E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with various hematological disease requiring Bone Marrow Transplantation, with Child-Pugh score A and B |
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E.1.1.1 | Medical condition in easily understood language |
Patients with various hematological diseases requiring Bone Marrow Transplantation with different levels of hepatic function. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067859 |
E.1.2 | Term | Allogenic stem cell transplantation |
E.1.2 | System Organ Class | 100000004865 |
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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 primary objective of the study is to assess the effect of moderate hepatic impairment on the pharmacokinetics of Thiotepa and its metabolite triethylenephosphoramide (TEPA) in pediatric patients undergoing allogeneic bone marrow transplantation. The pK parameters of Thiotepa and TEPA will be compared in two paediatric populations characterized by different levels of liver function as defined by Child-Pugh Score A vs score B. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the cardiac safety of Thiotepa, in particular in relation to the ventricular repolarization (QT/QTc interval analysis), in pediatric patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria:
1) Parents’/guardian’s written informed consent and patient’s assent (written, if applicable) before beginning any investigational procedures;
2) Male/ female subjects aged >1 and < 18 years;
3) Diagnosis of any haematological disease requiring allogeneic HPCT;
4) Eligible to allogeneic HPCT;
5) Subjects with no hepatic function impairment (Child-Pugh, score A) or with mild-moderate hepatic function impairment (Child-Pugh, score B);
6) Lansky or Karnofsky Index ≥ 60.
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E.4 | Principal exclusion criteria |
1) Patients who already underwent HPCT;
2) Child-Pugh score C;
3) Patients with clinically significant EGC abnormalities;
4) Hepatitis B or C;
5) HIV-positivity;
6) Any malignancy different from the one for which the HPCT is scheduled;
7) Severe neurological impairment;
8) Severe psychiatric disorders;
9) Clinically significant pleural effusion or ascites;
10) Severe organ impairment, as shown by:
a. LVEF < 40%, or
b. FEV1, FVC, DLCO <50% of predicted, or
c. Advanced liver cirrhosis, or
d. Liver function tests (bilirubin, AST/ALT transaminases, Alkaline Phosphatase) > 10 x upper limit of normal (ULN), or
e. Creatinine clearance < 40 ml/min;
11) Patients having received in the 10 days preceding the administration of Thiotepa, or requiring in concomitance with Thiotepa:
a. CYP2B6 inhibitors (e.g. clopidogrel, ticlopidine), or
b. CYP3A4 inhibitors (e.g. azole antimycotics, macrolides as erythromycin, clarithromycin, telitromycin and protease inhibitors), or
c. Cytocrome P450 inducers (as rifampicin, carbamazepin, phenobarbital).
12) Pregnancy or lactation;
13) Known hypersensitivity to trial drugs;
14) Non-cooperative behaviour of the patient or non-compliance.
15) Any other condition which, in the investigator's judgement, renders the subject unable to complete the study or increases the risk to the subject or which prevents optimal participation in achieving the objectives of the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Apparent total plasma clearance (CL/F)
- Area Under the concentration Curve (AUC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed during the 2 administrations of Thiotepa on sane day (blood drawings at 8 time points) |
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E.5.2 | Secondary end point(s) |
- ECG analysis of ventricular repolarisation (QT/QTc interval);
- Incidence of Treatment Emergent Adverse Events (TEAEs). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During and 24 hours after Thiotepa administration (also 7 days post administration on case of ECG alterations) |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Patients treated with same IMP (same dose level) grouped into 2 groups according to liver function |
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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.8.2.4 | 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 | No |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |