Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study

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Brief Title

Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study

Official Title

Effect of a Long-acting Somatostatin on Disease Progression in Nephropathy Due to Autosomal Dominant Polycystic Kidney Disease: a Long-term Three Year Follow up Study

Brief Summary

      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
      disease, responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western
      countries. At comparable levels of blood pressure control and proteinuria, patients with
      ADPKD have faster decline in glomerular filtration rate than those with other renal diseases
      and do not seem to benefit to the same extent of ACE inhibitor therapy. A reasonable
      explanation for the above findings is that in ADPKD progression is largely dependent on the
      development and growth of cysts and secondary disruption of normal tissue. Thus,
      renoprotective interventions in ADPKD - in addition to achieve maximal reduction of arterial
      blood pressure and proteinuria and to limit the effects of additional potential promoters of
      disease progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be
      specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and
      matrix interactions characteristic of the disease.

      Evidence that specific receptors for somatostatin are present in the kidney tissue, arises
      the possibility that somatostatin treatment in patients with ADPKD might inhibit fluid
      formation and eventually induce the shrinking of renal cysts.To evaluate the tolerability and
      the safety of long-acting somatostatin in ADPKD patients, a prospective cross-over controlled
      study has been recently performed. This pilot study demonstrated the safety of six month
      treatment of long-acting somatostatin in patients with ADPKD. Moreover, the percent increase
      of total kidney volume was significantly lower in patients on somatostatin than in placebo.
      Overall, these findings provide the basis for designing a long-term study in ADPKD patients
      aimed to document the efficacy of the somatostatin treatment in preventing further increase
      or even reducing the total kidney volume and the renal volume taken up by small cysts,
      eventually halting kidney disease progression.
    

Detailed Description

      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
      disease, responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western
      countries.

      At comparable levels of blood pressure control and proteinuria, patients with ADPKD have
      faster decline in glomerular filtration rate (GFR) than those with other renal diseases and
      do not seem to benefit to the same extent of ACE inhibitor therapy. A reasonable explanation
      for the above findings is that in ADPKD progression is largely dependent on the development
      and growth of cysts and secondary disruption of normal tissue. Thus, renoprotective
      interventions in ADPKD - in addition to achieve maximal reduction of arterial blood pressure
      and proteinuria and to limit the effects of additional potential promoters of disease
      progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be
      specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and
      matrix interactions characteristic of the disease.

      The fluid filling renal cysts in human polycystic kidney is formed mainly by a secretion
      process of the tubular epithelium lining the cysts. Secretion and re-absorption take place at
      approximately the same rate, with secretion slightly higher, so that the amount of fluid in
      the cysts increases slowly over time. The same process, via the secondary active chloride
      transport, is also involved in the secretion of fluid into the lumen of proximal tubules in
      teleost and elasmobranch fishes. Of interest, this process of chloride transport can be
      markedly inhibited by somatostatin, as demonstrated in the shark rectal gland.

      Recently, somatostatin analogues have become available and used with negligible side effects
      for long-term treatment of tumors (up to 8-12 months). To evaluate the tolerability and the
      safety of long-acting somatostatin in ADPKD patients, a prospective cross-over controlled
      study has been recently performed. This pilot study demonstrated the safety of six month
      treatment of long-acting somatostatin in patients with ADPKD. Moreover, the percent increase
      of total kidney volume was significantly lower in patients on somatostatin than in placebo.
      Preliminary data on late stage ADPKD also suggest that loss of renal function in these
      patients closely correlates with the increase in kidney volume taken by small cysts (<5 mm3),
      but not total cyst volume.

      Overall, these findings provide the basis for designing a long-term study in ADPKD patients
      aimed to document the efficacy of the somatostatin treatment in preventing further increase
      or even reducing the total kidney volume and the renal volume taken up by small cysts,
      eventually halting kidney disease progression.

      Aims

      The general aim of the study is to compare the effects on disease progression of three year
      treatment with long-acting somatostatin or placebo in patients with ADPKD and normal renal
      function or mild to moderate renal insufficiency. Specifically, the following aims will be
      pursued:

      Primary To compare in somatostatin and placebo ADPKD groups the change over baseline of the
      total kidney volume at 1 and 3 years follow-up (estimated by gadolinium contrast enhanced and
      T2-weighted magnetic resonance imaging, MRI).

      Secondary

        1. As secondary efficacy endpoints, the following parameters (absolute and percent change
           over baseline by MRI analysis) will be compared in the two ADPKD groups at baseline, at
           1 and 3 years follow-up:

             -  Renal cyst volume

             -  Total renal parenchymal volume

             -  Residual renal volume

             -  Renal parenchymal volume taken up by small cysts (<5 mm3)

        2. Additional functional parameters will be compared in the two groups at baseline and at
           1, 2, 3 years follow-up as follows:

             -  Systolic and diastolic blood pressure

             -  GFR (plasma iohexol clearance)

             -  GFR (over baseline)

             -  RPF (plasma PAH clearance)

             -  Serum creatinine concentration

             -  Diuresis

             -  24 h urinary protein excretion rate

             -  24 h urinary albumin excretion rate

             -  Protein, albumin, creatinine concentrations on spot morning urine samples

             -  Protein /creatinine ratio on spot morning urine samples

             -  Albumin/creatinine ratio on spot morning urine samples

             -  Urinary sodium, urea, glucose, phosphorus concentrations (24 hr samples)

             -  Urine osmolality (calculated)

        3. Correlation analyses between MRI and functional parameters will be also performed

      Patients Patients enrolled in this long-term follow-up study are those with ADPKD and normal
      renal function or mild to moderate renal insufficiency (estimated GFR >40 ml/min/1.73 m2 by
      MDRD equation), no evidence of associated systemic, renal parenchymal or urinary tract
      disease and no specific contraindication to the study drug.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Change over baseline of the total kidney volume at 1 and 3 years follow-up (estimated by gadolinium contrast enhanced and T2-weighted magnetic resonance imaging, MRI).

Secondary Outcome

 Absolute and percent change over baseline by MRI analysis will be compared in the two ADPKD groups at baseline, at one and three years follow-up of:

Condition

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Intervention

Long-acting somatostatin

Study Arms / Comparison Groups

 somatostatin
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

78

Start Date

April 2006

Completion Date

January 2012

Primary Completion Date

January 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Age>18 years

          -  Clinical and ultrasound diagnosis of ADPKD

          -  GFR >40 ml/min/1-73 m2 (estimated by the 4 variable MDRD equation)

          -  Written informed consent

        Exclusion Criteria

          -  Diabetes

          -  Overt proteinuria (urinary protein excretion rate >1g/24 hours) or abnormal urinalysis
             suggestive of concomitant, clinically significant glomerular disease

          -  Urinary tract lithiasis, infection or obstruction

          -  Cancer

          -  Psychiatric disorders and any condition that might prevent full comprehension of the
             purposes and risks of the study

          -  Pregnancy, lactation or child bearing potential and ineffective contraception
             (estrogen therapy in post menopausal women should not be stopped)
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Norberto Perico, MD, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT00309283

Organization ID

ALADIN

Secondary IDs

2005-005552-41

Responsible Party

Sponsor

Study Sponsor

Mario Negri Institute for Pharmacological Research


Study Sponsor

Norberto Perico, MD, Principal Investigator, Mario Negri Institute for Pharmacological Research


Verification Date

April 2013