Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for IBD Caused by IL-10R Gene Deficiency

Inflammatory Bowel Diseases Clinical Trial

Official title:

Multi-center Clinical Study of Cord Blood Stem Cell Transplantation in The Treatment of Very Early-Onset Inflammatory Bowel Disease Caused by Interleukin-10 Receptor Gene Deficiency

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04170192
• Other study ID #: CPBMT-IBD-2019
• Status: Active, not recruiting
• Start date: December 1, 2019
• Est. completion date: October 31, 2023

Study information

• Verified date: February 2020
• Source: Children's Hospital of Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Very early onset inflammatory bowel disease (VEO-IBD) is a special subtype of children's inflammatory bowel disease (IBD). VEO-IBD is mostly caused by single-gene defects and can be cured by allo-hematopoietic stem cell transplantation ( HSCT). Umbilical Cord Blood Transplantation (UCBT) is less reported in these patients.

Description:

Very early onset inflammatory bowel disease (VEO-IBD) is a special subtype of children's inflammatory bowel disease (IBD). The clinical characteristics of VEO-IBD patients include early onset, severe diarrhea, severe malnutrition, perianal diseases and repeated infection. Studies have found that VEO-IBD is mostly caused by single-gene defects and can be cured by allo-hematopoietic stem cell transplantation ( HSCT). VEO-IBD is a rare disease. At present, there is no large sample of clinical data for transplantation in these patients. Umbilical Cord Blood Transplantation (UCBT) is less reported. Therefore, many transplantation-related issues need to be further studied, including HSCT indications, transplantation timing, pre-transplantation drug therapy, intestinal protection during transplantation, prevention and treatment of post-transplantation complications and so on. The aim of this study is to investigate the efficacy of UCBT in the treatment of VEO-IBD caused by interleukin-10 receptor (IL10R) gene deficiency, including engraftment rate, disease-free survival rate and overall survival rate, and to evaluate transplant-related mortality and complications. All the selected cases are diagnosed as VEO-IBD with IL10R gene deficiency by enteroscopy, histopathology and gene detection. These patients have no matched sibling donors. Their organs function should be normal. The guardian of the patient has the desire and requirement for UCBT and signs the informed consent before treatment. Cord blood stem cell selection: HLA high-resolution detection of patients before transplantation, searching through cord blood stem cell bank, selecting cord blood stem cells that meet the following criteria: HLA-A, B, C, DRB1 high-resolution (genotype) > 6/8 matching, total number of nuclear cells > 5 x 10^7/kg. Conditioning regimen: fludarabine + busulfan + cyclophosphamide. GVHD prevention: tacrolimus (FK506) or cyclosporine A. Infection prevention: Micafungin/caspofungin before engraftment, voriconazole after engraftment to prevent fungi. Ganciclovir is used from the beginning of conditioning to the infusion of cord blood stem cells, and acyclovir is used to prevent virus infection. SMZ is used to prevent Pneumocystis carinii infection after engraftment until half a year after the withdrawal of immunosuppressive agents.

Procedure/Surgery: Cord Blood Stem Cell Transplantation Unrelated cord blood stem cell selection: HLA high-resolution detection should be performed before transplantation. High-resolution (genotype) matching of HLA-A, B, C and DRB1 should be selected. The total number of nuclear cells should be more than 5*107/kg.

Conditioning regime: fludarabine 30 mg/m2/d for 5 days, busulfan 1 mg/kg for 4 times for 3 days, cyclophosphamide 50 mg/kg for 2 days.

Prevention of GVHD: tacrolimus (FK506) 0.1 mg/kg/day, starting from day 4 before transplantation, taking orally twice on an empty stomach to monitor the blood concentration and keep it at 5-10 ng/ml.

Infection prevention: Micafungin/caspofungin before engraftment, voriconazole after engraftment to prevent fungi. Ganciclovir is used from the beginning of conditioning to the beginning of reinfusion, and acyclovir is used to prevent virus infection until immunosuppressive agents are discontinued after reinfusion. SMZ is used to prevents Pneumocystis carinii infection after engraftment.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: October 31, 2023
• Est. primary completion date: October 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

Inclusion Criteria:

1. Diagnosis: All selected cases will be diagnosed as very early-onset inflammatory bowel disease with interleukin-10 receptor gene deficiency through gastroenterology, pathology and gene diagnosis institutions to improve enteroscopy, histopathology and gene detection.

2. The patients have no HLA matched sibling donor.

3. All organs function normally and meet the following test criteria:

Liver function ALT, AST < 10 times normal value upper limit, TBIL < 5 times normal value upper limit.

Renal function BUN and Cr < 1.25 times the upper limit of normal value. ECG and echocardiography showed no cardiac insufficiency.

4. The legal guardian of the patient has the desire and requirement for the treatment of allogeneic umbilical cord blood stem cell transplantation, and signs the informed consent before treatment. The informed consent should inform all relevant contents of clinical research, patients are willing and abide by the treatment plan, follow-up plan, laboratory examination, etc.

Exclusion Criteria:

1. There are any contraindications of hematopoietic stem cell transplantation.

2. There are other serious diseases, such as severe damage to vital organ functions:

respiratory failure, cardiac insufficiency, decompensated liver insufficiency, renal insufficiency, uncontrollable infection and so on.

3. Other drug clinical researchers are under way.

4. Simultaneously suffering from other serious acute or chronic physical or mental diseases, or abnormal laboratory examinations, may affect patient's life safety and compliance, and affect informed consent, research participation, follow-up or result interpretation.

Related Conditions & MeSH terms

• Inflammatory Bowel Diseases
• Intestinal Diseases

Intervention

Procedure:
• Cord Blood Stem Cell Transplantation
Unrelated cord blood stem cell selection; Reduced intensity conditioning regime; GVHD prevention; Infection prevention.

Locations

Country	Name	City	State
China	Children's Hospital of Fudan University	Shanghai	Minhang

Sponsors (9)

Lead Sponsor	Collaborator
Children's Hospital of Fudan University	Beijing Children's Hospital, Children's Hospital Of Soochow University, Children’s Hospital of Nanjing Medical University, Guangzhou Women and Children's Medical Center, Shanghai Children's Hospital, Shenzhen Children's Hospital, The First Affiliated Hospital of Zhengzhou University, Wuhan Women and Children's Medical Center

Country where clinical trial is conducted

China, 

References & Publications (11)

Bianco AM, Girardelli M, Tommasini A. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World J Gastroenterol. 2015 Nov 21;21(43):12296-310. doi: 10.3748/wjg.v21.i43.12296. Review. — View Citation

Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, Shteyer E, Filiz S, Chee R, Elawad M, Hartmann B, Arkwright PD, Dvorak C, Klein C, Puck JM, Grimbacher B, Glocker EO. Clinical outcome in IL-10- and IL-10 receptor-deficient patie — View Citation

Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hätscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerb — View Citation

Huang Z, Peng K, Li X, Zhao R, You J, Cheng X, Wang Z, Wang Y, Wu B, Wang H, Zeng H, Yu Z, Zheng C, Wang Y, Huang Y. Mutations in Interleukin-10 Receptor and Clinical Phenotypes in Patients with Very Early Onset Inflammatory Bowel Disease: A Chinese VEO-I — View Citation

Kelsen JR, Dawany N, Moran CJ, Petersen BS, Sarmady M, Sasson A, Pauly-Hubbard H, Martinez A, Maurer K, Soong J, Rappaport E, Franke A, Keller A, Winter HS, Mamula P, Piccoli D, Artis D, Sonnenberg GF, Daly M, Sullivan KE, Baldassano RN, Devoto M. Exome s — View Citation

Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, Pfeifer D, Kreipe H, Pfister ED, Baumann U, Puchalka J, Bohne J, Egritas O, Dalgic B, Kolho KL, Sauerbrey A, Buderus S, Güngör T, Enninger A, Koda YK, Guariso G, Weiss B, Corbacioglu S, So — View Citation

Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters T, Sherlock M, Dubinsky M, Hyams JS. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm — View Citation

Peng K, Qian X, Huang Z, Lu J, Wang Y, Zhou Y, Wang H, Wu B, Wang Y, Chen L, Zhai X, Huang Y. Umbilical Cord Blood Transplantation Corrects Very Early-Onset Inflammatory Bowel Disease in Chinese Patients With IL10RA-Associated Immune Deficiency. Inflamm B — View Citation

Pigneur B, Escher J, Elawad M, Lima R, Buderus S, Kierkus J, Guariso G, Canioni D, Lambot K, Talbotec C, Shah N, Begue B, Rieux-Laucat F, Goulet O, Cerf-Bensussan N, Neven B, Ruemmele FM. Phenotypic characterization of very early-onset IBD due to mutation — View Citation

Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus EV Jr, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. Toward an i — View Citation

Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson DC, Travis SP, Turner D, Klein C, Snapper SB, Muise AM; COLORS in IBD Study Group and NEOPICS. The diagnostic approach to monogenic very early onset inflammatory bowel dis — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The occurrence of adverse events (AE)	The adverse events (AE) is a composite variable including liver and kidney function damage, nausea, vomiting, arrhythmia and dyspnea. The variable would be coded as 1 if any of these events occurs after transplantation for 3 years while 0 for none . These adverse events would be measured by assessment scale method according to NCI CTC AE v4.0 classification standard.	3 years after transplantation
Other	The occurrence of graft-versus-host disease (GVHD)	Acute and chronic GVHD is measured and graded as per standardised criteria.	3 years after transplantation
Other	Transplant-related mortality	Transplant-related mortality (TRM) is defined as the proportion of non primary disease death patients in the total number of cord blood stem cell transplantation patients in the same period within 100 days after transplantation.	3 years after transplantation
Other	The occurrence of transplant-related complications except GVHD	Transplant-related complications include infections, hepatic venous occlusion disease, hemorrhagic cystitis, capillary leakage syndrome, thrombotic microangiopathy, post-transplantation lymphoproliferative disease, idiopathic pneumonia syndrome and obstructive bronchiolitis, which are diagnosed according to the relevant diagnosis standards of each disease.	3 years after transplantation
Primary	Overall survival rate	Overall survival is defined as the survival status of patients by the end of 3 years after the transplanting, coded as 1 for dead and 0 for survive.	3 years after transplantation
Secondary	Disease free survival rate	Disease free survival is defined as the survival status of patients by the end of the third year after transplantation. Disease free survival is defined as survive without conditions including engraftment failure and death caused by any reasons. The variable is coded as 0 for disease free survive, and 1 for all conditions other than the defined status of "0".	3 years after transplantation
Secondary	Successful engraftment	The event of successful engraftment is defined as Neutrophil count = 0.5×10^9/L for continuous 3 days and platelet count = 20×10^9/L for continuous 7 days without transfusion. It is coded as 1.	3 years after transplantation