E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complex vascular anomalies causing debilitating functional and esthetic impairment that are resistant to standard care |
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E.1.1.1 | Medical condition in easily understood language |
Complex vascular anomalies |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10047047 |
E.1.2 | Term | Vascular anomalies congenital NEC |
E.1.2 | System Organ Class | 100000004850 |
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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 |
The primary objectives of this prospective multicentric study are
to assess the potential statistical efficacy of the drug
- whether sirolimus treatment can alleviate signs and symptoms caused by these complex vascular anomalies that are refractory to standard care
- whether patients with this rare disorder will see their quality of life improved.
- whether this treatment can statistically reduce the anemia and coagulation abnormalities observed in some patients with venous anomalies.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- to confirm the safety of this treatment
- to see which patients would benefit the most, and thus indicated for rapamycin in the future
- to assess whether sirolimus could reduce volume of the malformation (on MRI) on a long-term follow-up
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion is limited to children and adults from 3 months* to 70 years old:
* In Germany the inclusion is limited to adults only from 18 to 70 years old
- Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications)- – ref. page 57: Clinical parameters / diagnosis : Given the lack of response to conventional treatment ( compression stockings , anti- pain, low molecular weight heparin , sclerotherapy and / or surgery) (Dompmartin et al Phlebology 2010)
- Patients must have adequate bone marrow function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³. Except for infants with hemangioendothelioma with risk of Kasabach-Merritt phenomenon (very low platelet count (lower than 80 000/mm3).
- Patients must have the following laboratory values:
o Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome)
o Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
o Serum creatinine 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.
- Absence of severe proteinuria
- Karnofsky > 50
- Parents or legal relatives have to be able to sign the informed consent
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E.4 | Principal exclusion criteria |
Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results:
• Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP)
• Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)
• Known hypersensitivity to drugs or metabolites from similar classes as study treatment.
• Patient has other concurrent severe and /or uncontrolled medical condition that would,in the investigator’s judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest, etc.)
• Recent history of primary malignancy ≤ 5 years, including history of non-melanoma skin cancer, but with with exception of carcinoma in situ of cervix.
• Immunocompromised patients, including known seropositivity for HIV
• Pregnant or lactating women
• Prior treatment with PI3K and/or mTOR inhibitors
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E.5 End points |
E.5.1 | Primary end point(s) |
E.5.1 Primary End Point (repeat as necessary) : to assess the potential statistical efficacy of the drug
- whether sirolimus treatment can alleviate signs and symptoms caused by these complex vascular anomalies that are refractory to standard care
- whether patients with this rare disorder will see their quality of life improved.
- whether this treatment can statistically reduce the anemia and coagulation abnormalities observed in some patients with venous anomalies.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
every month for the first 3 months and then every 3 months during the treatment period (2 years). The patient will be followed-up during a total of 5 years (evaluation will be performed every three month during the first year of follow-up and then every 6 months |
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E.5.2 | Secondary end point(s) |
- to confirm the safety of this treatment
- to see which patients would benefit the most, and thus indicated for rapamycin in the future
- to assess whether sirolimus could reduce volume of the malformation (on MRI) on a long-term follow-up
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
every month for the first 3 months and then every 3 months during the treatment period (2 years). The patient will be followed-up during a total of 5 years (evaluation will be performed every three month during the first year of follow-up and then every 6 months. |
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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 | 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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
patients before and during the trial and on/off medication: historic control |
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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
| 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 | 10 |
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 | 9 |
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 | 9 |
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 |