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| Name | Class |
|---|---|
| Daiichi Sankyo | INDUSTRY |
| Daewoong Pharmaceutical Co. LTD. | INDUSTRY |
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Purpose of this study
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.
Rationale So, It is worth to do this study because
Objectives
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.
Study Flow
Period
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intensive education of low salt diet | Experimental | 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") |
|
| Conventional diet group | No Intervention | Education for low salt diet will be conducted as in office with brief communication with a patient and a physician. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intensive education of low salt diet | Behavioral | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| ∆Albuminuria by 24-hour Urine Protein Excretion | 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. | changes from week 8 at week 16 (week 8 - week 16) |
| Measure | Description | Time Frame |
|---|---|---|
| ∆Hemoglobin (0 Week - 16 Weeks) | The change of hemoglobin after prescription of Olmesartan | 0 week, 16 weeks |
| Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | Change of sodium excretion rate in 24 hour-urine collection by intensive education for low salt diet at week 16 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ho Jun Chin, PhD | Seoul National University Bundang Hospital | Principal Investigator |
| Chun-Soo Lim, PhD | SMG-SNU Boramae Medical Center | Study Chair |
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Seoul National University Bundang Hospital | Seongnam | Kyeong Ki | 463787 | South Korea | ||
| Dongguk University Ilsan Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18272844 | Background | 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. | |
| 19549737 | Background | 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. |
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We screened 312 patients before 8 weeks of study initiation, and 269 patients were enrolled. During the 1st 8 weeks of this study (ARB run-in), 13 patients were withdrawn. After that, 256 patients were randomized, 11 participants were dropped out between 8th week and 16th week, and 245 who completed the trial were included in the analysis .
Patients were selected from 7 centers in Korea (Seoul National University Boramae Medical Center, Seoul National University Bundang Hospital, Seoul National University Hospital, Konkuk University Hospital, Dongguk University Ilsan Hospital, Kyung Hee University Medical Center, and Seoul St. Mary's Hospital) and enrolled from Mar. 2012 to Mar. 2013.
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| ID | Title | Description |
|---|---|---|
| FG000 | Conventional Education of Low-salt Diet Group | Education for low salt diet will be conducted as in office with brief communication with a patient and a physician. |
| FG001 | Intensive Education of Low-salt Diet Group |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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|
| week 8 and week 16 |
| Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 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 | week 8 and week 16 |
| Ilsan |
| Kyeongki |
| 410773 |
| South Korea |
| Seoul National University Hospital | Seoul | Seoul | 110744 | South Korea |
| Kyung Hee University | Seoul | Seoul | 134727 | South Korea |
| Seoul St. Mary's Hospital | Seoul | Seoul | 137701 | South Korea |
| Konkuk University School of Medicine | Seoul | Seoul | 143729 | South Korea |
| SMG-SNU Boramae Medical Center | Seoul | Seoul | 156707 | South Korea |
| 19620514 | Background | 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. |
| 3416162 | Background | 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. doi: 10.1136/bmj.297.6644.319. |
| 15983240 | Background | 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. doi: 10.1161/01.HYP.0000172662.12480.7f. Epub 2005 Jun 27. |
| 37612109 | Derived | Hwang JH, Oh S, Chin HJ, Kim S, Kim DK, Kim S, Park JH, Shin SJ, Lee SH, Choi BS, Lim CS. Comparison of the performance of currently used estimated glomerular filtration rate equations with 24-hour urine creatinine clearance: sample analysis of randomised controlled trial participants. BMJ Open. 2023 Aug 23;13(8):e067398. doi: 10.1136/bmjopen-2022-067398. |
| 34164803 | Derived | 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(6):CD010070. doi: 10.1002/14651858.CD010070.pub3. |
| 33782940 | Derived | 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. |
| 26098847 | Derived | 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. |
| 25531146 | Derived | 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. |
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.
Intensive education for 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.
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Conventional Education of Low-salt Diet Group | Education for low salt diet will be conducted as in office with brief communication with a patient and a physician. |
| BG001 | Intensive Education of Low-salt Diet Group | 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. Intensive education for 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | ∆Albuminuria by 24-hour Urine Protein Excretion | 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. | Posted | Mean | Standard Deviation | mg/day | changes from week 8 at week 16 (week 8 - week 16) |
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| Secondary | ∆Hemoglobin (0 Week - 16 Weeks) | The change of hemoglobin after prescription of Olmesartan | Posted | Mean | Standard Deviation | g/dL | 0 week, 16 weeks |
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| Secondary | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | Change of sodium excretion rate in 24 hour-urine collection by intensive education for low salt diet at week 16 | Posted | Mean | Standard Deviation | mEq/day | week 8 and week 16 |
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| Secondary | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 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 | Posted | Mean | Standard Deviation | mm Hg | week 8 and week 16 |
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from week 8 to week 16 (for 8 weeks)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Conventional Education of Low-salt Diet Group | Education for low salt diet will be conducted as in office with brief communication with a patient and a physician. | 0 | 131 | 1 | 131 | ||
| EG001 | Intensive Education of Low-salt Diet Group | 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. Intensive education for 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. | 0 | 125 | 2 | 125 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated serum creatinine | Renal and urinary disorders | Systematic Assessment | Elevation of serum creatinine level : Physician assessed ARB could not be continued |
| |
| Headache | Nervous system disorders | Systematic Assessment | Headache |
|
The major limitation of this study is that we used a 24-hour volume urine collected at a single time point for each follow-up visit. Urine excretion can be influenced by the sodium intake of individual patients at certain point.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ho Jun Chin | Department of Internal Medicine, Seoul National University Bundang Hospital | +82-10-7360-7025 | mednep@snubh.org |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| D051436 | Renal Insufficiency, Chronic |
| D000419 | Albuminuria |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011507 | Proteinuria |
| D014555 | Urination Disorders |
| D020924 | Urological Manifestations |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D004039 | Diet, Sodium-Restricted |
| D000806 | Angiotensin-Converting Enzyme Inhibitors |
| ID | Term |
|---|---|
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
| D004032 | Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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| >=65 years |
|
| Male |
|
| Mean of ∆albuminuria (week 8-week 16); n=124, 118 |
|
| Mixed Models Analysis |
| 0.99 |
for 24-hour urine albumin excretion between 8 weeks and 16 weeks |
| 2-Sided |
| No |
| Superiority or Other |
| Mixed Models Analysis | 0.001 | for 24-hour urine albumin excretion between 8 weeks and 16 weeks in intensive education group | 2-Sided | No | Superiority or Other |
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