E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Familial adenomatous polyposis |
Familiaire adenomateuze polyposis |
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E.1.1.1 | Medical condition in easily understood language |
Familial adenomatous polyposis |
Familiaire adenomateuze polyposis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
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 |
The aim of our study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment |
Het doel van deze pilotstudie is het onderzoeken van het effect van sirolimus op intestinale adenomen bij patienten met FAP en het beoordelen van de veiligheid van deze behandeling |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
Niet van toepassing |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- ≥ 18 years -A genetically confirmed APC mutation -Classical FAP phenotype (100-1000 colorectal adenomatous polyps) -Subtotal colectomy with ileorectal anastomosis (IRA) or ileo-anal pouch anastomosis -Severe rectal or pouch polyposis, defined as having >25 polyps amenable to complete removal (InSiGHT 2011 Staging System score of 3) -Fertile patients must use effective contraception during study treatment and until 12 weeks after treatment |
- ≥ 18 jaar - Een genetisch bewezen APC mutatie - Klassiek FAP fenotype (100-1000 colorectale adenomen) - Subtotale colectomie met ileorectale anastomose (IRA) of een ileo-anale pouch anastomose - Ernstige rectale of pouch polyposis, gedefinieerd als >25 poliepen die compleet verwijderd zouden kunnen worden (InSiGHT 2011 Staging System score van 3) - Vruchtbare patiënten moeten een effectieve anticonceptie methode gebruiken gedurende de studieperiode en tot 12 weken na studiedeelname |
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E.4 | Principal exclusion criteria |
-Inability to give informed consent -Participation in another interventional clinical trial -Subjects who are pregnant or breast-feeding -Prior pelvic irradiation -Invasive malignancy in the past 5 years -Subjects who are HIV positive -Subjects with severe systemic infections, current or within 2 weeks prior to study start -Subjects with known severe restrictive or obstructive pulmonary disorders -History of pulmonary embolism or deep venous thrombosis -Major surgery less than or equal to 2 weeks prior to enrollment or any planned surgery within treatment period -Active post-operative complication, e.g. infection, delayed wound healing -History of hypersensitivity to sirolimus or to drugs of similar chemical classes -Regular NSAID use -Use of other FAP directed drug therapies -Subjects requiring systemic anticoagulation -Co-medication that could interact with sirolimus -Significant abnormalities in hepatic function -Significant hematologic abnormalities -Increased fasting serum cholesterol or triglyceride (whether or not on lipid-lowering therapy) -Increased glucose (venous, fasting): >6.4 mmol/L -Electrolyte abnormalities -Calculated glomerular filtration rate (GFR) less than 40 mL/min/1.73m2 using the simplified Modification of Diet in Renal Disease (MDRD) formula -Spot urine protein to creatinine ratio (UPr/Cr) greater than or equal to 0.5 |
-Niet in staat informed consent te geven -Deelname in een andere interventionele klinische trial -Personen die zwanger zijn of borstvoeding geven -In verleden bestraald in bekkengebied -Een invasieve maligniteit in de afgelopen 5 jaar -Personen die HIV positief zijn -Personen met ernstige systemische infecties, nu of binnen 2 weken voor deelname -Personen met ernstige restrictieve of obstructieve longaandoeningen -Longembolie of diepe veneuze trombose in voorgeschiedenis -Grote chirurgische ingreep binnen 2 weken van start deelname of een geplande operatie tijdens de studieperiode -Actieve post-operatieve complicatie -Hypersensitiviteit voor sirolimus or vergelijkbare geneesmiddelen -Regelmatig gebruik van NSAID -Gebruik van andere op FAP gerichte medicatie -Gebruik van systemische anticoagulantia -Comedicatie die interactie kan hebben met sirolimus -Significante hepatologische labafwijkingen -Significante hematologische labafwijkingen -Verhoogd serum cholesterol of triglyceriden -Verhoogd glucose -Electrolietafwijkingen -GFR < 40 mL/min/1.73m2 -Urine proteine creatinine ratio (UPr/Cr) > of gelijk aan 0.5 |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Size of 5 marked polyps 5 patients with FAP and a large intestinal polyp burden • Safety outcomes reported by summary analysis of adverse events , clinical laboratory abnormalities and regular physical examination |
• Grootte van 5 gemarkeerde poliepen bij 5 patiënten met FAP met een ernstige intestinale polyposis • Veiligheid van de behandeling (adverse events, labafwijkingen, lichamelijk onderzoek) |
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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) |
• Number of polyps • Global polyp burden • Histology (tubular, tubulovillous or villous histology and degree of dysplasia) • Patient reported quality of life using HRQoL questionnaires • Rate of cell proliferation in healthy intestinal mucosa and adenomatous tissue • Immunohistochemistry of mTOR targets (such as eEF2 kinase, phospho-S6) in healthy intestinal mucosa and adenomatous tissue |
• Aantal poliepen • 'Global polyp burden' • Histologie (tubulaire, tubulovilleuze of villeuze histologie en mate van dysplasie) • Patient gerapporteerde kwaliteit van leven mbv vragenlijsten • Celproliferatie in gezond en adenomateus intestinaal weefsel • Immunohistochemie van mTOR targets (zoals as eEF2 kinase, phospho-S6) in gezond en adenomateus intestinaal weefsel |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 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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LVLS |
Laatste bezoek van de laatste deelnemer |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |