E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
steroid resistant acute graft versus host disease |
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E.1.1.1 | Medical condition in easily understood language |
Acute reaction to bone marrow transplant from a donor not responding to treatment with steroid drugs |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066260 |
E.1.2 | Term | Acute graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of BEGEDINA® versus conventional therapy in steroid-resistant acute
graft-versus-host disease (GvHD) in terms of overall response at 28 days and transplant-related mortality (TRM) up to 180 days.
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E.2.2 | Secondary objectives of the trial |
Compare BEGEDINA and conventional therapy with respect to Overall Survival up to 180 days.
Efficacy. Compare BEGEDINA and conventional therapy with respect to:
• Change from baseline in stages of GvHD by target organ
• Incidence of chronic GvHD up to 180 days
• Cumulative steroid dose
• Incidence of Relapse and Relapse Related Mortality
• Change from baseline in Karnofksy Performance Status
Pharmacokinetic(PK).The PK objective for this study is to characterize the PK of BEGEDINA in subjects with Grades II-IV acute GvHD, who have failed to respond to steroid treatment.
Safety:
• To compare the safety and tolerability of BEGEDINA and conventional therapy.
• To gather additional information on the safety of BEGEDINA in subjects with Grades II-IV acute GvHD.
• To evaluate the immunogenicity of BEGEDINA.
• To evaluate the effect of BEGEDINA on glucose metabolism.
• To compare the incidence of second malignancies at the end of the FU between BEGEDINA and conventional therapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥18 and ≤65 years of age.
2. Recipient of an allogeneic hematopoietic stem cell transplantation(HSCT).Note: Subjects with steroid resistant GvHD following donor lymphocyte infusion post HSCT are also eligible
3. Steroid-resistant acute GvHD, Grade II-IV, defined as:
- progressive disease after 3 days of primary treatment with methylprednisolone 2 mg/kg, or equivalent.
or
- lack of at least a partial response after 7 days of primary treatment with methylprednisolone 2 mg/kg or equivalent.
or
- lack of a complete response after 14 days of primary treatment with methylprednisolone 2 mg/kg or equivalent.
Note: Subjects who may have received an increase in their steroid dose treatment prior to randomization will be eligible for enrollment. An increase in steroid dose will not be considered as second-line therapy.
4. Evidence of myeloid engraftment (absolute neutrophil count ≥0.5 x 109/L) .
5. Karnofsky Performance Status Scale ≥50%.
6. Adequate renal function as defined by serum creatinine ≤2 × upper limit of normal or calculated creatinine clearance (CrCl) of ≥30 mL/min using the Cockroft-Gault equation: Calculated CrCl= ([140-age in years] x [ideal body mass {IBM} in kg])/72 x (serum creatinine value in mg/dL), where IBM = IBM (kg) = ([height in cm–154] × 0.9) + (50 if male, 45.5 if female).
7. Subject must be willing and able to comply with the study requirements, remain at the clinic and return to the clinic for the follow up evaluation, as specified in this protocol during the study period.
8. Able and willing to provide signed informed consent. |
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E.4 | Principal exclusion criteria |
1. Prior second-line systemic treatment for GvHD.
2. Received agents other than steroids for primary treatment of acute GvHD.
3.Acute steroid resistant GvHD beyond 28 days from first-line therapy (primary treatment).
4.Stage 1-2 skin acute GvHD alone (with no other organ involvement).
5. Evidence of severe hepatic veno-occlusive disease or sinusoidal obstruction.
6. Evidence of encephalopathy.
7. Life expectancy <3 weeks.
8. Presence of chronic GvHD
9. Second or subsequent allogeneic transplant.
10. Previous solid organ transplant (with the exception of a corneal transplant >3 months prior to screening).
11. Relapsed disease after last transplant.
12. Human immunodeficiency virus positive.
13. Evidence of lung disease that is likely to require more than 2LPM of O2 via face mask or an estimated FiO2 of 28% via other delivery methods in order to sustain an O2 saturation of 92% within the next 3 days.
14.Any underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere with the evaluation of the subject including uncontrolled infection, heart failure, pulmonary hypertension. Any other serious medical condition, as judged by the investigator, which places the subject at an unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study.
15.Administration of any other investigational agents (not approved by the United States Food and Drug Agency/European Medicines Agency [FDA/EMA] for any indication) within 30 days of randomization. Participated in any interventional clinical trial for an acute GvHD therapeutic agent or for an immunomodulatory drug, within the past 30 days or within 5 half-lives of the study treatment, whichever is the greater. Participated or is currently participating in any bone marrow derived autologous and allogeneic stem cell or gene therapy study.
16. Known allergy to murine proteins.
17. Women who are pregnant, breastfeeding or at risk to become pregnant during study participation; female subjects of childbearing potential who have not been started on an anti-ovulatory regimen prior to initiation of chemo-inductive regimen must test negative for pregnancy (serum) at the time of enrollment.
18. Male and female subjects who do not agree to take adequate measures to avoid pregnancy (including abstinence) prior to study entry and for the duration of participation in the study (or for at least 3 months following the last dose of study drug, whichever is longer).
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E.5 End points |
E.5.1 | Primary end point(s) |
Two co-primary endpoints:
-The overall response at Study Day 28.
- TRM up to Study Day 180
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Study Day 28
-Up to Study Day 180
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E.5.2 | Secondary end point(s) |
Overall survival up to Study Day 180
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Not limited to PR2, PR3, PR4 for example Extracorporeal photopheresis |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
Italy |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |