Study of Lanreotide to Treat Polycystic Kidney Disease (DIPAK1)

• change in renal volume [ Time Frame: baseline and end of treatment (month 30) ] [ Designated as safety issue: No ]
  to determine whether Lanreotide modifies ADPKD progression as measured by change in renal volume in the overall study population. Renal volume is measured at baseline and after 30 months of treatment
• change in liver volume [ Time Frame: baseline-end of treatment (month 30) ] [ Designated as safety issue: No ]
  to determine whether Lanreotide modifies ADPKD progression as measured by change in liver volume in the subset of ADPKD patients with moderate to severe polycystic liver disease (measured at baseline and at month 30)
• change in quality of life [ Time Frame: baseline-end of treatment (month 30) ] [ Designated as safety issue: No ]
  to determine whether Lanreotide changes the quality of life (using specific questionnaires). These questionnaires will be filled in at baseline, after 3 months of treatment, after 1 year, after 2 years, at end of treatment (30 months) and at foolow-up (3 months after end of treatment)
• tolerance [ Time Frame: baseline-end of treatment(month 30) ] [ Designated as safety issue: Yes ]
  to determine whether lanreotide is safe and well tolerated. This is assessed by investigating (severe)adverse events, vital signs, performing physical examination and clinical laboratory tests.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys, in most patients leading to end stage renal disease. It is the most common hereditary renal disease with a prevalence of approximately 1 in 1,000 persons. The majority of patients also have progressive cyst formation in the liver, leading to pain, gastrointestinal discomfort and sometimes the need for liver transplantation. At present there is no proven therapeutic intervention to slow the rate of disease progression in human ADPKD. The development of renoprotective treatments that are well tolerated, is therefore of major importance.

In this respect, somatostatin analogues are promising for especially polycystic liver disease, but also for the renal phenotype. However, the studies that have been performed thus far with these agents, were underpowered and of too short duration to reach a definitive conclusion on the potential reno- and hepatoprotective efficacy of somatostatin analogues. Therefore, the present study is designed as a randomised clinical trial with sufficient duration of follow-up to investigate whether the somatostatin analogue Lanreotide slows progression of polycystic kidney and liver disease in ADPKD-patients.

To this end, 300 ADPKD patients, aged 18-60years, with an eGFR 30-60 ml/min/1.73 m2) will be randomized 1:1 to standard care or monthly subcutaneous lanreotide injections on top off standard care. These 300 subjects will go through 15 study visits in 3 years and 1 follow up visit. During these visits, questionnaires will be filled in, physical examinations will be performed, blood will be drawn and urine collected. After study completion, rate of renal function decline in lanreotide treated subjects will be compared to that of subject who received standard care.

Aims:

First, to determine whether Lanreotide attenuates progression of the renal phenotype in ADPKD patients as measured by change in rate of renal function decline and change in renal volume growth.

Second, to determine whether Lanreotide modifies progression of the liver phenotype in the subset of ADPKD patients with moderate to severe polycystic liver disease as measured by change in liver volume.

Methods:

Investigator driven, randomized, multi-center, controlled clinical trial.

Study population:

300 subjects, diagnosed with ADPKD, based on the revised Ravine criteria, with advanced disease and high likelihood of rapid disease progression (eGFR between 30 and 60 ml/min/1.73 m2 and age between 18 and 60 years).

Intervention:

Patients will be randomized (1:1) into two groups. One group will receive a dose of Lanreotide 120 mg sc every 28 days for 30 months. The dose of Lanreotide will be eGFR (BSA unadjusted) dependent. Subjects that reach an eGFR <30ml/min during the study will receive Lanreotide 90 mg sc every 28 days. Down-titration will also occur in case of dose related side effects. The other group of patients will receive standard care.

Main study endpoint:

Change in renal function in Lanreotide versus not treated patients, as assessed as slope through serial eGFR measurements over time during the treatment phase of the trial, with the value obtained at month 3 as first eGFR value for slope analysis.

Main secondary outcome variables:

• to determine whether Lanreotide modifies ADPKD progression as measured by change in renal volume in the overall study population,
• to determine whether Lanreotide modifies ADPKD progression as measured by change in liver volume in the subset of ADPKD patients with moderate to severe polycystic liver disease
• to determine whether Lanreotide changes the quality of life
• to determine whether Lanreotide is well tolerated

• No Intervention: standard care
  Subjects in this arm will receive standard care
• Experimental: Lanreotide
  Intervention: Drug: Lanreotide

Inclusion Criteria:

1. Diagnosis of ADPKD, based upon the modified Ravine criteria
2. Age between 18 and 60 years.
3. eGFR (MDRD) between 30 and 60 ml/min/1.73 m2.
4. Providing informed consent.

Exclusion Criteria:

1. Patients who, in the opinion of the study investigator may present a safety risk.
2. Patients who are unlikely to adequately comply with the trial's procedures [due for instance to medical conditions likely to require an extended interruption or discontinuation, history of substance abuse or noncompliance).
3. Patients taking medications or having concomitant illnesses likely to confound endpoint assessments (e.g. nephrotoxic medications such as chronic NSAID, cyclosporine, lithium immunosuppressant use, and e.g. diabetes mellitus and patients with proteinuria > 1 g /24hr).
4. Patients who underwent surgical or drainage interventions for cystic kidney disease the year before study-entry or are likely candidates for these procedures within 2 years of start of the study.
5. Patients taking other experimental (i.e., non marketed) therapies.
6. Patients having used Lanreotide (or another somatostatin analogue) in the 3 months before study start.
7. Patients with known intolerance for Lanreotide (or another somatostatin analogue).
8. Unwillingness to comply with reproductive precautions. Women who are capable of becoming pregnant must be willing to comply with approved birth control from two-weeks prior to, and for 60 days after taking investigational product.
9. Women, who are pregnant or breastfeeding.
10. Patients, who suffer from cardiac arrhythmia's, with the exception of stable atrial fibrillation.
11. Patients, who ever suffered from symptomatic gallstones and did not undergo cholecystectomy.
12. Patients, who have a medical history of pancreatitis.

In addition:

• Patients, who underwent liver cyst drainage or surgery in the year before, can enter the study, but will not be assessed for change in liver volume.
• Patients having contraindications to, or interference with MRI assessments, as dictated by local regulation, will not be allowed to undergo MR imaging. However, these patients can enter the study, but will not be assessed for change in kidney and/or liver volume.

• Leiden University Medical Center
• Erasmus Medical Center
• Radboud University