Amlodipine Prevents Morning Blood Pressure Surge Study
Amlodipine Prevents Morning Blood Pressure Surge Study
1. Study name:Amlodipine Prevents Morning Blood Pressure Surge Study

 2. Study drugs:amlodipine (Norvasc®) and nifedipine GITS (Adalat®)

 3. Rationale: Several recent studies compared 24-h blood pressure lowering effect of these
 2 dihydropyridine drugs, amlodipine and nifedipine GITS, but produced inconsistent
 results. Therefore, a randomized controlled trial with a larger sample size is required
 to compare these 2 dihydropyridines in the blood pressure control over 24 hours in
 general and during early morning hours and at night in particular.

 4. Objective: The primary objective of this study is to test the hypothesis that amlodipine
 compared with nifedipine GITS has a stronger effect in preventing morning blood pressure
 surge (4 am to 8 am) in mild to moderate hypertensive patients.The secondary objective
 of the study is to compare the effects of amlodipine and nifedipine GITS in reducing
 nighttime blood pressure (10 pm to 4 am) in patients with a decreased nocturnal blood
 pressure fall.

 5. Study design: The present study is designed as a randomized, actively controlled,
 multi-centre parallel group trial (phase Ⅳ) with two equally sized treatment groups:
 amlodipine and nifedipine GITS.

 6. Study population: 500 hypertensive patients meet the inclusion/exclusion criteria.

 7. Randomization and treatment: After stratification for centre, 500 eligible patients will
 be randomized into 2 groups. 250 will receive amlodipine 5 mg per day, and 250 will
 receive nifedipine GITS 30 mg per day. At 4 weeks of follow-up, the drug dosage per day
 may increase to 10 mg of amlodipine and 60 mg of nifedipine GITS, if blood pressure
 measured in doctor's office cannot be controlled to a level below 140/90 mm Hg. If there
 were no compelling indication, no other antihypertensive drug is allowed during the
 2-month trial.

 8. Follow up: All patients should give written informed consent at entry into the present
 study. In addition to 24-h ambulatory blood pressure monitoring, patients should also
 undergo a questionnaire survey and clinical measurements including clinic blood
 pressure. Patients will be followed up at the end of 4 weeks and 8 weeks after
 randomization.

 9. Sample size estimation: The number of required subject for the whole trial is 500.

 10. Timeline: October 2009 to July 2013.

 11. Organization: The Centre for Epidemiological Studies and Clinical Trials, Ruijin
 Hospital, Shanghai, China.
1. Study name: Amlodipine Prevents Morning Blood Pressure Surge Study (ARMORS)

 2. Study drugs: amlodipine (Norvasc®) and nifedipine GITS (Adalat®)

 3. Rationale:

 Previous meta-analyses of randomized controlled trials have demonstrated that the long acting
 dihydropyridine calcium channel blocker amlodipine (Norvasc®), compared with other
 antihypertensive drugs, provides more protection against stroke. The benefit of amlodipine
 against stroke is approximately 10% greater than diuretics/β-blockers, and 20% greater than
 angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Of all the
 dihydropyridine calcium channel blockers, only amlodipine provides protection against
 myocardial infarction similar as angiotensin-converting enzyme inhibitors, diuretics and
 β-blockers, and more than angiotensin receptor blockers. The benefit of amlodipine in the
 prevention of stroke might be attributable to its 24-h blood pressure control.

 24-h ambulatory blood pressure is more predictive of cardiovascular events than clinic
 pressure measured in doctor's office. The smoother the 24-h ambulatory blood pressure
 control, the lower the risk of target organ damage. Both systolic and diastolic blood
 pressure show a circadian rhythm with a nocturnal blood pressure fall and a morning blood
 pressure surge. The incidence of cardiovascular complications of hypertension, such as
 myocardial infarction and stroke, is higher in the early morning hours than the rest of the
 day. Several previous studies have demonstrated that an exaggerated morning blood pressure
 surge is associated with the incidence of stoke and with cardiovascular structural
 remodeling. Moreover, non-dipping of blood pressure at night (non-dipper, nighttime blood
 pressure fall less than 10%) is prevalent and is associated with a higher risk of
 cardiovascular event. In a recent study of controlled hypertensive patients, the prevalence
 of non-dipping of blood pressure at night was 62%. In our JingNing population study, we found
 that Chinese had a higher nighttime diastolic blood pressure than White populations, and the
 prevalence of isolated nocturnal hypertension was 10.9%. Patients with isolated nocturnal
 hypertension compared with normotensive subjects had an increased arterial stiffness. Thus, a
 preferable antihypertensive drug should not only reduce the 24-h mean level of blood
 pressure, but should also effectively control morning blood pressure surge and reduce
 nighttime blood pressure.

 At present, there are two mechanisms of long-acting antihypertensive agents. One is that the
 compound itself has a long half life time and hence shows a long term effect. Another is that
 the efficacy of a short-acting drug is elongated by using a slow release or a controlled
 release (such as GITS) technique. However, the latter mechanism may vary between individuals
 because of the difference in the gastrointestinal function. Therefore, a long-acting compound
 should be more reliable in the maintenance of long term efficacy than slow release or
 controlled release agents. In the class of dihydropyridine calcium channel blockers,
 amlodipine is a long-acting compound because of a long half life time (up to 50 hours), and
 nifedipine GITS uses a controlled release technique. Several recent studies compared 24-h
 blood pressure lowering effect of these 2 drugs, but produced inconsistent results. At least
 one study suggested that amlodipine may prevent morning blood pressure rise more effectively
 than nifedipine GITS. However, other studies demonstrated similar effect on morning blood
 pressure control of these 2 drugs. The inconsistency might be attributable to a chance
 finding, because of the small sample size (less than 100). Therefore, a randomized controlled
 trial with a larger sample size is required to compare these 2 dihydropyridines in the blood
 pressure control over 24 hours in general and during early morning hours and at night in
 particular.

 4. Objective: The primary objective of this study is to test the hypothesis that amlodipine
 compared with nifedipine GITS has a stronger effect in preventing morning blood pressure
 surge (4 am to 8 am) in mild to moderate hypertensive patients.

 The secondary objective of the study is to compare the effects of amlodipine and nifedipine
 GITS in reducing nighttime blood pressure (10 pm to 4 am) in patients with a decreased
 nocturnal blood pressure fall.

 5. Study design: The present study is designed as a randomized, actively controlled,
 multi-centre parallel group trial (phase Ⅳ) with two equally sized treatment groups:
 amlodipine and nifedipine GITS.

 6. Study population: In 20 research-oriented university hospitals in China and in a
 pre-defined timeframe, 500 patients will be considered for inclusion into the present study
 according to the inclusion/exclusion criteria.

 7. Randomization and treatment: After stratification for centre, 500 eligible patients will
 be randomized into 2 groups. 250 will receive amlodipine 5 mg per day, and 250 will receive
 nifedipine GITS 30 mg per day.

 At 4 weeks of follow-up, the drug dosage per day may increase to 10 mg of amlodipine and 60
 mg of nifedipine GITS, if blood pressure measured in doctor's office cannot be controlled to
 a level below 140/90 mm Hg. If there were no compelling indication, no other antihypertensive
 drug is allowed during the 2-month trial. All antihypertensive medication should be taken
 before breakfast from 6-8 clock in the morning.

 8. Follow up: All patients should give written informed consent at entry into the present
 study. In addition to 24-h ambulatory blood pressure monitoring, patients should also undergo
 a questionnaire survey and clinical measurements including clinic blood pressure. Patients
 should be followed up in normal working hours in the morning or in the afternoon. The precise
 follow-up time of the day should be recorded. At each follow-up visit, the responsible
 physician should measure a patient's blood pressure and pulse rate, and collect information
 on the use of medications, serious adverse events, adverse events and cardiovascular
 complications. At 4 and 8 weeks of follow-up, 24-h and 48-h ambulatory blood pressure
 monitoring will be performed, respectively. When 48-h ambulatory blood pressure monitoring is
 performed at 8 weeks of follow-up, the patient should not take any antihypertensive
 medication on the second day of monitoring.

 Only validated blood pressure monitors (SpaceLabs 90207 and 90217) will be used. Before each
 ambulatory blood pressure measurement, blood pressure monitors will be set up in a
 standardized way. A cuff of proper size should be secured to the left arm of the patient.
 Before the commencement of ambulatory blood pressure measurement, blood pressure will be
 measured twice using mercury sphygmomanometer. Immediately after these 2 measurements, blood
 pressure will be measured twice manually with the monitor. Then, blood pressure will be
 measured automatically according to predefined time intervals of the blood pressure monitor
 (every 20 minutes from 8 am to 10 pm and every 30 minutes from 10 pm to 8 am). At the end of
 ambulatory blood pressure monitoring, data will be transferred to a computer program. The
 same size cuff and the same arm should be used for all 3 ambulatory measurements for a
 patient. On the monitoring day, the patient should record the time to go to bed and to get
 up, the use of medications, and physical activity.

 9. Potential difficulties: During the study, ambulatory blood pressure monitoring may fail
 because of less than 20 readings during the whole day, less than 10 readings in the daytime
 or less than 5 readings at night. These failed measurements will have to be repeated.

 10. Sample size estimation and statistical analysis: It is projected that the standard
 deviation of morning blood pressure in the enrolled hypertensive patients is 12 mm Hg, and
 amlodipine, compared with nifedipine GITS, reduces morning blood pressure at 4 months of
 follow-up by 4 mm Hg. If α=0.05 and power=90%, the study will require a sample size of 190
 hypertensive patients per group to detect the projected difference in the morning blood
 pressure (4 am-8 am). After accounting for 5% of drop out rate and 20% patients on add-on
 therapy, the sample size for each group is 250. Thus the number of required subject for the
 whole trial is 500.

 The trial will mainly compare the amlodipine with nifedipine GITS group in the changes of
 morning blood pressure (4 am-8 am, about 8 blood pressure readings) and nighttime blood
 pressure (10 pm-4 am) at 4 and 8 weeks from baseline. The student t test will be used and 95%
 confidence interval of the differences between the 2 groups will be computed. In addition, an
 adjusted analysis (ANOVA) will also be performed while accounting for major baseline
 characteristics.

 11. Timeline: The trial will start from October 2009, 500 eligible patients would be
 randomized and followed up for 2 months. Database construction and statistical analysis will
 take 3 months. The trial will be published at the international congresses and in the English
 and Chinese literature in 2013.

 12. Organization: The principal investigator will be Professor Jiguang Wang from the Centre
 for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai, China. Professor
 Yan Li from the same centre will be the coordinator of the trial. 20 research oriented
 hospitals will participate in the recruitment of the study subjects. At least 20 subjects
 should be recruited in each of the participating hospitals.
Inclusion Criteria:

 -  Age: 40 to 70 years old.

 -  Untreated patients or those on monotherapy of antihypertensive drugs but with
 uncontrolled blood pressure in the ranges of 140-160/90-100 mmHg.

 -  Patients on antihypertensive medication should discontinue their antihypertensive
 treatment for at least 4 weeks. During the 4 weeks run-in period, all patients should
 have 2 clinic visits. At each visit, blood pressure will be measured 3 times
 consecutively. The average of these 6 readings from 2 clinic visits should be in the
 range of 140-180 systolic or 90-110 diastolic mm Hg. 24-h mean blood pressure should
 be equal to or higher than 130 mm Hg systolic and 80 mm Hg diastolic.

 -  The patients should sign the consent form prior to the participation in the trial,
 adhere to the study design, and can visit the outpatient clinic on his/her own.

 Exclusion Criteria:

 -  With life-threatening disease.

 -  With myocardial infarction or stroke in the last 2 years.

 -  With contraindications to a dihydropyridine calcium channel blocker.

 -  Current participation in another trial or trials.