Clinical trial NCT01552954: Effects of Low Sodium Intake on the Anti-proteinuric Efficacy in Hypertensive Patient With Olmesartan
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Chronic Kidney Disease
Microalbuminuria
Keywords: hypertension
Chronic kidney disease
albuminuria
low salt diet
Angiotensin II receptor blocker
Lead sponsor: Seoul National University Bundang Hospital
Sponsor class: OTHER
Collaborators: name: Daiichi Sankyo
name: Daewoong Pharmaceutical Co. LTD.
First posted: 2012-03-13
Enrollment: 269
Sex: ALL
Minimum age (years): 19
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: ∆Albuminuria by 24-hour Urine Protein Excretion
timeFrame: changes from week 8 at week 16 (week 8 - week 16)
Secondary outcomes:
measure: ∆Hemoglobin (0 Week - 16 Weeks)
timeFrame: 0 week, 16 weeks
measure: Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16
timeFrame: week 8 and week 16
measure: Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16
timeFrame: week 8 and week 16
Other outcomes:
Locations:
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Kyeong ki
city: Ilsan
country: Korea, Republic of
facility: Dongguk University Ilsan Hospital
state: Kyeongki
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University School of Medicine
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
Study officials:
affiliation: Seoul National University Bundang Hospital
name: Ho Jun Chin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: SMG-SNU Boramae Medical Center
name: Chun-Soo Lim, PhD
role: STUDY_CHAIR
affiliation: Seoul National University Hospital
name: Dong Ki Kim, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital
name: Suhnggwon Kim, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul St. Mary's Hospital
name: Bum Soon Choi, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kyunghee University
name: Sang-Ho Lee, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Konkuk University
name: Jung-Hwan Park, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: DongGuk University
name: Sung Joon Shin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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(3):CD013119. doi: 10.1002/14651858.CD013119.pub2.
citation: 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.
citation: 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.