprednisolone Drug: Diphenhydramine Drug: Acetaminophen Drug: anti-thymocyte globulin (rabbit) Drug: lymphocyte immune globulin Biological: Peripheral Blood Stem Cell Infusion Drug: Cytoxan||Phase 1 Phase 2|
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.
- To evaluate the incidence of HSCT related complications, i.e. viral reactivations (CMV, Adenovirus, EBV, BK virus) or fungal infections.
- To evaluate the impact of HSCT on quality of life and school productivity.
- 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).
- Change in Crohn's disease endoscopic index after 6 and 12 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||15 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Autologous Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease|
|Estimated Study Start Date :||January 1, 2020|
|Estimated Primary Completion Date :||January 1, 2023|
|Estimated Study Completion Date :||January 1, 2024|
Experimental: HSCT after mobilization and conditioning
Mobilization and leukopheresis allow for stem cell harvest. Then conditioning is provided prior to stem cell transplantation, followed by post-transplant conditioning.
Stem Cell Mobilization: Infused according to institutional guidelines;
Post-PBSC Infusion Conditioning: Mesna provided with Cytoxan according to institutional protocol.
Other Name: Mesnex
Stem Cell Mobilization:
Cyclophosphamide (CY) infused intravenously over 1 hour: 50 mg/kg (25 mg/kg/day on 2 consecutive days)
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
Procedure: Apheresis catheter placement
Subjects will require placement of an Apheresis catheter by Intervention Radiologists on the day of collection of stem cells.
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.
Preparative/Conditioning Regime Fludarabine given as 30 mg/m2 per dose x 4 days, beginning on day -6.
Other Name: Fludara
Preparative/Conditioning Regime r-ATG pre-medication according to institutional guidelines
Other Name: solu-medrol
Preparative/Conditioning Regime r-ATG premedication according to institutional guidelines
Other Name: Benadryl
Preparative/Conditioning Regime r-ATG premedication according to institutional guidlines
Other Name: Tylenol
Drug: 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.
Other Name: thymoglobulin
Drug: lymphocyte immune globulin
Preparative/Conditioning Regime In patients who develop severe allergic reactions to rATG (Thymoglobulin), it may be substituted by horse ATG (hATG, ATGAM, Pharmacia & Upjohn, Kalamazoo, MI). The recommended dose of hATG is 25 mg/kg/day for 3 doses.
Other Name: ATGAM
Biological: Peripheral Blood Stem Cell Infusion
PBSC (peripheral blood stem cell) infusion on day 0 as per institutional guidelines.
Post-PBSC Infusion Conditioning Cytoxan infused intravenously: 50mg/kg/day x 2 days. Infused over 2 hours with adequate hydration or according to institutional guidelines.
Other Name: Cyclophosphamide
- Change in mucosal healing [ Time Frame: Change from pre-HSCT (baseline) to 6 months and 12 months post HSCT ]Change mucosal healing as determined by the simple endoscopic score for crohn's disease (SES-CD). The SES-CD assesses the size of mucosal ulcers, the ulcerated surface, the endoscopic extension and the presence of stenosis. Each are measured on a scale of 0-3 and are summed to create a total score. For total score, 0-2 indicates remission, 3-6 indicates mild endoscopic activity, 7-15 indicates moderate endoscopic activity, and > 15 indicates severe endoscopic activity.
- Change in erythrocyte sedimentation rate (SED rate) [ Time Frame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT ]Change in SED rate (mm/hour)
- Change in fecal calprotectin concentration [ Time Frame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT ]Change in fecal calprotectin concentration
- Change in C reactive protein (CRP) [ Time Frame: Change from pre-HSCT (baseline) to 2, 4, 6, 12, and 24 months post HSCT ]Change in C reactive protein (CRP)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Up to 24 months post HSCT ]Number of treatment-emergent adverse events (including death (transplant related mortality, TRM) and severe toxicity (≥ grade 3 toxicity; NCI Toxicity Criteria version 4.0)
- Incidence of HSCT Related Complications [ Time Frame: Up to 24 months post HSCT ]The incidence of HSCT related complications, i.e. viral reactivations (CMV, Adenovirus, EBV, BK virus) or fungal infections.
- Change in clinical measures of sustained remission [ Time Frame: Up to 24 months post HSCT ]Change in CDAI score (Crohn's Disease Activity Index). The CDAI measure the signs, symptoms, and history of Crohn's Disease based on the past 7 days. The index measures abdominal pain, stools per day, general wellbeing, HCT, ESR, Albumin, height, weight, abdominal exam, perirectal disease, and extra-intestinal manifestations each scaled between 0-10. The sum of these measures creates a total score between 0-100 with the higher score representative of more disease activity.
- Change in quality of life [ Time Frame: 0, 2, 4, 6, 12 and 24 months post HSCT ]Change in score on the IMPACT-III Questionnaire (A Quality of Life Questionnaire for Children with Inflammatory Bowel Disease) after HSCT. It is a self-report measure with 35 closed questions encompassing six proposed domains: Bowel Symptoms (7 items), Systemic Symptoms (3 items), Social Functioning (12 items), Body Image (3 items), Treatment/Interventions (3 items), and Emotional Functioning (7 items). The IMPACT-III uses 5-point Likert scale ranging from 1 to 5 for all answers. The outcome score ranges from 35 to 175, with higher scores suggesting better quality of life.
- Change in school and work productivity [ Time Frame: 0, 2, 4, 6, 12 and 24 months post HSCT ]Change in school productivity and activity impairment as determined by the modified Work Productivity and Activity Impairment (WPAI) Index score. The Modified WPAI yield four types of scores: absenteeism (school time missed), presenteeism (impairement at school), school productivity (overall work impairment/absenteeism plus presenteeism), and activity impairement. WPAI outcomes are expressed as impairement percentages, with higher numbers indicating greater impairement and less productivity.
- Change in thymopoiesis after HSCT [ Time Frame: 0, 2, 4, 6, 12 and 24 months post HSCT ]the amount of T-cell receptor excision circles (TREC) will be determined. TRECs are excision circles of DNA excised during the process of T cell receptor (TCR) rearrangement. Since these TRECs do not replicate during cell division, they can also be a measure for recent thymic emigrants.
- Change in T-cell repertoire after HSCT using spectratyping [ Time Frame: 0, 2, 4, 6, 12 and 24 months post HSCT ]The CDR3 (complement determining region) of the TCRβ chain is the most variable region of the TCR and is generated by recombination of the variable, diversity and joining region of the DNA. The length of this region differs between different T-cell clones due to nucleotide transferases or removed nucleotides during recombination, and the variability of these lengths can be used to estimate thymic diversity. This variability can be determined by electrophoresis, after amplification of this region by PCR.
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): NCT04224558
|Contact: David Ziring, MDfirstname.lastname@example.org|
|Contact: Kayleen Ports, BSemail@example.com|
|United States, California|
|Cedars-Sinai Medical Center|
|Los Angeles, California, United States, 90048|
|Contact: David Ziring, MD 310-423-7100 firstname.lastname@example.org|
|Contact: Kayleen Ports, BS 3104235314 Kayleen.Ports@cshs.org|
|Principal Investigator: David Ziring, MD|
|Sub-Investigator: Shervin Rabizadeh, MD|
|Principal Investigator: Ronald Paquette, MD|