E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation |
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E.1.1.1 | Medical condition in easily understood language |
acute Graft versus host disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066262 |
E.1.2 | Term | Acute graft versus host disease in skin |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066264 |
E.1.2 | Term | Acute graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066263 |
E.1.2 | Term | Acute graft versus host disease in liver |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the trial is to compare the efficacy of ruxolitinib with best available therapy in patients with corticosteroid refractory acute Graft vs. Host Disease by assessing the overall response rate (either complete or partial response without requiring additional systemic therapies) based on organ stage scoring. |
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E.2.2 | Secondary objectives of the trial |
The key secondary objective of the trial is to measure the durable response rate of patients who are corticosteroid refractory acute graft vs. host disease and to compare those patients treated with ruxolitinib vs. best available therapy.
The other secondary objectives relate to further measurements comparing patients treated with ruxolitinib vs. best available therapy:
Their survival over a 2 year time period.
Whether steroids are successfully tapered to lower doses.
Whether they develop chronic graft vs. host disease, and other standard transplant outcomes including control of their underlying hematologic disease for which the transplant was performed.
The safety of ruxolitinib and best available therapy.
Measurements of each patient’s reported quality of life will be compared in patients treated with ruxolitinib vs. best available therapy for their corticosteroid refractory acute graft vs. host disease.
To estimate the rate of Best Overall Response (BOR) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or
cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive
therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- Confirmed diagnosis of corticosteroid refractory aGvHD defined as:
• Patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
• Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
• Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day)
OR
• Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days. |
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E.4 | Principal exclusion criteria |
- Has received more than one systemic treatment for steriod refractory aGvHD,
- Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
- Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection.
Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial.
- Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
Other protocol-defined inclusion/exclusion criteria may apply.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR)
• ORR is defined as the proportion of patients with a best overall response defined as complete response or partial response without requirement for additional systemic therapy for an early progression, mixed response, or non response. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Durable Overall Response Rate
o Proportion of all patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56.
2. Proportion of patients who achieved OR (CR+PR) at Day 14.
3. Duration of response
o DOR is the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD.
4. Cumulative steroid dose
o Weekly cumulative steroid dose for each subject up to Day 56 or end of treatment
5. Overall Survival (OS)
o OS is defined as the time from the date of randomization to the date of death due to any cause.
6. Event-free survival
o Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause.
7. Failure-Free survival (FFS)
o FFS is defined as the time from the date of randomization to date of hematologic disease relapse/progression, non- relapse mortality, or addition of new systemic aGvHD treatment.
8. Non Relapse Mortality (NRM)
o NRM is defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression
9. Malignancy Relapse/Progression (MR)
o MR is defined as the time from date of randomization to hematologic malignancy relapse/progression.
Calculated for patients with underlying hematologic malignant disease.
10. Incidence of cGvHD
o cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe
11.Best Overall Response (BOR), defined as proportion of patients who achieved RO(CR+PR) at any time pointup to and including D28 and before the start of additional systemic therapy for aGvHD
12. Pharmacokinetics (PK) of ruxolitinib in Steroid Refractory -acute GvHD patients
o Ruxolitinib plasma concentrations after a single dose and at steady state.
13. Exposure-response relationship of ruxolitinib in SR-aGvHD
o Pharmacokinetics (exposure) and efficacy (ORR, OS or other relevant endpoints) relationship. Pharmacokinetics (exposure) and safety (AEs) relationship.
14. Patient Reported Outcomes (PROs): Change in FACT-BMT from baseline, only in adults
15. Patient Reported Outcomes (PROs): Change in EQ-5D-5L from baseline
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 56
2. Day 14
3. Up to 24 weeks
4. 56 Days
5. Up to 24 months
6. Up to 24 months
7. Up to 24 months
8. Up to 24 months
9. Up to 24 months
10. Up to 24 months
11. Up to Day 28
12. 168 Days
13. 168 Days
14. Baseline, Up to 30 day follow-up visit
15. Baseline, Up to 30 day follow-up visit |
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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 | No |
E.8.1.6 | Cross over | Yes |
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 |
Best available therapy (BAT) |
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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 | 104 |
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 |
Argentina |
Australia |
Canada |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Saudi Arabia |
Taiwan |
Turkey |
Austria |
Bulgaria |
Czechia |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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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End of Study (EoS) will occur when all patients have reached Month 24 (2 years from randomization), unless the patient withdraws consent. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |