Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency

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Brief Title

Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency

Official Title

A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED CLINICAL TRIAL TO ASSESS THE EFFECTS OF LONG-ACTING SOMATOSTATIN (OCTREOTIDE LAR) THERAPY ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND MODERATE TO SEVERE RENAL INSUFFICIENCY

Brief Summary

      The general aim of the trial is to assess the efficacy of one year treatment with long-acting
      somatostatin analogue (Octreotide LAR) compared with placebo in slowing kidney and liver
      growth rate in patients with ADPKD and moderate/severe renal insufficiency and to assess
      whether and to which extent this translates into slower renal function decline over 3-year
      follow-up.
    

Detailed Description

      Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common hereditary cystic renal
      disease, has an incidence of 1 in 800 live births and account for 7-10% of patients on
      dialysis in developed countries. Clinically, ADPKD is characterized by renal and extra renal
      manifestations. In the kidneys, multiple cysts grow from distal and collecting tubular
      epithelial cells producing progressive renal enlargement with relatively initial stable renal
      functions. Thereafter, both tubular and secondary interstitial damage lead to faster renal
      loss and end-stage renal disease (ESRD) in approximately half of all patients affected in
      their fifth or sixth decade of life. More than 50% of the patients display hepatic cysts
      derived from cholangiocyte proliferation and fluid secretion. Pancreatic and intestinal cysts
      as well as increased risk of aortic aneurysms, heart-valve defects and sudden death due to
      rupture of intracerebral aneurysms are extra-renal manifestations.

      Patients with ADPKD, at similar levels of proteinuria and blood pressure control, do not seem
      to benefit to the same extent of ACE inhibitor therapy and have faster decline in glomerular
      filtration rate (GFR) compared with other chronic kidney diseases. Thus, in ADPKD
      renoprotective interventions - in addition to achieving maximal reduction of arterial blood
      pressure and proteinuria, and limiting the effects of other potential disease progression
      promoters (such as dyslipidemia, chronic hyperglycemia, or smoking)- should also be
      specifically aimed to correct the dysregulation of epithelial cell growth, fluid secretion,
      and extracellular matrix deposition that is characteristic of this disease. Up to now, no
      specific therapies for ADPKD are available, but drugs like somatostatin, rapamycin, and
      tolvaptan targeting to growth and chloride secretion pathways are now being testing worldwide
      in some clinical trials.

      We have performed some years ago a pilot prospective cross-over controlled study with
      long-acting somatostatin analog in patients with ADPKD and different degree of renal
      dysfunction. We found that in these patients, 6 month treatment with octreotide was safe,
      well tolerated, and slowed the time-dependent increase in total kidney volume to a
      significant extent compared to placebo. The net effect in kidney volume resulted from an
      action of the drug on cyst volume and on parenchyma volume. Moreover, more recent post-hoc
      analysis of the concomitant liver disease progression in the same ADPKD patients demonstrated
      a significant reduction in the total liver volume during octreotide treatment, not
      appreciably observed during placebo. Moreover, in the untreated ADPKD patients enrolled in
      our study, computed tomography evaluation of disease progression showed that the ratio of
      faintly contrast-enhanced parenchyma volume over total parenchyma volume strongly correlated
      with basal GFR and GFR changes during the observation period.

      The good safety profile of octreotide and the slowing of renal growth demonstrated in our
      short-term clinical study did suggest the feasibility of a randomized trial in larger series
      of ADPKD patients with normal renal function or mild renal insufficiency to verify whether
      long-term somatostatin treatment may eventually provide effective renoprotection. This trial
      - the ALADIN study - is ongoing and the planned ADPKD patients have been enrolled. So far, no
      particular side effects have been reported. More important, preliminary interim analysis of
      data from patients who reached 1 year treatment, confirmed the beneficial effect of
      octreotide in slowing the growth of total kidney volume compared to placebo.

      The findings of the safety and potential benefit of octreotide in few patients with severe
      renal insufficiency observed in our initial pilot study and the encouraging preliminary
      long-term effect results of octreotide on kidney growth, make worth investigating the
      efficacy of a long-acting somatostatin (Octreotide LAR) in slowing or even halting the kidney
      enlargement and renal function decline in ADPKD patients with moderate/severe renal failure.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Total kidney volume (TKV) change (delta TKV) as assessed by spiral computed tomography (spiral CT) scan.

Secondary Outcome

 Total renal cyst volume.

Condition

Autosomal Dominant Polycystic Kidney Disease

Intervention

Octreotide-LAR

Study Arms / Comparison Groups

 Saline solution.
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

100

Start Date

May 2011

Completion Date

October 18, 2017

Primary Completion Date

October 18, 2017

Eligibility Criteria

        Inclusion Criteria:

          -  Age > 18 years

          -  Clinical and ultrasound diagnosis of ADPKD

          -  Estimated GFR between 15 and 40 ml/min/1.73m2 (by the MDRD 4 variable equation)

          -  Written informed consent

        Exclusion Criteria:

          -  24-h Urinary protein excretion rate >3g (suggestive of a concomitant glomerular
             disease that could benefit of specific therapy)

          -  Symptomatic urinary tract lithiasis or obstruction

          -  Uncontrolled diabetes mellitus (HbA1c >8%) or hypertension (systolic/diastolic BP
             >180/110 mmHg)

          -  Current urinary tract infection

          -  Symptomatic biliary tract lithiasis

          -  Active cancer

          -  Psychiatric disorders or 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

, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT01377246

Organization ID

ALADIN2

Secondary IDs

2011-000138-12

Responsible Party

Sponsor

Study Sponsor

Mario Negri Institute for Pharmacological Research


Study Sponsor

, , 


Verification Date

January 2018