E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric acute lymphoblastic leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Pediatric acute lymphoblastic leukemia, hematologic malignancy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 aim of this study is to investigate if addition of allopurinol during maintenance therapy for acute lymphoblastic leukemia gives the same effects as in inflammatory bowel disease, i.e. higher 6-tioguaninen (6TG), lower 6-methylmercaptopurine and reduced hepatotoxicity. More specifically we will investigate if allopurinol increases the proportion of patients with 6TG levels above 200 nail/mmol Hb and reduces the proportion with 6MMP levels in excess of 15000 nail/mmol Hb. |
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E.2.2 | Secondary objectives of the trial |
Secondary aims are to document how allopurinol affects laboratory parameters for hepatotoxicity and metabolic function after fasting. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All children with standard or intermediate risk acute lymphoblastic leukemia, aged 0-18 years at time of diagnosis of leukemia and treated according to ALL2008 protocols and with TPMT wild type who start maintenance 2 phase are eligible. |
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E.4 | Principal exclusion criteria |
-Mature B celL lymphoblastic leukemia; t(9;22) positive acute lymphoblastic leukemia
-Unknown TPMT status or presence of TPMT mutation (both heterozygous and homozygous)
-Known intolerance to any of the chemotherapeutic drugs in the protocol
-Major organ failure precluding administration of planned chemotherapy
-Sever liver toxicity defined as persistent (≥ two weeks) elevation of either S-bilirubin > 50 ��mol/l or S-GPT > 20 x UNL (upper normal limit) or P-Protrombin complex > 1.5
-Reduced kidney function defined as S creatine ≥ 2 x UNL
-Lactating female or female of childbearing potential not using adequate contraception |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the fraction of patients with &TG levels above 200 nmol/mmol Hb after 12 weeks of allopurinol treatment (week 25) vs. after 12 weeks of standard maintenance therapy. |
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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 are to compare the following parameters with or without allopurinol treatment:
-tThe mean level of 6TG and DNA-TGN at week 13 and 25
-The mean level of 6MMP at week 13 and 25
-The weighted mean level of Hb, WBC, platelets and ANC during the respective treatment phases
-Laboratory measures of hepatotoxicity (weighed mean S-Bilirubin and S-GPT) during treatment phases
-Laboratory measures of hypoglycaemia and metabolic dysfunction (cumulative incidence of hypoglycaemia during the treatment phases)
-Serious adverse events (cumulative incidence during the treatment phases)
-The mean cumulative doses of 6MP and Mix days with treatment interruption during the two treatment phases |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 13 and 25
Treatment phases weeks 1-13 and 13-25 |
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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 | No |
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) | 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 | 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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Addition of allopurinol to maintenance therapy |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
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 | 10 |