| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Acute graft-versus-host disease (aGvHD) | |
| E.1.1.1 | Medical condition in easily understood language | | Graft-versus-host disease is a complication of bone marrow transplantation in which immune cells in the transplanted marrow recognize the recipients as "foreign" and mount an immunological attack | |
| 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 | 10018651 | | E.1.2 | Term | Graft versus host disease | | E.1.2 | System Organ Class | 10021428 - Immune system disorders | |
| 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 extracorporeal photopheresis (ECP) in pediatric patients with steroid-refractory aGvHD | |
| E.2.2 | Secondary objectives of the trial | • To assess the safety of ECP
• To assess the duration of response to ECP
• To assess the steroid-sparing effect of ECP
• To assess the organ-specific response to ECP
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Patients must meet all of the following criteria:
1. Male or female 1 to 21 years of age at the time of consent.
2. Steroid-refractory grade B-D aGvHD
* Steroid-refractory is defined as a failure to respond to steroid treatment, with failure to respond defined as any grade B-D (IBMTR grading) aGvHD that shows progression ≥ 3 days, or no improvement by 5 days of treatment with 2 mg/kg/day of methylprednisolone or equivalent in patients with lower GI or liver disease, or skin disease associated with bullae. Grade D organ involvement will be limited to skin and liver.
* Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of methylprednisolone or equivalent in patients with disease confined to upper GI disease or lesser degrees of skin GvHD.
* Patients with lack of complete response after 2 weeks of steroid treatment.
3. A Lansky Scale Performance Status score ≥ 30.
4. Laboratory values are within the following limits, assessed within 3 days of the first study treatment:
* Absolute neutrophil count > 0.5 × 109/L
* Creatinine level < 2 times the upper limit of normal
5. For patients with isolated upper gastrointestinal (GI) symptoms, pre-Screening biopsy results to confirm diagnosis of aGvHD.
6. Female patients of childbearing potential and nonsterilized males who are sexually active with a female partner must be practicing highly effective, reliable, and medically approved contraceptive regimen throughout their participation in the study and for 3 months following the last ECP treatment. Or, for the US only, abstinence may be used in place of an approved contraceptive regimen. Females of childbearing potential are those who have reached the onset of menarche, or 8 years of age, whichever comes first. Approved contraceptive methods for female patients of childbearing potential or nonsterilized males who are sexually active with a female partner are as follows:
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Established use of oral, injectable, or implanted hormonal methods of contraception.
* Placement of an intrauterine device or intrauterine system.
7. Signed informed consent/assent is obtained before conducting any study procedures; the parent, legal guardian, or legally authorized representative of a minor must also provide written informed consent. | |
| E.4 | Principal exclusion criteria | Any of the following would exclude the patient from participation in the study:
1. Currently enrolled in another clinical trial for the treatment of aGvHD.
2. Use of any experimental regimens or medication(s) for aGvHD treatment.
3. Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30 days prior to the first study treatment.
4. Overt signs of relapse of the underlying condition.
5. Uncontrolled viral, fungal, or bacterial infection.
6. Platelet count < 20.0 × 109/L, despite platelet transfusion.
7. Total bilirubin value ≥ 15 mg/dL.
8. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment.
9. Uncontrolled GI bleeding.
10. Veno-occlusive liver disease.
11. Life expectancy < 4 weeks.
12. Patient requires invasive ventilation or vasopressor support.
13. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of seronegativity within 6 months of screening is required).
14. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients.
15. Known hypersensitivity or allergy to heparin and Anticoagulant Citrate Dextrose Formula-A (ACD-A).
16. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) or aphakia.
17. Coagulation disorders that cannot be corrected with simple transfusion.
18. Co-existing melanoma, basal cell, or squamous cell skin carcinoma.
19. Previous splenectomy.
20. White blood cell count greater than 25,000 mm3.
21. Currently being treated with any systemic immunosuppressive or biologic therapy for the treatment of a medical condition other than aGvHD.
22. Female patient is breastfeeding or pregnant.
23. Any medical concerns that may pose risk to the patient.
24. Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and the follow-up schedule. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The proportion of patients reaching an overall response (CR+PR) after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering, or fewer treatments if they discontinued treatment. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering. | |
| E.5.2 | Secondary end point(s) | * Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and SAEs
* Proportion of patients who achieve an overall response 8 weeks (Day 56) and 12 weeks (Day 84) after initiation of ECP treatment
* Duration of response, defined as the length of time a patient maintains a response through Week 16 of the Follow-up Period on a perpatient basis
* Proportion of patients who achieve an overall response after 4 weeks (Day 28, 8 weeks (Day 56) and 12 weeks (Day 84) of ECP treatment according to the modified Glucksberg criteria
* Source data will be collected for each patient and entered into the eCRF, and a scoring algorithm will be applied to calculate the grade of aGvHD using the Modified Glucksberg Criteria
* Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks (Day 84) after initiation of ECP treatment
* Organ-specific grade at 4 weeks (Day 28, 8 weeks (Day 56) and 12 weeks (Day 84) after initiation of ECP treatment | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 | | Austria | | France | | Germany | | Hungary | | Italy | | Spain | | Turkey | | United Kingdom | | United States | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
