E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male and female children with non-malignant diseases requiring myeloablative conditioning treatment with following allogeneic haematopoietic stem cell transplantation (allo-HSCT) – i.e. primary immunodeficiencies, inborn errors of metabolism, haemoglobinopathies and bone marrow failure syndromes. |
Kinder, männlichen und weiblichen Geschlechts, mit nicht-bösartigen Erkrankungen, die eine myeloablative Konditionierungstherapie mit anschließender allogener hämatopoetischer Stammzelltransplantation (allo-HSZT) benötigen - primäre Immundefekte, Stoffwechselerkrankungen, Hämoglobinopathien und Knochenmarkversagen. |
|
E.1.1.1 | Medical condition in easily understood language |
Children with non-malignant diseases requiring conditioning treatment prior to stem cell transplantation |
Kinder mit nicht-bösartigen Erkrankungen, die eine Konditonierungsbehandlung vor Stammzelltransplantation benötigen |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10021606 |
E.1.2 | Term | Inborn errors of metabolism NEC |
E.1.2 | System Organ Class | 100000004850 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10036700 |
E.1.2 | Term | Primary immunodeficiency syndromes |
E.1.2 | System Organ Class | 100000004870 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10018903 |
E.1.2 | Term | Haemoglobinopathies congenital |
E.1.2 | System Organ Class | 100000004850 |
|
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 |
Comparative evaluation of freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from the day of first administration of study medication (day -7) until day +100 after HSCT. |
|
E.2.2 | Secondary objectives of the trial |
1. Comparative evaluation of neutropihil and platelet engraftment after HSCT. 2. Comparative evaluation of safety including early toxicity until day +100 after HSCT, SARs until the end of longer-term follow-up phase. 3. Comparative evaluation of HSOS, lung toxicity, hepatic toxicity and infections of any CTCAE grade until day +100. 4. Comparative evaluation of chimerism on day +28, day +100 and 12 months after HSCT. 5. Comparative evaluation of OS until 12 months after HSCT. 6. Comparative evaluation of graft failure until 12 months after HSCT. 7. Comparative evaluation of acute (until day +100) and chronic (until 12 months after HSCT) GvHD. 8. Comparative evaluation of use of rescue therapies including DLIs and further conditioning regimens. 9. Evaluation of PK parameters of Treosulfan and its epoxides and to develop a PK model for assessing relevant covariates. 10. Comparative evaluation of graft failure, cGvHD, OS and TRM during the longer-term follow-up phase.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Non-malignant disease indicated for first myeloablative allogeneic HSCT, including inborn errors of metabolism, primary immunodeficiencies, haemoglobinopathies and bone marrow failure syndromes. 2. First allogeneic HSCT. 3. Available matched sibling donor (MSD), matched family donor (MFD) or matched unrelated donor (MUD). For bone marrow (BM) and peripheral blood (PB) match is defined as at least 9/10 allele matches after four digit typing in human leucocyte antigen (HLA)-A, -B, -C, –DRB1 and DQB1 antigens. For umbilical cord blood (UCB) match is defined as at least 5/6 matches after two digit typing in HLA-A and -B and four digit typing in DRB1 antigens. 4. Age at time of registration from 28 days to less than 18 years of age. 5. Lansky (patients <16 years of age) or Karnofsky (patients ≥ 16 years of age) performance score of at least 70%. 6. Written informed consent of the parents/legal guardians and patient’s assent/consent according to national regulations. 7. Female patients of child-bearing potential or partner of male patients with child-bearing potential must use a highly effective method of contraception (pearl index < 1%) such as complete sexual abstinence, combined oral contraceptive, hormone intrauterine contraceptive device (IUCD), vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients or male partners during the study and at least six months thereafter. 8. Negative pregnancy test for females of child-bearing potential.
|
|
E.4 | Principal exclusion criteria |
1. Second or later HSCT. 2. HSCT from mismatched donor (less than 9/10 BM/peripheral blood stem cells (PBSC) or less than 5/6 matched cord donor). 3. Preterm newborn infants (<37 weeks gestational age) and term newborn infants aged 0 – 27 days at time of registration. 4. Obese paediatric patients with body mass index weight (kg)/[height (m)]² > 30 kg/m². 5. Diagnosis of Fanconi anaemia and other chromosomal breakage disorders, radiosensitivity disorders (deoxyribonucleic acid (DNA) Ligase 4, Cernunnos- X-ray repair cross-complementing protein 4 (XRCC4) like factor (XLF), Nijmegen Breakage Syndrome (NBS)) and Dyskeratosis Congenita. 6. Treatment with cytotoxic drugs within 10 days prior to day 7. 7. Impaired liver function indicated by Bilirubin > three times the upper limit of normal (ULN) or aspartate aminotransferase/alanine aminotransferase (AST/GOT, ALT/GPT) > ten times ULN, or clinically significant coagulopathy, or active infectious hepatitis with clinical evidence. 8. Impaired renal function indicated by estimated glomerular filtration rate ([GFR], according to the Schwartz formula) < 60 mL/min/1.73m2. 9. Impaired cardiac function: severe cardiac insufficiency indicated by left ventricular ejection fraction (LVEF) 35%. 10. Requirement for supplementary continuous oxygen. 11. Severe active infection requiring deferral of conditioning. 12. Human immunodeficiency virus (HIV) positivity. 13. Severe concomitant illness, comorbidity or condition that would severely limit life expectancy. 14. Known pregnancy, breast feeding. 15. Known hypersensitivity to Treosulfan, Busulfan, Fludarabine and/or Thiotepa. 16. Participation in another interventional clinical study with an experimental drug, within four weeks prior to patient inclusion.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Comparative evaluation of freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from the day of first administration of study medication (day -7) until day +100 after HSCT. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Comparative evaluation of engraftment after HSCT, defined as the first of three consecutive days for each of the following four criteria: - a leukocyte count of more than 1 x 109/L - an absolute neutrophil count (ANC) of more than 0.5 x109/L - a platelet count of at least 20 x109/L - a platelet count of at least 50 x109/L. 2. Comparative evaluation of safety including early toxicity, based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 until day +100 after HSCT, serious adverse reactions (SARs) until the end of longer-term follow-up phase (three years after HSCT of last patient). 3. Comparative evaluation of hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity (according Bearman’s criteria) and infections of any CTCAE grade (non-serious and serious) until day +100. 4. Comparative evaluation of donor-type chimerism on day +28, day +100 and 12 months after HSCT. 5. Comparative evaluation of overall survival (OS) until 12 months after HSCT. 6. Comparative evaluation of primary and secondary graft failure until 12 months after HSCT. 7. Comparative evaluation of incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD). 8. Comparative evaluation of use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens. 9. Evaluation of PK parameters of Treosulfan and its epoxides and to develop a PK model for assessing relevant covariates. 10. Comparative evaluation of secondary graft failure, cGvHD, OS and TRM during the longer-term follow-up phase.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day +28, day +100 and 12 months after HSCT and/or until the end of the longer-term follow-ip phase. |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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 | 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
Subsequent to the 12-months follow-up, all patients will be followed on a yearly basis for a minimum of two additional years. This longer-term follow-up phase is scheduled until three years after HSCT of the last patient enrolled into the study. The end of the trial is defined as last follow-up visit of last subject. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
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 | 6 |
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 |