E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Graft Versus Host Disease (cGVHD) |
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E.1.1.1 | Medical condition in easily understood language |
cGVHD is immune system attack on normal tissue following transplantation of cells from a donor |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
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 | 10066261 |
E.1.2 | Term | Chronic 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 evaluate the efficacy of ibrutinib in combination with prednisone (Arm A) versus placebo in combination with prednisone (Arm B) based on the response rate at 48 weeks (the proportion of responders [CR orPR]) as determined by NIH Consensus Development Project criteria in subjects with new onset moderate to severe cGVHD. |
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E.2.2 | Secondary objectives of the trial |
To compare the two treatment arms in terms of the following: Efficacy - Response rate at 24 weeks (the proportion of responders [CR or PR]) as defined by the NIH Consensus Development Project (2014) - Duration of response (DOR) - Proportion of subjects obtaining steroid dose level less than 0.15 mg/kg/d at 24 weeks - Time to withdrawal of all immunosuppressants (with the exception of ibrutinib/placebo) - Overall survival (OS) - Lee cGVHD symptom scale improvement
Safety - Safety and tolerability - Differences in steroid-related morbidities (eg, hyperglycemia, hypertension) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Prior to randomization, each potential subject must satisfy all of the following inclusion criteria.
Disease related 1. New onset moderate or severe cGVHD as defined by the NIH Consensus Development Project Criteria (2014, see Appendix M, Appendix N and Appendix O of protocol). 2. History of an allogeneic hematopoietic cell transplant. 3. Need for systemic treatment with corticosteroids for cGVHD. 4. No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP]). 5. Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d. 6. Participants may have received pre-transplant BTK inhibitors for other reasons besides cGVHD such as for the treatment of leukemia or lymphoma, but must not have received a BTK inhibitor since the time of transplant.
Demographic 7. Age ≥12 years old. 8. Karnofsky or Lansky (subjects <16 years) performance score ≥60.
Laboratory 9. Adequate renal function defined as estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault formula) 10. Adequate hepatic function as defined by: - Total bilirubin of ≤ 1.5 x ULN (unless of non-hepatic origin or due to Gilbert's Syndrome) or - Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to GVHD 11. Adequate hematological function defined as: - Absolute neutrophil count ≥1.0 x 109/L and off growth factor support for 7 days - Platelets ≥30 x 109/L and no transfusion for 7 days 12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonist, then INR ≤3.0 (Section 6.2.3 of protocol).
Ethical/Other 13. Male and female subjects of reproductive potential who agree to use both a highly effective methods of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days for both females and males after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
To be enrolled in the study, potential subjects must meet NONE of the following exclusion criteria:
Disease related 1. Received any previous systemic treatment for cGVHD with the following exception - Corticosteroids for cGVHD received within 72 hours prior to signing the informed consent form. 2. Inability to begin a prednisone dose ≥0.5 mg/kg/d for the treatment of cGVHD. 3. Presence of single-organ, genito-urinary involvement with cGVHD as the only manifestation of cGVHD.
Concurrent conditions 4. Received any investigational agent ≤28 days before randomization. 5. Received donor lymphocyte infusion (DLI) ≤56 days before randomization. 6. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. 7. Any uncontrolled active systemic infection or active infection requiring systemic treatment that was ongoing ≤7 days before randomization. This does not include secondary prophylaxis of well controlled fungal infections, ongoing treatment of controlled viral reactivations (eg, CMV), or treatment or prophylaxis of controlled low grade central line infections (eg, Staphylococcus epidermidis). 8. Progressive underlying malignant disease or active post-transplant lymphoproliferative disease. 9. History of other malignancy (not including the underlying malignancy that was the indication for transplant), with the following exceptions: - Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician - Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease - Adequately treated cervical carcinoma in situ without current evidence of disease 10. Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the subject. 11. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). 12. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 13. Known history of human immunodeficiency virus (HIV). 14. Subject with chronic liver disease with hepatic impairment per Child-Pugh classification Class C (Appendix E). Please note that acute liver dysfunction due to cGVHD is not applicable to the evaluation of Child-Pugh classification. 15. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before randomization. Those who are PCR positive will be excluded. 16. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 17. Major surgery within 4 weeks of randomization. 18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk. 19. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 20. Subjects requiring treatment with a strong CYP3A inducer are not eligible, unless a transition to an agent with less CYP3A induction is planned (Appendix D). 21. Female subject who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months of last dose of study drug. Male subject who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug. 22. Unwilling or unable to participate in all required study evaluations and procedures. 23. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the response rate at 48 weeks. Response will be defined by the NIH Consensus Development Project Criteria (2014) and must occur: - In the absence of new therapy for cGVHD In the absence of progression of the underlying disease that was the indication for transplant (or post transplant lymphoproliferative disease [PTLD]), or death |
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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) |
Secondary endpoints will assess for additional clinical benefits including Week-24 response, duration of response (DOR), corticosteroid dose reduction, time to withdrawal of all immunosuppressants, overall survival (OS) and Lee cGVHD symptom scale. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for the secondary end points are detailed in the 'Schedule of assessments' in Appendix A of the protocol |
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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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 21 |
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 |
Australia |
Austria |
Canada |
China |
Croatia |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Singapore |
Spain |
Taiwan |
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 | 6 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 15 |