Salt Intake and Antiproteinuric Effect of Paricalcitol in Type 2 Diabetes (PROCEED)

A Prospective, Randomized, Cross-over, Double-blind, Placebo-controlled Study to Assess the Antiproteinuric Effect of Selective Vitamin d Receptor Activation by Paricalcitol in Type 2 Diabetes Patients on Low or High Sodium Diet and Stable Ras Inhibitor Therapy

Proteinuria is an independent risk factor for cardiovascular morbidity and mortality and for renal disease progression. More proteinuria is associated with faster progression, whereas treatments that reduce proteinuria are renoprotective in both diabetic and non diabetic chronic kidney disease. Of note, lower the residual proteinuria achieved by treatment slower is the disease progression in the long term. On the basis of the above findings, proteinuria has become a target of renoprotective therapy.

Among different antihypertensive medications, those that inhibit the Renin Angiotensin System, such as angiotensin converting enzyme (ACE)inhibitors and angiotensin receptor blockers (ARBs), are those that at comparable blood pressure control, more effectively reduce proteinuria and slow renal disease progression. Thus they have become the key component of renoprotective therapy in patients with proteinuric chronic kidney disease. Observational studies found that their effectiveness, however, is limited or even fully blunted in patients who eat large amount of salt.

Experimental evidence indicates a renoprotective role of the vitamin D system in chronic renal disease. A recent randomized, controlled trial, add-on therapy with selective Vitamin D receptor activator paricalcitol showed an additive antiproteinuric effect in subjects with type 2 diabetes and chronic kidney disease on background Renin-angiotensin-system inhibitor therapy. This effect, however, was largely restricted to subjects with daily sodium intake exceeding 12 grams and was negligible in those with lower sodium intake. Thus, treatment with paricalcitol appears to be effective in particular in those patients who do not appreciably benefit of renin angiotensin system (RAS) inhibitors therapy because of high salt intake. Thus, whether the antiproteinuric effect of paricalcitol is modified by concomitant salt intake in patients with chronic kidney disease (CKD) on background RAS inhibitors therapy, is worth investigating.

The broad aim of this study is to evaluate the interaction between paricalcitol therapy and sodium intake in type 2 diabetes patients with proteinuric kidney disease on stable background RAS inhibitor therapy.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Paricalcitol; Other: placebo

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bergamo, Italy
    • Azienda Ospedaliera Ospedali Riuniti di Bergamo
  • BG
    • Romano di Lombardia, BG, Italy
      • Azienda Ospedaliera di Treviglio e Caravaggio - Unit of Diabetology and Metabolic Diseases
    • Seriate, BG, Italy
      • Azienda Ospedaliera Bolognini - Unità di Medicina
    • Treviglio, BG, Italy
      • Azienda Ospedaliera di Treviglio e Caravaggio - Unit of Diabetology and Metabolic Diseases
  • Bergamo
    • Brembate, Bergamo, Italy, 24030
      • ASL of Ponte San Pietro - Diabetologic Unit
    • Ranica, Bergamo, Italy, 24020
      • Clinical Research Center fo Rare Diseases Aldo and Cele Daccò

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients;
• Age > 18 years;
• Type 2 diabetes patients on low or high sodium diet and stable RAS inhibitor therapy with the following conditions:

Urinary albumin excretion (UAE) rate >300mg/24 hours (200 mcg/min); Serum creatinine <2 mg/dL, PTH ≥ 20 mEq/L and <110 mEq/L; Calcium and phosphorus levels < 9.5 mg/dl and < 5mg/dl, respectively; Controlled BP (systolic/diastolic <140/90 mmHg) while on stable RAS inhibitor therapy;

- Written informed consent.

Exclusion Criteria:

• Previous Vitamin D or Vitamin D analogs therapy (within 3 months prior to the study entry);
• Evidence of toxicity to Vitamin D;
• History of kidney stones;
• Poorly controlled Diabetes: Hb1Ac > 12%;
• Therapy with calcitonin, bisphosphonates, cinacalcet, glucocorticoids, immunosuppressive drugs or other drug that may affect calcium or bone metabolism;
• Cancer and any severe systemic disease or clinical condition that may jeopardize data interpretation or completion of the study;
• Any clinically relevant conditions that might affect study participation and/or study results;
• Any contraindication to be exposed to Paricalcitol;
• Pregnancy or lactating;
• Women of childbearing potential without following a scientifically accepted form of contraception;
• Legal incapacity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Other: placebo; 1-month Placebo Treatment
Experimental: Paricalcitol	Drug: Paricalcitol; 1-month Paricalcitol 2mcg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in urinary albumin excretion from baseline at 4 month.	At baseline and 1,2,3 and 4 month.

Secondary Outcome Measures

Outcome Measure	Time Frame
Ambulatory and 24-hour blood pressure profile.	At 1 month.
Ambulatory and 24-hour blood pressure profile.	At 2 month.
Ambulatory and 24-hour blood pressure profile.	At 3 month.
Ambulatory and 24-hour blood pressure profile.	At 4 month.

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: Abbott

Publications and helpful links

General Publications

• Prabhu RA, Saraf K. Vitamin D in diabetic nephropathy. J Postgrad Med. 2018 Jan-Mar;64(1):5-6. doi: 10.4103/jpgm.JPGM_311_17. No abstract available.
• Parvanova A, Trillini M, Podesta MA, Iliev IP, Ruggiero B, Abbate M, Perna A, Peraro F, Diadei O, Rubis N, Gaspari F, Carrara F, Stucchi N, Belviso A, Bossi AC, Trevisan R, Remuzzi G, de Borst M, Ruggenenti P; PROCEED Study Organization and the Scientific Writing Academy (SWA) 2016. Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial. Lancet Diabetes Endocrinol. 2018 Jan;6(1):27-40. doi: 10.1016/S2213-8587(17)30359-5. Epub 2017 Nov 2.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: July 12, 2011
• First Submitted That Met QC Criteria: July 12, 2011
• First Posted (Estimate): July 13, 2011

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: March 2, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Proteinuria; Paricalcitol; Sodium intake
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: PROCEED; 2011-001713-14 (EudraCT Number)