EBMT ADWP Prospective Non-interventional Study: Post-AHSCT Management in SSC Patients (NISSC-2)

• Conditions: Autoimmune Diseases
• Interventions: Procedure: Autologous HSCT

• Registration Number: NCT03444805
• Lead Sponsor: European Society for Blood and Marrow Transplantation

Brief Summary

The aim of the study is to assess the effectiveness of various post-transplant treatment management approaches on clinical and immune biological responses after Autologous Hematopoietic Stem Cell transplantation (AHSCT) for Systemic Sclerosis (SSc) as currently performed by the different treatment protocols used in routine clinical practice across Europe in various EBMT centres

Detailed Description

NISSc-2 is a prospective observational study specifically designed to assess the effectiveness of various post-transplant treatment management approaches on clinical and immune biological responses after Autologous Hematopoietic Stem Cell transplantation (AHSCT) for Systemic Sclerosis (SSc) as currently performed by the different treatment protocols used in routine clinical practice across Europe in various EBMT centres through the careful recording and analysis of routinely collected clinical and immune biological data, and specific data regarding post-transplant use of SSc active treatments, including:

* Steroids,

* SSc active treatments after AHSCT such as mycophenolate mofetil (MMF), azathioprine, cyclophosphamide (oral or IV), methotrexate, polyclonal antibodies (such as ATG) or monoclonal antibodies (rituximab, belimumab or any others) as well as their respective dosage and duration of each treatment. These post-transplant treatments can be administered for various reasons, which can be specified by local investigators, such as per local protocol decision for maintenance therapy, or for disease progression with or without prior clinical response, during routine clinical follow-up. Patients who do not receive any post-transplant therapy will also be observed.

Different protocols are used in the different centres, but it is not yet clear, which approach will be the most efficient and the safest. The role of stem cell purification with CD34-selection also needs to be determined prospectively.

In addition, the EBMT Autoimmune Diseases and Immunobiology Working Parties developed and implemented guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after AHSCT \[16\]. To follow post-transplant immune reconstitution according to ADWP GCP, results of routine analyses performed by centres under standardized conditions on available biological samples will be investigated in correlation to clinical outcome parameters. Every centre will follow its own local protocol for AHSCT, which usually refers to the recent update of the EBMT guidelines for AHSCT in autoimmune disease.

We therefore specifically designed NISCC-II to prospectively capture various post-ASHCT management protocols and their effect on the observed clinical response after AHSCT.

Study Timeline

• Study First Submitted: 2018-02-19
• Study First Submitted QC: 2018-02-22
• Study First Posted: 2018-02-23
• Study Start: 2019-07-01
• Status Verified: 2019-08
• Last Update Submitted: 2019-08-29
• Last Update Posted: 2019-09-03
• Primary Completion: 2021-12-31
• Study Completion: 2023-03-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. • Autologous HSCT
2. • Age above 18 years at time of transplant.
3. -. Established diagnosis of progressive SSc according to 2013 ACR/EULAR classification criteria

Exclusion Criteria

1. Pregnancy or inadequate contraception

2. Severe concomitant disease

3. Reduced lung, cardiac or renal function

   a. .Reduced lung function with FVC < 50% or DLCO < 30% (of predicted values) b; .Pulmonary arterial hypertension with baseline (resting) PASP > 40 mmHg or mPAP > 25 mmHg or a PASP > 45 mmHg or mPAP > 30 mmHg after fluid challenge or Pulmonary vascular resistance > 3 Wood units on RHC c. Severe heart failure with Ejection Fraction < 45% by cardiac echocardiography d. D-sign of septal bounce on cardiac MRI e. Unrevascularized severe coronary artery disease f. Untreated severe arrhythmia g. Cardiac tamponade h. Constrictive pericarditis i. Kidney insufficiency: creatinine clearance <30ml/min Previously damaged bone marrow

   1. Leukopenia < 2.0 x 109/L (total white cell count)
   2. Thrombocytopenia < 100 x 109/L

4. Uncontrolled severe or chronic infection (Hepatitis B/C, HIV, Salmonella carrier, syphilis, tuberculosis)

5. Severe concomitant psychiatric illness (depression, psychosis)

6. Concurrent neoplasms or myelodysplasia in the past 5 years

7. Smoking (current)

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
NISSC-2	Autologous HSCT	SSC patients treated with AHSCT

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS),	2 years post transplant	defined as survival since AHSCT without evidence of progression of SSc.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	2 years post-transplant	Overall survival
Infectious complications, CMV / EBV reactivation	2 years post-transplant	Infectious complications, CMV / EBV reactivation
Treatment related toxicity	100 days post-transplant	Treatment related toxicity throughout the study period using WHO toxicity parameters (expressed as maximum grade toxicity per organ system, see appendix) Incidence of Adverse Events (AE) and Serious Adverse Events (SE) Neutrophil and platelet engraftment, defined as first day after transplantation with absolute neutrophil count \> 0.5 x 109/L and platelet count \>20 x 109/L (without platelet transfusion).
100 days Treatment Related Mortality (100d TRM)	100 days post-transplant	defined as any death during 100 days following transplant that cannot be attributed to progression or relapse of the disease
Use of prednisone equivalent	1 year and 2 years post-transplant	Use of prednisolone equivalent \> 6 mg/day for more than 3 months
Use of immunosuppressive drugs	2 years post-transplant	defined as use of any post-transplant immunosuppressive drugs (mycophenolate mofetil, azathioprine, oral or iv cyclosphosphamide or methotrexate) for either causes (maintenance therapy as per local protocol decision, SSc progression or relapse) and total duration of exposure to this post-transplant immunosuppressive treatment (average monthly daily dose and months duration)
Use of post-transplant biotherapies	2 years post-transplant	defined as use of any monoclonal (i.e. anti CD20, anti-BLyS, alemtuzumab or polyclonal (i.e. ATG) antibodies for either causes (per local protocol decision, EBV infection or reactivation, progression or relapse) and total doses (in number and g/kg)
Response to treatment	1 year and 2 years post-transplant	defined as any of the following changes; * 25% improvement in mRSS and/or; * ≥10% improvement in DLCO or FVC as compared to baseline (before mobilisation)
Secondary autoimmune diseases and secondary malignancy	2 years post-transplant	defined, autoimmune thrombocytopaenia, autoimmune thyroid disease, autoimmune haemolytic anaemia, Evans' syndrome, acquired haemophila, ulcerative colitis, rheumatoid arthritis and spondyloarthropathy, autoimmune hepatitis, others) and secondary malignancy (EBV lymphoproliferative disorders, AML, MDS, skin cancers, and any others
Immune reconstitution	2 years post-transplant	Results of routine analysis performed by centres will be investigated in correlation to clinical outcomes parameters and will allow to follow post-transplant immune reconstitution according to ADWP GCP.

Trial Locations

Locations (1)

Badoglio Manuela- EBMT Paris Office; 🇫🇷 Paris, France