Influence of Amlodipine on the Mortality of Patients With End-Stage Renal Failure
Condition: Kidney Failure, Chronic
MeSH terms: Renal Insufficiency; Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with end-stage renal failure have a markedly higher mortality because of
      cardiovascular events in comparison with the normal population. Disorders in the calcium
      metabolism, such as calcification of the vessel walls, occur very frequently. There are
      indications that calcium channel blockers are capable of lowering the cardiovascular
      mortality in patients with end-stage renal failure.

      It is intended to carry out a prospective, randomized, double-blind, placebo-controlled,
      multicenter study in order to find out if the calcium channel blocker amlodipine is able to
      reduce the mortality of patients with end-stage renal failure.

      The investigation will be carried out after suitable explanation and written informed consent
      in 356 patients aged between 18 and 90 years with end-stage renal failure and chronic
      haemodialysis treatment. The patients will be randomized to either treatment with amlodipine
      10 mg/day or placebo. The occurrence of events will be documented and evaluated prospectively
      over a period of 30 months.
    

Detailed description: 
      Trial protocol for ADAM Study

      1.1 General Data:

        1. Title of the Study: Influence of Amlodipine on the Mortality of Patients with End-Stage
           Renal Failure (abbreviated title: ADAM [Amlodipine and Dialysis Patients, Action on
           Mortality])

        2. Study Directors:

           Prof. Dr. med. Martin Tepel, Charite University of Berlin, Campus Benjamin Franklin,
           Medizinische Klinik IV, Hindenburgdamm 30, 12200 Berlin, Germany. Tel.: +49-30 8445
           2305, Fax: +49-30 8445 4235, e-mail: Martin.Tepel@charite.de

           Statistics:

           PD Dr. rer. nat. Dr. med. Werner Th. Hopfenmüller, Charite University of Berlin, Campus
           Benjamin Franklin, Institut für Medizinische Statistik und Biometrie, Hindenburgdamm 30,
           12200 Berlin, Germany. Tel.: +49-30 8445 3512 Fax: +49-30 8445 4471

        3. Summary of the ADAM Study:

           Patients with end-stage renal failure have a markedly higher mortality because of
           cardiovascular events in comparison with the normal population. Disorders in the calcium
           metabolism, such as calcification of the vessel walls, occur very frequently. There are
           indications that calcium channel blockers are capable of lowering the cardiovascular
           mortality in patients with end-stage renal failure. It is intended to carry out a
           prospective, randomized, double-blind, placebo-controlled, multicenter study in order to
           find out if the calcium channel blocker amlodipine is able to reduce the mortality of
           patients with end-stage renal failure.

           The investigation will be carried out after suitable explanation and written informed
           consent in 356 patients aged between 18 and 90 years with end-stage renal failure and
           chronic haemodialysis treatment. The patients will be randomized to either treatment
           with amlodipine 10 mg/day or placebo. The occurrence of events will be documented and
           evaluated prospectively over a period of 30 months.

        4. Sponsor:

           There is no sponsor for this study. The study was initiated by the study directors
           themselves. The Pfizer company (Karlsruhe) is supporting the project financially and
           materially.

        5. Trial Center:

           It is planned to carry out the study in the Berlin/Brandenburg area and in North Rhine
           Westphalia. The doctors responsible in the respective Trial Centers will be notified to
           the Ethics Committee immediately after enrolment. At present there are no enrolled Trial
           Centers.

        6. Ethics Committee:

           The present Trial Protocol has been presented to the Ethics Committee of the Free
           University of Berlin (chairman: Prof. Dr. med. D. Ganten) for review.

        7. Other Ethics Committees:

           This Trial Protocol has so far not been presented to any other institutions for
           assessment.

        8. Classification of the Study:

           This is a Phase IV study. The study will be carried out with a licensed medicament
           (amlodipine) with a licensed indication (hypertension). This is a clinical study in
           patients who are legally competent and who are capable of understanding the nature,
           importance and scope of the clinical trial.

        9. Legal Basis German Medicines Act

      1.2 Justification and Aim of the Study:

        1. Aim and Hypothesis:

           The aim of the study is to show that the administration of the calcium antagonist
           amlodipine significantly reduces mortality in patients with end-stage renal failure.

           Hypothesis: Amlodipine reduces the mortality in patients with end-stage renal failure.

        2. Current Status of Research and Basis for the Performance of the Study:

           The life expectancy of patients with end-stage renal failure is nowadays still less than
           10 years. The annual mortality rate of patients with end-stage renal failure is almost
           25%. Death of patients with end-stage renal failure is frequently the consequence of
           cardiovascular events. Cardiovascular events in patients with dialysis-dependent renal
           failure are particularly frequently seen because the traditional risk factors, such as
           diabetes, hypertension, hyperlipidemia and smoking, are frequently present in this
           group. In addition, there are also numerous risk factors associated with the renal
           failure, such as increased oxidative stress, inflammatory vascular changes, excess salt
           and water load. Important cofactors for the increased mortality in dialysis patients are
           an inadequate removal of the "uremia toxins" or a uremia-induced malnutrition.

           In patients with end-stage dialysis-dependent renal failure, increased calcification of
           the coronary vessels, of the cardiac valves and other myocardial tissue, as well as an
           increase in the calcium x phosphate product is frequently seen. An association is also
           seen with an increased mortality. Block and colleagues were able to show that the
           relative mortality risk in patients with an increased calcium x phosphate product is
           increased and that increased cardiovascular causes of death could be seen. An increased
           calcium x phosphate product potentiates the calcification of arterial vascular walls and
           thus produces reduced elasticity. Using electron beam computer tomography it could be
           shown that calcification in the region of the coronary vessels was observed much more
           frequently in patients with end-stage renal failure than in healthy control persons.

           In the general population it has been shown that calcium channel blockers are very good
           vasodilators and antihypertensive drugs. In the general population calcium antagonists
           of the types long-acting dihydropyridines, verapamil or diltiazem are used
           preferentially for the treatment of elderly patients or patients with isolated systolic
           hypertension. However, patients with end-stage renal failure also profit from the
           administration of calcium channel blockers, as these reduce the blood pressure, reduce
           the uremia toxin-induced calcinosis of the vessels and produce a reduced influx of
           calcium into the vessel walls. Calcium channel blockers inhibit macrophage
           proliferation. Calcium channel blockers can also reduce raised calcium levels in
           B-lymphocytes of patients with end-stage renal failure.

           In a preliminary retrospective investigation, the study directors investigated the
           effects of the administration of calcium antagonists on mortality. 188 patients with
           end-stage renal failure and chronic regular haemodialysis were observed for 30 months
           from July 1998. Parameters such as age, sex, laboratory values, clinical data and
           dialysis dose were recorded. Up to December 2000 51 patients had died (27%). The
           investigation showed advanced age and low body-mass index to be causes of increased
           mortality. In contrast, the availability of calcium channel blockers was favorable.
           After statistical analysis of the data using a Cox risk-regression model it was found
           that the patients taking the calcium channel blockers showed a significantly lower
           mortality (relative risk 0.22 [95% confidence interval 0.17-0.67] p < 0.001). This
           preliminary investigation thus shows that the use of calcium channel blockers
           significantly lowers mortality in patients with end-stage dialysis-dependent renal
           failure who have an increased mortality due to cardiovascular events.

           2 Ethical Aspects:

           Patients with end-stage renal failure and existing, or a history of known, arterial
           hypertension have a clearly increased mortality because of cardiovascular events in
           comparison with a normal population. So far there are no medicaments that have been
           demonstrated in studies to reduce the mortality of patients with dialysis-dependent
           renal failure. In a preliminary study there were indications that calcium channel
           blockers, and in particular amlodipine, lead to a reduction of cardiovascular mortality.

           The investigation will be carried out after appropriate explanation has been given and
           written informed consent has been obtained from the patients.

           Provisions for Monitoring of the Study by the Ethics Committee:

           The applicants, Prof. Dr. med. M. Tepel and Dr. med. M. van der Giet, are prepared to
           enable authorized members of the Ethics Committee to observe the trial at any time.

           3 Study Timetable:

           3.1 Justification of the Timetable: Every patient will be observed for a period of 30
           months. Patients with end-stage renal failure of non-diabetic origin have a five-year
           survival expectation of about 35 - 40%, whereas patients with end-stage renal failure of
           diabetic origin have a five-year survival rate of about 20% (United States Renal Data
           System: Annual Data Report 2000. Am. J. Kidney Dis. 2000; 36 Suppl. 2, p. 127). It is
           therefore to be assumed that within 30 months about 35 - 40% of the examined patients
           will die. This period should be sufficient to observe any possible positive effects of
           amlodipine on mortality.

           The medicinal preparation is licensed for long-term therapy, so that negative effects
           due to the medicament are not to be expected.

           4. General Planning:

           A randomized, double-blind, placebo-controlled, multicenter study with two groups will
           be carried out in order to show reduction of the mortality in patients with end-stage
           renal failure. The study will be carried out over a period of 30 months. A check will be
           made every six months to see if an event has occurred.

           All patients who fulfil the inclusion criteria and who are prepared to participate in
           the study will be randomly assigned at the first issue of the study medicament to one of
           the groups. The patient will receive either amlodipine 10 mg or placebo. Both
           medicaments will be given as a single daily dose in the form of tablets in the morning.
           The study medication will not be changed during the course of the study, insofar as no
           side-effects are observed. Patients who are already taking a calcium channel blocker,
           and in whom a withdrawal phase is possible according to the opinion of their physician,
           will first undergo a wash-out phase of 4 weeks before starting with the double-blind
           treatment. During the study, the administration of all other necessary medicaments for
           the patient, apart from the administration of calcium channel blockers, is permitted. A
           check will be carried out at intervals of 6 months to see whether an event has occurred.
           Each patient will be observed for a period of 30 months.

           4.2 Course of the Study:

           Visit 1 (initial examination): First of all the patient will be informed about the
           study. If the patient consents to participate, a short clinical history and physical
           examination will be carried out. Then the criteria of inclusion and exclusion will be
           checked. The blood pressure, pulse rate and body mass index will be determined.
           Subsequently the patient will be asked about previous diseases, with specific
           questioning about the occurrence of diabetes mellitus, coronary heart disease, stroke
           (including transitory ischaemic attacks [TIA] and prolonged reversible ischaemic
           neurological deficit [PRIND]) and peripheral arterial occlusive disease. The patient
           will be enrolled in the study if he/she fulfils the inclusion criteria and there are no
           exclusion criteria. Should the patient be taking a calcium channel blocker at the time
           of enrolment in the study, this will be withdrawn insofar as the attending physician
           considers that this is possible. Other existing medication will be retained. The
           interval between Visit 1 and Visit 2 is one week.

           Visit 2 (start of study, month 0): The patient's current medication will be recorded
           (with particular reference to the following concomitant medication: ACE inhibitors,
           AngII blockers, statins, erythropoietin, beta-blockers). Questions will be asked about
           newly developed diseases with special attention to the occurrence of diabetes mellitus,
           coronary heart disease, stroke (including transitory ischaemic attacks [TIA] and
           prolonged reversible ischaemic neurological deficit [PRIND]) and peripheral arterial
           occlusive disease. The blood pressure, pulse rate and body mass index will be recorded.
           Study medication for 28 weeks will be issued. The patient will be informed about taking
           the medicament. Laboratory values will be recorded in the course of the routine
           monitoring of the patients (abbreviated and extensive routine laboratory examinations:
           hemoglobin, leukocyte count, platelet count, calcium, calcium x phosphate product, urea,
           serum creatinine, total protein, parathyroid hormone, cholesterol, triglycerides and
           ferritin). The patient will be asked about current symptoms.

           Visits 3 - 6 (follow-up observation, months 6, 12, 18 and 24): The current medication of
           the patient will be recorded (with especial emphasis on the following concomitant
           medications: ACE inhibitors, AngII blockers, statins, erythropoietin, beta-blockers).
           Questions will be asked about newly developed diseases with special attention to the
           occurrence of diabetes mellitus, coronary heart disease, stroke (including transitory
           ischaemic attacks [TIA] and prolonged reversible ischaemic neurological deficits
           [PRIND]) and peripheral arterial occlusive disease. The blood pressure, pulse rate and
           body mass index will be recorded. The study medication will be counted. New supplies of
           study medication for 28 weeks will be issued. Questions will be asked about
           side-effects. The patient will be asked about current symptoms. Laboratory values will
           be recorded in the course of the routine monitoring of the patient (abbreviated routine
           laboratory: hemoglobin, leukocyte count, platelet count, calcium, calcium x phosphate
           product, urea, serum creatinine, total protein).

           Visit 7 (study closure, month 30): The current medication of the patient will be
           recorded (with especial emphasis on the following concomitant medications: ACE
           inhibitors, AngII blockers, statins, erythropoietin, beta-blockers). Questions will be
           asked about newly developed diseases with special attention to the occurrence of
           diabetes mellitus, coronary heart disease, stroke (including transitory ischaemic
           attacks [TIA] and prolonged reversible ischaemic neurological deficits [PRIND]) and
           peripheral arterial occlusive disease. The blood pressure, pulse rate and body mass
           index will be recorded. The study medication will be counted. Questions will be asked
           about side-effects. The patient will be asked about current symptoms. Laboratory values
           will be recorded in the course of the routine monitoring of the patients (abbreviated
           and extensive routine laboratory: hemoglobin, leukocyte count, platelet count, calcium,
           calcium x phosphate product, urea, serum creatinine, total protein, parathyroid hormone,
           cholesterol, triglycerides and ferritin).

           After completing the study, the data will be recorded after unblinding and evaluated
           (duration about 2 months) and prepared for publication.

           Checks on the Observation of the Protocol: The study directors will employ a monitor for
           the duration of the study who will visit all the centers at intervals of six months and
           check observation of the study protocol.

           4.3 Study Medication (trial preparation, blinding, concomitant medication):

           Amlodipine 10 mg will be used as the trial preparation Amlodipine is a calcium
           antagonist that has already been the licensed within the European Union for the
           indications: essential hypertension, chronic stable angina pectoris (angina on effort).
           Placebo will be used as control.

           4.3.1 Blinding:

           All members of the study team and all personnel who are involved in the course of the
           study will work under blind conditions throughout the entire period of the trial. The
           study directors and investigators will be provided with the randomization code in sealed
           envelopes. The placebo and active drug do not differ in form, color, odor or weight.

           4.3.2 Actions and Unblinding for Side-Effects:

           Blinding is essential in order to maintain the integrity of the study. Should, however,
           an emergency develop in which knowledge of the substance administered is necessary, then
           the blinding can be broken by the attending physician. If unblinding takes place, the
           responsible study directors must be contacted. All cases of unblinding will be recorded
           in the study record sheets. The study directors may be contacted in emergencies at any
           time by the telephone hotline (+ 49-30 8445 2305). Reports on serious adverse events
           should be made within 24 hours. These reports of serious adverse events must be sent to
           the study directors (Prof. Dr. med. M. Tepel or Dr. med. van der Giet, Freie Universität
           Berlin, Universitätsklinikum Benjamin Franklin, Medizinische Klinik IV, Hindenburgdamm
           30, 12200 Berlin, Tel/Fax: +49-30 8445 2305). Other side-effects will be recorded by the
           attending physician, documented and registered at the control visits.

           4.3.3 Concomitant Medication:

           The patients may take all the medicines that their attending physicians consider to be
           necessary throughout the course of the study. Exception: the administration of a calcium
           channel blocker during the study is not permissible. The medication will be recorded in
           detail at the regular monitoring visits.

           5. Objectives:

           5.1 Primary Parameters: The primary parameter will be the survival rate.

           5.2 Secondary Parameters: No secondary parameters will be investigated during the study.

           5.3 Methods for Recording Efficacy and Safety:

           All patients will be encouraged to maintain their diet and regular physical exercise
           throughout the duration of the study.

           All patients will be followed up at intervals of 6 months. At these visits, side-effects
           and changes in vital status will be recorded.

           When the medicament is issued for the first time, all patients will be observed for 2
           hours after taking it.

           5.4 Compliance: The study medication and the concomitant medicaments will be checked at
           6 month intervals. If necessary, the patients will be reminded of the necessity to take
           the drug.

           6. Data Management: All data for the study will be entered in the Clinical Record Forms
           and submitted for central analysis of the data (study directors). One copy of the
           Clinical Record Form will be retained by the attending physician. The study directors
           will ensure that the data are analyzed and statistically evaluated. Current Data
           Protection Regulations will be observed. The data will be analyzed in an anonymised
           form. The patient must consent to the data being recorded in the context of the clinical
           trial, being analyzed and being submitted at the request of the pertinent supervisory
           authorities. Each patient will be assigned a number on enrolment in the study and his
           /her initials will be recorded. Unequivocal patient identification will be possible via
           a patient identification list consisting of the patient number, initials, date of birth,
           name and first name. All data will be archived for a period of 10 years.

           6.1 Statistical Procedures:

           This 30-month-long, double-blind, placebo-control study is intended to show that the
           administration of calcium antagonists reduces the mortality of patients undergoing
           regular haemodialysis.

           The hypotheses to be tested are:

           H0: the mortality rates are the same; HA: the mortality rates are different.

           The log-rank test will be used to test for possible statistically significant
           differences (probability p = 0.05, two-tailed test).

           It is not intended to carry out any interim analysis.

           6.2 Estimation of Number of Cases:

           The sample size is calculated by comparison of two survival curves (Computer-Programm:
           "n-Query": Log-rank-Test of survival in two groups).

           The size of the sample is calculated on the basis of alpha = 0.05, power 80%, two-tailed
           test for a difference of 14% between amlodipine and placebo with a sample size of 163
           per group (log-rank test or survival in two groups, followed for fixed time, constant
           hazard ratio). Expected mortality rate: placebo 40% and amlodipine 26% .

           It is assumed that 30 patients will drop out of the study from the two groups together
           (e.g. change of dialysis center).

           Therefore, 356 patients (178 patients amlodipine versus 178 patients placebo) are to be
           investigated.

           7. Financing of the Study:

           The study will be supported financially and materially by the Pfizer company
           (Karlsruhe). The company will provide the medication/placebo.

           8. Miscellaneous:

           8.1 Insurance and Liability:

           An application for patient insurance has been made to the Gerling company and will be
           accordingly submitted.
    

Intervention name(s): Amlodipine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10mg; 10mg
Other intervention name(s): Placebo
Intervention MeSH terms: Amlodipine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: End-stage renal disease, hemodialysis