Please select the eligibility criteria that correspond to the clinical trial below.
Title: Pulsed Oral Sirolimus in Autosomal Dominant Polycystic Kidney Disease - The Vienna RAP Study
Brief Summary: Sirolimus (SIR) has lead to a reduction of overall kidney size, a decrease in cyst density and general tubular cell proliferation in animal models, and to a reduction of the increase in creatinine and blood urea nitrogen by 34 and 39 percent respectively, as well as a reduction of cyst proliferation, expressed by a 30 percent reduction of overall kidney enlargement, a reduction in general cyst volume, and a reduction of the cyst volume density in the renal cortex in humans.

However, despite promising data from animal- and in vivo studies, most mammalian target of rapamycin inhibitor (mTOR-I) studies in patients with autosomal-dominant polycystic kidney disease (ADPKD) produced only subtle if any clinically relevant effects on cyst growth and the preservation of renal function.

In this study we will investigate if pulsed administration of SIR in a fixed weekly oral dose of 3 mg over 24 months compared to placebo significantly reduces cyst growth and preserves excretory renal function in patients with ADPKD and an estimated glomerular filtration (eGFR) rate below 60 mL/min per 1.73m2.


Options:
A: Inclusion Criteria:

* Prior participation in designated tolvaptan ADPKD studies (156-04-248, 156-04-249).
* Able to give Informed Consent.

Exclusion Criteria:

* Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
* In the opinion of the study investigator or sponsor may present a safety risk.
* Patients who are unlikely to adequately comply with study procedures.
* Patients who at Day 1 have an estimated glomerular filtration rate (GFR) below 30 mL/min or who anticipate renal-replacement therapy within one year of study entry.
* Patients having contraindications to magnetic resonance imaging (MRI) or gadolinium contrast will be eligible but will not be able to participate in MRI.
* Patients taking a diuretic within 1 week of enrollment or likely to need diuretic therapy prior to Month 2.
B: Inclusion Criteria:

* Patients who completed 5-day repeated administrations and the follow-up observation in the preceding study (156-04-001)
* Patients in whom the safety of repeated administration was confirmed based on the investigator's reports from the preceding study (156-04-001)

Exclusion Criteria:

* Patients with serum creatinine concentration of 2.5 mg/dL or higher at the screening examination
* Patients with any of the following complications

  * Uncontrolled hypertension
  * Serious cardiovascular disease (eg. heart failure) or hepatic disease (eg. cirrhosis)"
* Patients with any of the following complications or history thereof

  * Clinically significant drug allergies (anaphylaxis) or hypersensitivity (especially, hypersensitivity to benzazepine derivatives or suspected hypersensitivity thereto)
  * Inability to personally give consent due to a mental disease "
* Patients with SBP (in sitting position) \<90 mm Hg (at screening examination)
* Patients with history of massive bleeding or bleeding tendency
* Patients with a history of drug or alcohol abuse within 6 months prior to the screening examination
* Pregnant women, lactating women, or women who may become or plan to become pregnant
* Patients who received any investigational drug other than OPC-41061 within 30 days prior to commencement of administration of OPC-41061
* Any patient who, in the opinion of the principle investigator or attending investigators, should not participate in the study
C: Inclusion Criteria:

* ADPKD, as confirmed by history, ultrasound, computed- or magnetic resonance tomography
* Eighteen years of age, or older
* Baseline eGFR 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

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 protein: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 cytochrome P450 (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
D: Inclusion Criteria:

* 18 \< age ≤ 70 years
* Polycystic liver disease (PCLD), defined as ≥ 20 liver cysts
* Total liver volume must be at least 2500 mL
* Symptomatic defined as ECOG-PS ≥ 1 (see fig 3.1)38, and having at least three out of ten PCLD symptoms:
* Abdominal pain
* Abdominal distension
* Abdominal fullness
* Dyspnea
* Early satiety
* Back pain
* Nausea/vomiting
* Anorexia
* Weight loss
* Jaundice
* Informed consent, patients are willing and able to comply with the study drug regimen and all other study requirements

Exclusion Criteria:

* ADPKD patients
* Use of oral anticonceptives or estrogen supplementation
* Females who are pregnant or breast-feeding or patients of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to the administration of study medication.
* Intervention (aspiration or surgical intervention) within three months before baseline
* Treatment with somatostatin analogues within three months before baseline
* Patients with a kidney transplant
* History or other evidence of chronic pulmonary disease associated with functional limitation
* History of severe cardiac disease (eg, NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases). In addition, patients with documented or presumed coronary artery disease or cerebrovascular disease should not be enrolled.
* History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
* Symptomatic gallstones (octreotide decreases gall bladder volume)
* Hypercholesterolemia (fasting cholesterol \> 8 mmol/l) or hypertriglyceridaemia (\> 5 mmol/l) not controlled by lipid lowering therapy
* Granulocytopenia (white blood cell \< 3,000/mm3) or thrombocytopenia (platelets \< 100,000/mm3)
* Infection with hepatitis B, hepatitis C, HIV, TBC (in medical history)
* Mental illness that interferes with the patient ability to comply with the protocol
* Drug or alcohol abuse within one year of baseline
* Co-medication with strong inhibitor of CYP3A4 and or P-gp like voriconazole, ketoconazole, diltiazem, verapamil, erythromycin or with a strong CYP3A4 and or P-gp inductor like rifampicin
* Known hypersensitivity to everolimus or one of its excipients
* Enrolment in another clinical trial of an investigational agent while participating in this study
* Moderate or severe reaction on contrast in medical history
* Treatment with I131 during the course of the trial
* Use of metformin
* Morbus Kahler or Morbus Waldenstrom with excretion of light chains in urine in medical history
* Kidney dysfunction (MDRD-GFR \< 60 ml/min/1.73m2 and ECC \< 60 ml/min, calculated by the Cockcroft-Gault formula); in case of decreased body muscle mass, exact ECC is measured using serum and urine creatinine

Answer: C