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

• ClinicalTrials.gov Identifier: NCT00309283
• Recruitment Status: Completed
• First Posted: March 31, 2006
• Last Update Posted: April 24, 2013
• Sponsor: Mario Negri Institute for Pharmacological Research
• Information provided by (Responsible Party): Mario Negri Institute for Pharmacological Research

Tracking Information

• First Submitted Date: March 30, 2006
• First Posted Date: March 31, 2006
• Last Update Posted Date: April 24, 2013
• Study Start Date: April 2006
• Actual Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 8, 2007): 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). [ Time Frame: Basal, 1 and 3 years follow-up ]
• Original Primary Outcome Measures (submitted: March 30, 2006): 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).

Current Secondary Outcome Measures (submitted: June 8, 2007)

• 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: [ Time Frame: Basal, 1 and 3 years follow-up ]
• Total renal parenchymal volume [ Time Frame: Basal, 1 and 3 years follow-up ]
• Residual renal volume [ Time Frame: Basal, 1 and 3 years follow-up ]
• Renal parenchymal volume taken up by small cysts, minor of five mmcubic [ Time Frame: Basal, 1 and 3 years follow-up ]

Original Secondary Outcome Measures (submitted: March 30, 2006)

• 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:
• Renal cyst volume
• Total renal parenchymal volume
• Residual renal volume
• Renal parenchymal volume taken up by small cysts, minor of five mmcubic

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Intervention

• Drug: Long-acting somatostatin
  Patients randomized to treatment will be given intramuscularly long-acting somatostatin (Sandostatin-LAR, Novartis, Basel) at the dose of 40 mg every 28 days (in two intragluteal 20 mg injections).
• Other: Saline solution
  Patients randomized to placebo will be given intramuscularly the same volume of solvent used to dissolve somatostatin every 28 days (in two intragluteal injections).

Study Arms

• Experimental: somatostatin
  Intervention: Drug: Long-acting somatostatin
• Placebo Comparator: Saline solution
  Intervention: Other: Saline solution

• Publications *: Caroli A, Perico N, Perna A, Antiga L, Brambilla P, Pisani A, Visciano B, Imbriaco M, Messa P, Cerutti R, Dugo M, Cancian L, Buongiorno E, De Pascalis A, Gaspari F, Carrara F, Rubis N, Prandini S, Remuzzi A, Remuzzi G, Ruggenenti P; ALADIN study group. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet. 2013 Nov 2;382(9903):1485-95. doi: 10.1016/S0140-6736(13)61407-5. Epub 2013 Aug 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2009): 78
• Original Enrollment (submitted: March 30, 2006): 66
• Actual Study Completion Date: January 2012
• Actual Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT00309283
• Other Study ID Numbers: ALADIN; 2005-005552-41 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Mario Negri Institute for Pharmacological Research
• Study Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: Not Provided

Investigators

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

• PRS Account: Mario Negri Institute for Pharmacological Research
• Verification Date: April 2013