Effects of Low Sodium Intake on the Anti-proteinuric Efficacy in Hypertensive Patient With Olmesartan (ESPECIAL)

• ClinicalTrials.gov Identifier: NCT01552954
• Recruitment Status: Completed
• First Posted: March 13, 2012
• Results First Posted: December 18, 2014
• Last Update Posted: December 18, 2014
• Sponsor: Seoul National University Bundang Hospital
• Collaborators: Daiichi Sankyo, Inc.; Daewoong Pharmaceutical Co. LTD.
• Information provided by (Responsible Party): Ho Jun Chin, Seoul National University Bundang Hospital

Study Description

Brief Summary:

Purpose of this study

1. Intensive education for low salt diet will be enhance the anti-proteinuric effect of Olmesartan, a popular anti-hypertensive drug of angiotensin II receptor blocker, in Koreans compared to conventional prescription of medication.
2. Intensive education for low salt diet will decrease the amount of 24 hour-urine sodium excretion compared to control group, effectively.

Condition or disease	Intervention/treatment	Phase
Hypertension; Chronic Kidney Disease; Microalbuminuria	Behavioral: Intensive education of low salt diet	Phase 4

Detailed Description:

1. Background

   A. The chronic kidney disease (CKD) is the one of the main burden of chronic diseases and the prevalence of CKD is increasing in worldwide. In Korea, the prevalence of CKD was reported as 13.7% among urban Korean adults in 2008 by our study group.

   B. It is well known the CKD is the most important risk factor to cardiovascular events, cardiovascular mortality, all cause-mortality, and hospitalization. The cost of the management for the CKD was high and it took 3.25% of all budgets for medical reimbursement in 2004 for all Koreans, which was ranked on the top of expenditure for single disease category.

   C. The most popular risk factors to CKD progression are aging, obesity, hyperlipidemia, diabetes mellitus, hypertension, and proteinuria. The hypertension and proteinuria also cause the cardiovascular events and increase the mortality rate.

   D. The inhibitors for renin-angiotensin aldosterone system, angiotensin II type I receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI), are well known medications to prevent cardiovascular events and renal functional deterioration to end stage renal disease(ESRD) in patients with hypertension, non-diabetic CKD, or diabetic nephropathy. One of the adverse events of ARB is the decrease of hemoglobin. Inoue et al reported the level of hemoglobin was decreased in amount of 0.45 ±0.89 g/dL after prescription of ARB and valsartan decreased the erythropoietin in 6 days after medication. The exact mechanism of decrease of hemoglobin by ARB was not fully verified but it is related to decrease effects of angiotensin II on aggravating hypoxia in the kidney and on the activation of hypoxia-inducible factor 1α (HIF1a) and then decrease the production of erythropoietin as in the report of Durmus et al. Considering that the relationships between ARB usage and decrease of proteinuria in transplanted kidney, between aggravation of hypoxia or HIF1a and CKD, and between ARB and the decrease of HIF1a or erythropoietin(EPO), we could postulate that the decrease of hemoglobin would not be a adverse effect of ARB to deteriorate patients' condition but a co-phenomenon of ARB's anti-RAS effect and a marker of ARB's effectiveness.

   E. The anti-proteinuric effect of ARB is decreased by high salt intake. For example, ARB treatment without low salt intake decreased proteinuria by 30% in patients with proteinuria 2-10g/day compared to baseline value and addition of low salt diet to ARB treatment further decreased proteinuria up to 25%. But, using slow salt tablets, increase of daily intake of sodium diminished the anti-proteinuric effect of ARB in diabetic nephropathy.

   F. The previous studies for the effect of ARB on proteinuria affected by sodium intake took the methods of controlled diet by researcher or using slow salt tablet but these method are not practical to adopt in real clinical practice.

   G. The moderate and mild decrease of daily sodium intake which lower the daily excretion of sodium by 55 mEq/day had an effect of decrease of proteinuria by 11% in hypertensive patients.

   H. The mean amount of sodium of Korean diets was reported as high as 208 mmol/day in Intersalt study, which is more than 11 g of salt. The recent reports also showed the trend of high salt-intake by Koreans.

2. Rationale So, It is worth to do this study because

   • high salt intake is prevalent in Koreans,
   • high salt diet diminishes the effect of ARB on proteinuria
   • the methods used in previous studies were not suitable to apply to clinical practice,
   • and there were no study to reveal the decrease of hemoglobin would the marker for the effect of ARB and not be a adverse event of ARB.

3. Objectives

   1. Primary objective: The difference between amount of albuminuria after usage of Olmesartan and amount of albuminuria after prescription of Olmesartan with intensive diet education in intervention group is higher than the difference of albuminuria in control group.
   2. Secondary objective:

   Item 1: In all patients, Olmesartan decreases the albuminuria. Item 2: In all patients, the change of hemoglobin after prescription of Olmesartan is proportional to the change of albuminuria and serum erythropoietin.

   Item 3: Intensive education for low salt diet induces the significant decrease of daily sodium excretion in Intervention group compared to control group.

   Item 4: Intensive education for low salt diet induces the significant decrease of blood pressure in Intervention group compared to control group.

4. Study Flow

   • Period

     1. Washout period (-8 weeks;Point 0 to 0 weeks; Point 1)
     2. Olmesartan Period ( 0 week; point 1 to 8 weeks; point 2)
     3. Intervention period (8 week ; point 2 to 16 weeks; point 3)
   • For patients with taking ACEI, other ARB, diuretics, or renin inhibitor, already; Initial wash-out period for 8 weeks, and then (point 1) prescription of Olmesartan 40 mg qd for 8 weeks, and then (point 2) allocation to Intensive group or control group for 8 weeks, and then the study will be over (point 3).
   • For patients without taking ACEI, other ARB, diuretics, or renin inhibitor; For initial 8 weeks, adjust the blood pressures around 140/90 mmHg, and then (point 1) prescription of Olmesartan 40 mg qd for 8 weeks, and then (point 2) allocation to Intensive group or control group for 8 weeks, and then the study will be over (point 3).
   • Blood pressure control Adjust the blood pressures around 140/90 mmHg with other hypertensive drugs except ACEI, other ARB, diuretics, or renin inhibitor during whole period.
   • Intensive diet education:

For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 269 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effects of Low Sodium Intake on the Anti-proteinuric Efficacy of Olmesartan in Hypertensive Patients With Albuminuria Through Open-label Randomized Trial
• Study Start Date: February 2012
• Actual Primary Completion Date: June 2013
• Actual Study Completion Date: October 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intensive education of low salt diet; For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks. (*Intervention in this trial is the "intensity of education")	Behavioral: Intensive education of low salt diet; For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks.; Other Names: low salt diet; Angiotensin II converting enzyme; albuminuria; chronic kidney disease
No Intervention: Conventional diet group; Education for low salt diet will be conducted as in office with brief communication with a patient and a physician.

Outcome Measures

Primary Outcome Measures :

1. ∆Albuminuria by 24-hour Urine Protein Excretion [ Time Frame: changes from week 8 at week 16 (week 8 - week 16) ]

   Change in albuminuria as a 24-hour urine protein excretion by intensive education of low salt diet during taking olmesartan

   *In outcome measure data table, the 24-hour urine collection at 16th week was omitted in 3 out of 245 patients (1 for intensive education group and 2 for conventional education group). Values of each study week were "mean" of all participants on specific study week, but "∆albuminuria (week 8 - week 16)" value was "mean" of ∆ values of "8 weeks-16 weeks" in each individuals. Therefore, values of 3 patients were excluded in "mean of ∆albuminuria (week 8 - week 16)". That's why simple subtraction (week 8 - week 16) of values are not matched with the data.

Secondary Outcome Measures :

1. ∆Hemoglobin (0 Week - 16 Weeks) [ Time Frame: 0 week, 16 weeks ]
   The change of hemoglobin after prescription of Olmesartan
2. Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 [ Time Frame: week 8 and week 16 ]
   Change of sodium excretion rate in 24 hour-urine collection by intensive education for low salt diet at week 16
3. Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 [ Time Frame: week 8 and week 16 ]
   Change in Systolic and Diastolic Blood Pressure from Week 8 to Week 16 in the Intensive Education Group compared to the Conventional Education Group

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Aged 19 years or more and 75 years or less
• Hypertension patients: Patients whose blood pressure is 140/90mmHg and over, patients is newly diagnosed with hypertension or is prescribed antihypertensive medications.
• Hypertensive patients verified 2 times or more of albuminuria 30 mg/g cr or more in a spot urine sample with interval of 1 week or more in recent 6 months
• Estimated glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) equation 30 ml/min/1.73 m2 or more
• Patients who give written consent to this study by oneself

Exclusion Criteria:

• Blood pressure more than 160/100 mmHg
• Pregnant
• Serum potassium level more than 5.5 mEq/L at screening period
• Patients with malignancy, acute cerebral infarction, acute myocardial infarction, unstable angina, percutaneous coronary arterial intervention (PCI), or coronary artery bypass graft (CABG) in recent 6 months
• Patients with diabetes mellitus
• Patients who have an allergy to Olmesartan
• Patients who were involved in other clinical trial in recent 1 month or are participated in screening period
• Patients taking medication(s) of corticosteroid or immunosuppressant in a screening period

Contacts and Locations

Locations

Korea, Republic of

Seoul National University Bundang Hospital

Seongnam, Kyeong ki, Korea, Republic of, 463787

Dongguk University Ilsan Hospital

Ilsan, Kyeongki, Korea, Republic of, 410773

Seoul National University Hospital

Seoul, Korea, Republic of, 110744

Kyung Hee University

Seoul, Korea, Republic of, 134727

Seoul St. Mary's Hospital

Seoul, Korea, Republic of, 137701

Konkuk University School of Medicine

Seoul, Korea, Republic of, 143729

SMG-SNU Boramae Medical Center

Seoul, Korea, Republic of, 156707

Sponsors and Collaborators

Seoul National University Bundang Hospital

Daiichi Sankyo, Inc.

Daewoong Pharmaceutical Co. LTD.

Investigators

• Principal Investigator: Ho Jun Chin, PhD; Seoul National University Bundang Hospital
• Study Chair: Chun-Soo Lim, PhD; SMG-SNU Boramae Medical Center
• Principal Investigator: Dong Ki Kim, PhD; Seoul National University Hospital
• Principal Investigator: Suhnggwon Kim, PhD; Seoul National University Hospital
• Principal Investigator: Bum Soon Choi, PhD; Seoul St. Mary's Hospital
• Principal Investigator: Sang-Ho Lee, PhD; Kyunghee University
• Principal Investigator: Jung-Hwan Park, PhD; Konkuk University
• Principal Investigator: Sung Joon Shin, PhD; DongGuk University

More Information

Publications:

Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol. 2008 May;19(5):999-1007. doi: 10.1681/ASN.2007060693. Epub 2008 Feb 13.

Ekinci EI, Thomas G, Thomas D, Johnson C, Macisaac RJ, Houlihan CA, Finch S, Panagiotopoulos S, O'Callaghan C, Jerums G. Effects of salt supplementation on the albuminuric response to telmisartan with or without hydrochlorothiazide therapy in hypertensive patients with type 2 diabetes are modulated by habitual dietary salt intake. Diabetes Care. 2009 Aug;32(8):1398-403. doi: 10.2337/dc08-2297. Epub 2009 Jun 23.

He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, MacGregor GA. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension. 2009 Sep;54(3):482-8. doi: 10.1161/HYPERTENSIONAHA.109.133223. Epub 2009 Jul 20.

Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ. 1988 Jul 30;297(6644):319-28.

Swift PA, Markandu ND, Sagnella GA, He FJ, MacGregor GA. Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial. Hypertension. 2005 Aug;46(2):308-12. Epub 2005 Jun 27.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McMahon EJ, Campbell KL, Bauer JD, Mudge DW, Kelly JT. Altered dietary salt intake for people with chronic kidney disease. Cochrane Database Syst Rev. 2021 Jun 24;6:CD010070. doi: 10.1002/14651858.CD010070.pub3.

Conley MM, McFarlane CM, Johnson DW, Kelly JT, Campbell KL, MacLaughlin HL. Interventions for weight loss in people with chronic kidney disease who are overweight or obese. Cochrane Database Syst Rev. 2021 Mar 30;3:CD013119. doi: 10.1002/14651858.CD013119.pub2.

An JN, Hwang JH, Lee JP, Chin HJ, Kim S, Kim DK, Kim S, Park JH, Shin SJ, Lee SH, Choi BS, Lim CS. The Decrement of Hemoglobin Concentration with Angiotensin II Receptor Blocker Treatment Is Correlated with the Reduction of Albuminuria in Non-Diabetic Hypertensive Patients: Post-Hoc Analysis of ESPECIAL Trial. PLoS One. 2015 Jun 22;10(6):e0128632. doi: 10.1371/journal.pone.0128632. eCollection 2015.

Baek SH, Kim S, Kim DK, Park JH, Shin SJ, Lee SH, Choi BS, Chin HJ, Kim S, Lim CS. A low-salt diet increases the estimated net endogenous acid production in nondiabetic chronic kidney disease patients treated with angiotensin receptor blockade. Nephron Clin Pract. 2014;128(3-4):407-13. doi: 10.1159/000369558. Epub 2014 Dec 18.

• Responsible Party: Ho Jun Chin, Associate Professor, Seoul National University Bundang Hospital
• ClinicalTrials.gov Identifier: NCT01552954
• Other Study ID Numbers: B-1112/142-008
• First Posted: March 13, 2012
• Results First Posted: December 18, 2014
• Last Update Posted: December 18, 2014
• Last Verified: December 2014

Keywords provided by Ho Jun Chin, Seoul National University Bundang Hospital:

hypertension; Chronic kidney disease; albuminuria; low salt diet; Angiotensin II receptor blocker

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Hypertension; Vascular Diseases; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Angiotensin II; Vasoconstrictor Agents