E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development and uncontrolled proliferation of innumerable epithelial-lined cysts that stem from renal tubular cells, which compress and/or destroy vital renal tissue with a gradual decline in renal function, and terminal kidney failure with the need for renal reaplacement therapy. As yet, other than supportive care there is no viable therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Autosomal dominant polycystic kidney disease (ADPKD) is an incurable hereditary disease that leads to renal insufficiency and need for renal replacement therapy. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036046 |
E.1.2 | Term | Polycystic kidney, autosomal dominant |
E.1.2 | System Organ Class | 100000004850 |
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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 |
Tubular cells, the target of mTOR-I in ADPKD, develop a resistance towards sirolimus in vitro as well as in vivo with continuous exposure to the drug. Pulsed administration of the mTOR-inhibitor sirolimus in a fixed weekly oral dose of 3 mg compared to placebo significantly reduces cyst growth and preserves excretory renal function in patients with autosomal-dominant polycystic kidney disease and an estimated glomerular filtration rate below 60 mL/min per 1.73m2.
Null hypothesis: Pulsed administration of the mTOR-inhibitor sirolimus in a fixed weekly oral dose of 3 mg compared to placebo does not reduce cyst growth and preserve excretory renal function in patients with autosomal-dominant polycystic kidney disease and an estimated glomerular filtration rate below 60 mL/min per 1.73m2. |
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E.2.2 | Secondary objectives of the trial |
Safety, change in proteinuria, as indicated by albumin/creatinine- and protein/creatinine ratio, respectively. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• ADPKD, as confirmed by history, ultrasound, computed- or magnetic resonance tomography • Eighteen years of age, or older • Baseline estimated glomerular filtration rate (eGFR; 4 variable MDRD equation) below 60 mL/min per 1.73m2 • Negative serum pregnancy test prior to administration of sirolimus and agreement to use contraception throughout the study and three months after • Written informed consent |
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E.4 | Principal exclusion criteria |
• Need for renal replacement therapy • Pregnancy/lactation • Plans to become pregnant in the near future • Refusal to use sufficient contraception • Proteinuria as defined as proteine:creatinine ratio >1000 or >1g/d, respectively • History of life threatening complications of ADPKD • Evidence of active systemic- or localized major infection • Evidence of infiltrate or consolidation on chest X-ray • Use of any investigational drug or -treatment up to 4 weeks prior to enrolment and during the study • Known allergy/hypersensitivity to sirolimus and its derivatives • Medication that will interfere with the CYP3A4/CYP3A5 system • Total white blood cell count below or equal to 3000/mm3 • Platelet count below or equal to 100.000/mm3 • Fasting triglycerides above or equal to 400 mg/dL • Fasting total cholesterol above or equal to 300 mg/dL • Concomitant glomerular diseases • Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study • History of malignancy, with the exception of adequately treated basal cell- and squamous cell carcinoma of the skin • HIV positivity |
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E.5 End points |
E.5.1 | Primary end point(s) |
Fifty percent reduction in doubling of serum creatinine, or initiation of dialysis over a period of two years. Less or equal than 1.5 fold increase in serum creatinine without initiation of dialysis over two years is considered a beneficial outcome, increases in serum creatinine greater than 1.5 over two years or initiation of dialysis are considered a nonbeneficial outcome.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 months of therapy. |
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E.5.2 | Secondary end point(s) |
Safety, change in proteinuria, as indicated by albumin/creatinine- and protein/creatinine ratio, respectively. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 24 months of 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 | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
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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Last visit of the last subject undergoing the trial after 24 months of trial particpiation. |
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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 |