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Graft Versus Host DiseasePhase 2NCT01810926

T&B Depletion Non Malignant

A Phase 2 study testing polyclonal antibody, Rituximab and Treosulfan in people with Graft Versus Host Disease, run by Franco Locatelli at 4 sites in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Read more about this study

Who is it for?
Ages 28 days to 64 years
Conditions the study is for
Graft Versus Host Disease
What is being tested?
polyclonal antibody, Rituximab and Treosulfan
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
130 participants
Where
4 sitesItaly
Study dates
Sep 2011to Oct 2016
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 28 days to 64 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • non malignant haematological and inherited metabolic disorders benefiting from an allogeneic HSCT conditioned with a myeloablative regimen
  • Availability of a matched related donor (MRD) or Matched Unrelated Donor (MUD)
  • Lansky or Karnofsky Index ≥ 60
  • Inherited metabolic disorders: DQ ≥ 70 (+ MRI Loes score ≤ 9 for adrenoleukodystrophy)
  • Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
Show all 13Show fewer
  • Heart shortening fraction (left-ventricle) > 28 % or LVEF > 55%
  • Serum bilirubin ≤ 1.5 × ULN (except for Wolman disease),
  • AST and ALT ≤ 2.5 × ULN (except for thalassemic syndromes and Wolman disease)
  • Pulmonary function: if cooperative: FEV1 and FVC on pulmonary function testing > 60 %; if non cooperative: pulse oximetry > 95 % in room air
  • Availability of autologous back up marrow (> 2 x 108 TNC+ cells/kg or > 2 x 106 CD34+ cells/kg) for MUD
  • Adequate contraception in female patients of child-bearing potential
  • Signed informed consent

Who cannot join

  • Any malignancy
  • Liver cirrhosis evidenced on liver histology (performed in suspicious cases or in case of Wolman disease)
  • HIV- positivity
  • Clinically significant pleural effusion or ascites
  • Pregnancy or lactation
  • Known hypersensitivity to trial drugs
Show all 9Show fewer
  • Participation in another experimental drug trial in the 2 months preceding enrollment
  • Non-cooperative behaviour or non-compliance
  • Previous HSCT

Trial locations and contacts

4 sites in 1 country.

Italy4 sites, 1 recruiting

  • University of Cagliari

    Cagliari, Italy, 09126

    Active, not recruiting

  • San Raffaele Scientific Institute

    Milan, Italy, 20132

    Active, not recruiting

  • University of Milano-Bicocca San Gerardo Hospital

    Monza, Italy, 20052

    Active, not recruiting

  • Bambino Gesù Hospital and Research Institute

    Rome, Italy, 00165

    Maria Ester Bernardo, MD, mebernardo@gmail.com

    Franco Locatelli

    Recruiting

Other trials in Italy

About this study

Official title: A Phase II Multicentre, Randomized, Controlled Open-label Study on the Use of Anti-thymocyte Globulin and Rituximab for Immunomodulation of Graft-versus-host Disease in Allogeneic Matched Transplants for Non Malignancies

  • The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients.

The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.

Read the detailed description

For patients transplanted from a MRD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

  • primary and secondary graft failure,
  • aGVHD II-IV,
  • cGVHD,
  • death, whichever occurs first.

For patients transplanted from a MUD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

  • aGVHD II-IV,
  • EBV viremia, whichever occurs first.
Being tested
polyclonal antibody, Rituximab, Treosulfan, Fludarabine, Thiotepa
Keywords
indication for HSCT, matched related donor, MRD, Matched Unrelated Donor, MUD
Medical subject headings
Graft vs Host Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • polyclonal antibodyBiological

    Also called ATG S Fresenius

    iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)

  • RituximabDrug

    Also called Mabthera

    single infusion of200 mg/m2 on day -1

  • TreosulfanDrug

    Also called Medac

    iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)

  • FludarabineDrug

    Also called Fludara

    iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan

  • ThiotepaDrug

    Also called Tepadina

    iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals

  • Cyclosporine ADrug

    Also called Neoral

    iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL

  • MethotrexateDrug

    iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

  • MethotrexateDrug

    iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11

Study groups in NCT01810926
Study groupRoleWhat they receive
MRD-Regimen&Polyclonal antibodyExperimentalPatients MRD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 \& ATG-Fresenius S® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2
Receives: Biological: polyclonal antibody; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate
MRD-RegimenSham comparatorPatients receiving stem cell transplantation from a matched related donors (MRD) will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²) + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 (total dose of 150 mg/m²) after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals (total dose of 8 mg/kg)+ Cyclosporine A iv at a starting dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL (In the absence of GvHD CSA will be tapered after day + 180 and stopped at 9-12 months) + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6
Receives: Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate
MUD-Regimen & RituximabExperimentalPatients MUD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 \& Rituximab in a single infusion of 200 mg/m2 on day -1
Receives: Biological: polyclonal antibody; Drug: Rituximab; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate
MUD-RegimenSham comparatorPatients MUD will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2
Receives: Biological: polyclonal antibody; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD

    For patients transplanted from a MRD

    The cumulative incidence of a combined end-point defined as the time from randomization to:

    • primary and secondary graft failure,
    • aGVHD II-IV,
    • cGVHD,
    • death, whichever occurs first.

    For patients transplanted from a MUD

    The cumulative incidence of a combined end-point defined as the time from randomization to:

    • aGVHD II-IV,
    • EBV viremia, whichever occurs first.

    Measured: From date of randomization assessed up to 100 months

Secondary outcomes (3)

  1. Chronic graft-versus-host disease (cGVHD)

    The cumulative incidence and severity of cGVHD

    Measured: From date of randomization assessed up to 100 months

  2. Treatment related mortality (TRM)

    The incidence of TRM

    Measured: From date of randomization assessed up to 100 months

  3. Overall survival (OS)

    The overall survival probability

    Measured: From date of randomization assessed up to 100 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Mar 2013 (estimated)
  2. Study startSep 2011
  3. Primary completionAug 2015 (estimated)
  4. Study completionOct 2016 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
130 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01810926
Sponsor's protocol ID
OPBG_361.11
Other IDs
2011-004730-34
Status last verified
Mar 2013
First submitted
16 Jan 2012
Last updated
14 Mar 2013
Results posted
No
Data monitoring committee
Yes

Publications

  • Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Sacchi N, van Lint MT, Bosi A; Gruppo Italiano Trapianti Midollo Osseo (GITMO). Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006 May;12(5):560-5. doi: 10.1016/j.bbmt.2005.12.034.

    PubMed 16635791

  • Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001 Nov 15;98(10):2942-7. doi: 10.1182/blood.v98.10.2942.

    PubMed 11698275

  • Ballet JJ, Griscelli C, Coutris C, Milhaud G, Maroteaux P. Bone-marrow transplantation in osteopetrosis. Lancet. 1977 Nov 26;2(8048):1137. doi: 10.1016/s0140-6736(77)90592-x. No abstract available.

    PubMed 73050

  • Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, Egeler M, Lankester AC, Egberts AC, Zwaveling J, Boelens JJ. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):231-41. doi: 10.1016/j.bbmt.2008.11.022.

    PubMed 19167683

  • Bartelink IH, Bredius RG, Ververs TT, Raphael MF, van Kesteren C, Bierings M, Rademaker CM, den Hartigh J, Uiterwaal CS, Zwaveling J, Boelens JJ. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008 Jan;14(1):88-98. doi: 10.1016/j.bbmt.2007.09.015.

    PubMed 18158965

  • Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A, Huber C, Fauser AA, Schwerdtfeger R. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant. 2005 May;35(10):1011-8. doi: 10.1038/sj.bmt.1704957.

    PubMed 15821768

  • Bernardo ME, Zecca M, Piras E, Vacca A, Giorgiani G, Cugno C, Caocci G, Comoli P, Mastronuzzi A, Merli P, La Nasa G, Locatelli F. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major. Br J Haematol. 2008 Nov;143(4):548-51. doi: 10.1111/j.1365-2141.2008.07385.x.

    PubMed 18986389

  • Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier JP, Yakouben K, Thuret I, Bordigoni P, Fischer A, Lutz P, Stephan JL, Dhedin N, Plouvier E, Margueritte G, Bories D, Verlhac S, Esperou H, Coic L, Vernant JP, Gluckman E; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. doi: 10.1182/blood-2007-03-079665. Epub 2007 Jul 2.

    PubMed 17606762

  • Chiesa R, Cappelli B, Crocchiolo R, Frugnoli I, Biral E, Noe A, Evangelio C, Fossati M, Roccia T, Biffi A, Finizio V, Aiuti A, Broglia M, Bartoli A, Ciceri F, Roncarolo MG, Marktel S. Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy. Biol Blood Marrow Transplant. 2010 May;16(5):622-8. doi: 10.1016/j.bbmt.2009.11.024. Epub 2009 Dec 4.

    PubMed 19963071

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing polyclonal antibody, Rituximab and Treosulfan in people with Graft Versus Host Disease, run by Franco Locatelli at 4 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD (time frame: From date of randomization assessed up to 100 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01810926, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Mar 2013.

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