E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Segmental overgrowth caused by somatic PI3K hyperactivation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
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 if sirolimus is effective at reducing overgrowth in PIK3CA-related overgrowth, and to quantify its efficacy.
To measure the effect size of sirolimus therapy in reducing pathological overgrowth in PIK3CA related overgrowth to enable statistical power calculations for a future randomised controlled trial (RCT) |
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E.2.2 | Secondary objectives of the trial |
To establish optimal sirolimus dosing algorithms for a future RCT To establish if inter-patient comparison will be feasible in a future RCT To evaluate alternative treatment outcomes for inclusion as primary or secondary end-points in a future RCT
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Have given, or their guardian has given written informed consent to participate Aged: 3-65 years inclusive Male or female Post-zygotic PIK3CA mutation Clinically stable in the opinion of the investigator Measurably progressive overgrowth, in current progression or with clinical history of overgrowth progression Have undergone an MRI and/or DXA scan in the previous 6 months as part of the Investigation of Segmental Overgrowth Disorders study All women of childbearing potential and all sexually active male participants must agree to use effective contraception |
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E.4 | Principal exclusion criteria |
The participant may not enter the study if ANY of the following apply:
• Aged 2 years or younger or aged 66 years or older • Pregnant or breastfeeding • Male and Female participants of childbearing potential who are not using an effective method of contraception (during treatment and up to 12 weeks after sirolimus discontinuation) • Hypersensitivity to sirolimus or any of the excipients • Any current medical disorder or medication likely to impair ability to follow the study protocol safely and effectively • Incapacity to give informed consent • Sirolimus treatment in the prior 4 weeks • Personal history of malignancy or ongoing investigations for malignancy • Active skin infections requiring antibiotics or anti-viral medication • HCV/HBV/HIV seropositivity • Previous/ active MTB infection • Active Pneumonitis • Inability to attend study visits • If less than 3 months post-surgery • Inadequate bone marrow function defined as: - Peripheral absolute neutrophil count (ANC) < 1.0 x10^9/l - Platelet count < 100 x10^9/l - Haemoglobin <10.0 g/dL • Inadequate renal function defined as: A serum creatinine based on age as follows: Age (years) Maximum Serum Creatinine (µmol/l) ≤ 5 70.4 6<age≤10 80 11<age≤15 105.6 >16 132
OR a creatinine clearance or radioisotope GFR < 70ml/min/1.73 m2 • Inadequate liver function defined as: - Bilirubin (sum of conjugated + unconjugated) > 1.5 x upper limit of normal (ULN) for age, and - SGPT (ALT) > 5 x upper limit of normal (ULN) for age, and - Serum albumin > 30 g/dL. • Inadequate Fasting LDL cholesterol > 4.2 mmol/l
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E.5 End points |
E.5.1 | Primary end point(s) |
To calculate an effect size of sirolimus therapy in the treatment of PIK3CA-related overgrowth |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This will be evaluated at the end of the trial following completion of 6 months of sirolimus therapy. |
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E.5.2 | Secondary end point(s) |
I To establish optimal sirolimus dosing algorithms for a future RCT II To establish if inter-patient comparison will be feasible in a future RCT III To evaluate alternative treatment outcomes for inclusion as primary or secondary end-points in a future RCT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
This will be evaluated at the end of the trial following completion of 6 months of sirolimus therapy. |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |