Ignite Creation Date:
2025-12-25 @ 1:47 AM
Ignite Modification Date:
2025-12-26 @ 3:56 AM
Study NCT ID:
NCT06395194
Status:
COMPLETED
Last Update Posted:
2024-05-02
First Post:
2024-04-10
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Effects of Valsartan vs Amlodipine and Low BP on Kidney Outcomes in Essential Hypertension
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D000075222', 'term': 'Essential Hypertension'}, {'id': 'D006973', 'term': 'Hypertension'}, {'id': 'D007674', 'term': 'Kidney Diseases'}], 'ancestors': [{'id': 'D014652', 'term': 'Vascular Diseases'}, {'id': 'D002318', 'term': 'Cardiovascular Diseases'}, {'id': 'D014570', 'term': 'Urologic Diseases'}, {'id': 'D052776', 'term': 'Female Urogenital Diseases'}, {'id': 'D005261', 'term': 'Female Urogenital Diseases and Pregnancy Complications'}, {'id': 'D000091642', 'term': 'Urogenital Diseases'}, {'id': 'D052801', 'term': 'Male Urogenital Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000068756', 'term': 'Valsartan'}, {'id': 'D057911', 'term': 'Angiotensin Receptor Antagonists'}, {'id': 'D017311', 'term': 'Amlodipine'}, {'id': 'D002121', 'term': 'Calcium Channel Blockers'}], 'ancestors': [{'id': 'D013777', 'term': 'Tetrazoles'}, {'id': 'D001393', 'term': 'Azoles'}, {'id': 'D006573', 'term': 'Heterocyclic Compounds, 1-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}, {'id': 'D014633', 'term': 'Valine'}, {'id': 'D000597', 'term': 'Amino Acids, Branched-Chain'}, {'id': 'D000596', 'term': 'Amino Acids'}, {'id': 'D000602', 'term': 'Amino Acids, Peptides, and Proteins'}, {'id': 'D000601', 'term': 'Amino Acids, Essential'}, {'id': 'D045504', 'term': 'Molecular Mechanisms of Pharmacological Action'}, {'id': 'D020228', 'term': 'Pharmacologic Actions'}, {'id': 'D020164', 'term': 'Chemical Actions and Uses'}, {'id': 'D004095', 'term': 'Dihydropyridines'}, {'id': 'D011725', 'term': 'Pyridines'}, {'id': 'D049990', 'term': 'Membrane Transport Modulators'}, {'id': 'D000077264', 'term': 'Calcium-Regulating Hormones and Agents'}, {'id': 'D045505', 'term': 'Physiological Effects of Drugs'}, {'id': 'D002317', 'term': 'Cardiovascular Agents'}, {'id': 'D045506', 'term': 'Therapeutic Uses'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE3'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'QUADRUPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR'], 'maskingDescription': 'Preparation of the two drugs (to compare, valsartan and amlodipine) made identical'}, 'primaryPurpose': 'PREVENTION', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Investigator-designed, prospective, multi-national, double-blind, randomized, active-controlled, parallel-group design which was event driven (until accumulated 1450 primary cardiac endpoints)'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 15313}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '1997-09-27', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2024-04', 'completionDateStruct': {'date': '2003-12-05', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2024-04-29', 'studyFirstSubmitDate': '2024-04-10', 'studyFirstSubmitQcDate': '2024-04-29', 'lastUpdatePostDateStruct': {'date': '2024-05-02', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2024-05-02', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2003-09-05', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Composite cardiac event (mostly myocardial infarction and heart failure hospitalization)', 'timeFrame': 'Up to 6 years', 'description': 'Composite cardiac events, which included a combination of fatal or non-fatal myocardial infarction, sudden cardiac death, death from revascularization procedures or heart failure, hospitalization for heart failure, and emergency procedures to prevent myocardial infarction'}], 'secondaryOutcomes': [{'measure': 'End-stage kidney failure', 'timeFrame': 'Up to 6 years', 'description': 'Incident end-stage kidney disease being patients in need for dialysis or kidney transplantation'}, {'measure': 'Worsened kidney function', 'timeFrame': 'Up to 6 years', 'description': 'No of patients with at least 50% increase of serum creatinine.'}, {'measure': 'All cardiovascular events', 'timeFrame': 'Up to 6 years', 'description': 'All cardiovascular events'}, {'measure': 'Stroke', 'timeFrame': 'Up to 6 years', 'description': 'Fatal and non-fatal stroke'}, {'measure': 'Myocardial infarction', 'timeFrame': 'Up to 6 years', 'description': 'Fatal and non-fatal myocardial infarction'}, {'measure': 'Heart failure', 'timeFrame': 'Up to 6 years', 'description': 'Hospitalized for heart failure'}, {'measure': 'Cardiovascular mortality', 'timeFrame': 'Up to 6 years', 'description': 'All deaths from cardiovascular disease'}, {'measure': 'Non-cardiovascular mortality', 'timeFrame': 'Up to 6 years', 'description': 'All deaths from causes other than cardiovascular disease'}, {'measure': 'All-cause mortality', 'timeFrame': 'Up to 6 years', 'description': 'All deaths during folllow-up, from all causes'}]}, 'oversightModule': {'isUsExport': False, 'oversightHasDmc': True, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Hypertension', 'Blood pressure', 'valsartan', 'amlodipine', 'kidney disease'], 'conditions': ['Essential Hypertension']}, 'referencesModule': {'references': [{'pmid': '15207952', 'type': 'RESULT', 'citation': 'Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004 Jun 19;363(9426):2022-31. doi: 10.1016/S0140-6736(04)16451-9.'}, {'pmid': '40397037', 'type': 'DERIVED', 'citation': 'Olsen E, Soraas CL, Schmieder RE, Jamerson K, MacDonald TM, Mancia G, Heimark S, Mehlum MH, Liestol K, Larstorp ACK, Mariampillai JE, Mo R, Halvorsen LV, Hoieggen A, Rostrup M, Kjeldsen SE, Weber MA. Low Achieved Systolic Blood Pressure Related to Kidney Protection in Diabetic and Non-Diabetic High-Risk Hypertensive Patients. Am J Hypertens. 2025 Nov 17;38(12):1106-1119. doi: 10.1093/ajh/hpaf093.'}]}, 'descriptionModule': {'briefSummary': 'The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial tested the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. The present study investigates effects of valsartan and amlodipine on pre-specified secondary kidney outcomes.', 'detailedDescription': 'VALUE was a multicenter, prospective, double-blinded randomized clinical trial initiated and led by the investigators. The study took place from 1997 to 2004. The sponsor was Novartis, who had an interactive role with the investigators for the study design, and Novartis monitored study sites and provided source data verifications. In 2011, Ullevaal University Hospital, Oslo, Norway, took over the database with conditions detailed in a written agreement with the funder. One author (S.E.K.) had from then full access to all the data and took responsibility for its integrity and the data analysis. Thus, the data file resides in the hands of the authors, and Novartis had no role in the present study.\n\nThe trial was approved by ethics committees and written informed consent collected from all the participants in 31 countries.\n\nThe study compared, in a prospective, randomized double-blinded design, the effects of two different antihypertensive treatment regimens on cardiac morbidity and mortality in hypertensive patients aged 50 years or older. One regimen was based on the ARB valsartan, and the other on the CCB amlodipine.\n\nVALUE participants were selected based on predefined combinations of risk factors, including age, male gender, and the presence of certain conditions such as electrocardiographic left ventricular hypertrophy (ECG-LVH), determined by Cornell voltage-duration product or Sokolow-Lyon voltage criteria with or without a strain pattern, serum creatinine ≥150 μmol/l, proteinuria (positive dipstick in morning urine at two different visits), diabetes mellitus (DM), or verified coronary, cerebrovascular, or peripheral artery disease.\n\nExclusion criteria included pregnancy, renal artery stenosis, either myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery during last three months, medically relevant valvular disease, cerebrovascular events last 3 months, severe hepatic disease, severe chronic kidney failure (serum creatinine \\>3.0 mg/dl, \\>265 µmol/L), congestive heart failure requiring angiotensin converting enzyme inhibitor and patients using beta-blocker for both coronary artery disease and hypertension.\n\nParticipants were followed for 4-6 years, until a minimum of 1450 primary cardiac events ("endpoint driven") with monthly visits during the initial six months after randomization and later at six-month intervals. BP was measured at each visit using a calibrated sphygmomanometer or a validated digital device with an appropriate size cuff. Patients were seated quietly for 5 minutes before the measurement of BP. Blood samples were collected and analyzed at central labs in each continent. Serum creatinine was measured yearly.\n\nThe primary goal of the study was to determine the time to the occurrence of the first cardiac event, which included a combination of fatal or non-fatal myocardial infarction, sudden cardiac death, death from revascularization procedures or heart failure, hospitalization for heart failure, and emergency procedures to prevent myocardial infarction. The secondary endpoints were all cardiovascular events, fatal and non-fatal stroke, myocardial infarction, hospitalized heart failure, cardiovascular-, non-cardiovascular-, and all-cause mortality.\n\nPre-specified secondary kidney endpoints were end-stage kidney disease (ESKD) in patients with need for dialysis or kidney transplantation and worsened kidney function (WKF) with at least 50% increase in serum creatinine from baseline. To ensure impartiality, the endpoint committee was not informed of the treatment assignments when assessing events.\n\nPatients who were previously treated for hypertension (92%) were eligible if SBP was \\<210 mmHg and diastolic(D) BP was \\<115 mmHg. Untreated hypertensive patients were eligible if SBP was between 160 and 210 mmHg, and DBP was \\<115 mmHg. Patients who already were on treatment, discontinued their previous antihypertensive medications when randomized to one of the trial\'s masked study arms (valsartan or amlodipine) without a run-in phase ("rolled over"). Valsartan treatment started at a dosage of 80 mg daily, and amlodipine treatment started at 5 mg daily. If BP did not reach \\<140/90 mmHg, the dose of either drug was doubled to 160 mg or 10 mg, respectively, and hydrochlorothiazide (12.5 mg and 25 mg daily) and other antihypertensive drugs were added in sequential steps.\n\nAge, the presence of coronary heart disease, and the presence of ECG-LVH at baseline were used in the randomized study as à priori covariates to account for the effects of key risk predictors at baseline.\n\nTo minimize the influence of potential confounding factors, hazard ratios (HRs) in the observational analysis of different achieved BP levels were adjusted for treatment allocation and baseline covariates including age, sex, SBP, diastolic blood pressure, body mass index, smoking status, high serum total cholesterol (\\>6.2 mmol/L or \\>240 mg/dL), presence of diabetes mellitus, proteinuria, ECG-LVH, previous stroke, previous myocardial infarction, and previous peripheral artery disease.\n\nStatistical power was calculated for the original comparison of valsartan vs amlodipine on the primary endpoint.15 The trial was endpoint driven, needed 1450 primary events to close, and showed no difference between valsartan and amlodipine on the primary endpoint, which allowed consolidation of data from both treatment arms for other studies of this hypertensive population like investigation BP variability and the influence of achieved BPs on certain endpoints. Of the 15,245 hypertensive patients enrolled by 969 investigators, 13,803 patients did not experience any cardiovascular event during the initial six months of treatment after randomization and had attended a minimum of three study visits after that period. A minimum of three visits was decided à priori to ensure meaningful follow up of representative achieved BPs. Patients with cardiovascular events during the first six months after randomization were excluded because of the uncontrolled BP following discontinuation of previous antihypertensive drugs and concomitant up-titration of the randomized medications; these early BPs were neither included as they were not representative for the later achieved average BPs.\n\nTreatment effects on kidney endpoints in the RCT were measured by hazard ratios and their 95% CIs based on Cox regression models and analyzed as intention-to-treat. Event rates over time are presented as Kaplan-Meier curves. Similar multivariate adjusted Cox models were used to analyze the kidney endpoints for patients who achieved average SBP \\<135 mmHg vs SBP ≥135 mmHg up to the occurrence of a prespecified endpoint, or throughout the treatment period if no event occurred. Similar comparisons were done for patients who achieved average DBP \\<85 mmHg vs ≥85 mmHg and for groups with SBP ≥135 and/or DBP ≥85 mmHg vs patients with SBP \\<135 and DBP \\<85 mmHg.\n\nStatistical significance was determined with a two-sided p-value of \\<0.05. Data analysis was carried out using SPSS (IBM SPSS Statistics: Version: 28.0.1.0, Armonk, NY, USA). Data are presented as means with standard deviations (SDs), absolute numbers with percentages in parentheses, or point estimates with 95% confidence intervals (CIs).'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '85 Years', 'minimumAge': '50 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* hypertension, and predefined combinations of risk factors, including:\n* age\n* male gender\n* the presence of electrocardiographic left ventricular hypertrophy (LVH, determined by Cornell voltage-duration product or Sokolow-Lyon voltage criteria with or without a strain pattern)\n* serum creatinine ≥150 μmol/l\n* proteinuria (positive urine dipstick at two occasions)\n* type 2 diabetes mellitus\n* verified coronary, cerebrovascular, or peripheral artery disease\n\nExclusion Criteria:\n\n* pregnancy\n* renal artery stenosis\n* myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery during last three months\n* medically relevant cardiac valvular disease\n* cerebrovascular events last 3 months\n* severe hepatic disease\n* severe chronic kidney failure (serum creatinine \\>3.0 mg/dl, \\>265 µmol/L)\n* congestive heart failure requiring angiotensin converting enzyme inhibitor (ACEI)\n* use of beta-blocker for both coronary artery disease and hypertension'}, 'identificationModule': {'nctId': 'NCT06395194', 'acronym': 'VALUE', 'briefTitle': 'Effects of Valsartan vs Amlodipine and Low BP on Kidney Outcomes in Essential Hypertension', 'organization': {'class': 'OTHER', 'fullName': 'Oslo University Hospital'}, 'officialTitle': 'The Valsartan Antihypertensive Long-term Use Evaluation Trial', 'orgStudyIdInfo': {'id': 'OsloUHtheValueTrial'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'ACTIVE_COMPARATOR', 'label': 'Valsartan', 'description': 'Treatment based on the ARB valsartan', 'interventionNames': ['Drug: Cardiac outcomes on treatment with valsartan']}, {'type': 'ACTIVE_COMPARATOR', 'label': 'Amlodipine', 'description': 'Treatment based on the CCB amlodipine', 'interventionNames': ['Drug: Cardiac outcomes on treatment with amlodipine']}], 'interventions': [{'name': 'Cardiac outcomes on treatment with valsartan', 'type': 'DRUG', 'otherNames': ['Angiotensin-receptor blocker'], 'description': 'Patients who already were on treatment, discontinued their previous antihypertensive medications when randomized to one of the trial\'s masked study arms (valsartan or amlodipine) without a run-in phase ("rolled over"). Valsartan treatment started at a dosage of 80 mg daily. If BP did not reach \\<140/90 mmHg, the valsartan dose was doubled to 160 mg, and then hydrochlorothiazide (12.5 mg and 25 mg daily) and other antihypertensive drugs were added in sequential steps.', 'armGroupLabels': ['Valsartan']}, {'name': 'Cardiac outcomes on treatment with amlodipine', 'type': 'DRUG', 'otherNames': ['Calcium-channel blocker'], 'description': 'Patients who already were on treatment, discontinued their previous antihypertensive medications when randomized to one of the trial\'s masked study arms (valsartan or amlodipine) without a run-in phase ("rolled over"). Amlodipine treatment started at 5 mg daily. If BP did not reach \\<140/90 mmHg, the amlodipine dose was doubled to 10 mg, and then hydrochlorothiazide (12.5 mg and 25 mg daily) and other antihypertensive drugs were added in sequential steps.', 'armGroupLabels': ['Amlodipine']}]}, 'contactsLocationsModule': {'overallOfficials': [{'name': 'Sverre E Kjeldsen, MD, PhD', 'role': 'STUDY_CHAIR', 'affiliation': 'University Of Oslo Hospital'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO', 'description': 'Partial IPD sharing with the BPLTTC Group in Oxford'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Oslo University Hospital', 'class': 'OTHER'}, 'collaborators': [{'name': 'University of Oslo', 'class': 'OTHER'}], 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Professor Emeritus', 'investigatorFullName': 'Sverre Erik Kjeldsen', 'investigatorAffiliation': 'Oslo University Hospital'}}}}