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 | 19.1 |
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 our prospective multicentric study are 1) to assess the potential statistical efficacy of sirolimus on signs and symptoms caused by these complex vascular anomalies that are refractory to standard care, 2) to evaluate the effect of sirolimus on the quality of life of the patient and 3) to see whether sirolimus can statistically reduce the coagulation abnormalities observed in patients with venous anomalies
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are 1) to confirm the security of this treatment, 2) to see which patients would benefit the most, and thus indicated for sirolimus in the future and 3) to see whether this treatment will reduce the 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) - Infants with hemangioendothelioma with risk of Kasabach-Merritt phenomenon (very low platelet count (lower than 80 000/mm3) - Except for infants (not in Germany) described just above, all patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/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 (or <5.0 x ULN if hepatic metastases are present) 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. - Karnofsky > 50 - Patients or legal relatives (no children in GERMANY) have to be able to sign the informed consent - Negative urine pregnancy test in females with a childbearing potential. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. - Sexually active female patients (and female partners of male patients) must use adequate contraceptive measures while on study and for up to 8 weeks after ending treatment. Highly effective birth control methods include: o combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation o progestogen-only hormonal contraception associated with inhibition of ovulation o intrauterine device (IUD) o intrauterine hormone-releasing system ( IUS) o bilateral tubal occlusion o vasectomised partner o sexual abstinence (with regular verification by PI)
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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.) - 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) |
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 for 2 years |
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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 for 2 years |
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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 |