Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency (ALADIN 2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Mario Negri Institute for Pharmacological Research
Sponsor:
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT01377246
First received: June 20, 2011
Last updated: March 6, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Autosomal Dominant Polycystic Kidney Disease.
Drug: Octreotide-LAR
Other: Saline solution.
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mario Negri Institute for Pharmacological Research:

Primary Outcome Measures:
  • Total kidney volume (TKV) change (delta TKV) as assessed by spiral computed tomography (spiral CT) scan. [ Time Frame: At 0, 12 and 36 month. ] [ Designated as safety issue: No ]
    Short-term (1 year)outcome.

  • Rate of GFR decline as assessed by serial measurements of the iohexol plasma clearance. [ Time Frame: At 0, 12, 24 and 36 month. ] [ Designated as safety issue: No ]
    Long-term (3 year)outcome.


Secondary Outcome Measures:
  • Total renal cyst volume. [ Time Frame: At 0,12 and 36 month. ] [ Designated as safety issue: No ]
  • Total renal parenchyma volume. [ Time Frame: At 0, 12 and 36 month. ] [ Designated as safety issue: No ]
  • Total renal intermediate volume. [ Time Frame: At 0,12 and 36 month. ] [ Designated as safety issue: No ]
  • Total liver and liver cyst volumes. [ Time Frame: At 0, 12 and 36 month. ] [ Designated as safety issue: No ]

Estimated Enrollment: 98
Study Start Date: May 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Saline solution. Other: Saline solution.
At the same volume of study drug every 28 days (in two intragluteal injections) for three years.
Experimental: Octrotide-LAR Drug: Octreotide-LAR
40 mg every 28 days (in two intragluteal 20 mg injections) for three years

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01377246

Contacts
Contact: Norberto Perico, MD 0039 035 45351 norberto.perico@marionegri.it

Locations
Italy
Ospedale San giovanni di Dio Recruiting
Agrigento, AG, Italy
Contact: Antonio Granata, MD    0039 0922442292    antonio.granata4@tin.it   
Principal Investigator: Antonio Granata, MD         
Clinical Research Center fo Rare Diseases Aldo and Cele Daccò Recruiting
Ranica, Bergamo, Italy, 24020
Contact: Norberto Perico, MD    0039 035 453531    norberto.perico@marionegri.it   
Sub-Investigator: Matias Trillini, MD         
Hospital "Vito Fazzi" Recruiting
Lecce, Italy
Contact: Erasmo Buongiorno, MD    0039 0832 661544    erasmo.buongiorno@libero.it   
Principal Investigator: Erasmo Buongiorno, MD         
Hospital "Ospedale Maggiore policlinico, Mangiagalli e Regina elena" Recruiting
Milan, Italy
Contact: Piergiorgio Messa, MD    0039 02 55034552    pmessa@pliclinico.mi.it   
Principal Investigator: Piergiorgio Messa, MD         
University "Federico II" Recruiting
Naples, Italy
Contact: Antonio Pisani, MD    0039 081 7462614    antonio.pisani@libero.it   
Principal Investigator: Antonio Pisani, MD         
Ospedale Cà Foncello Recruiting
Treviso, Italy
Contact: Mauro Dugo, MD       maurodugo59@gmail.com   
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
  More Information

No publications provided

Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT01377246     History of Changes
Other Study ID Numbers: ALADIN 2, 2011-000138-12
Study First Received: June 20, 2011
Last Updated: March 6, 2014
Health Authority: Italy: Ministry of Health

Keywords provided by Mario Negri Institute for Pharmacological Research:
Somatostatin.
Polycystic kidney disease.
Renal insufficiency.

Additional relevant MeSH terms:
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Kidney Diseases
Renal Insufficiency
Urologic Diseases
Kidney Diseases, Cystic
Octreotide
Somatostatin
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014