Amlodipine Prevents Morning Blood Pressure Surge Study
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Amlodipine (Norvasc®); Nifedipine GITS (Adalat® XL 30
Intervention type(s): Drug; Drug
Intervention description(s): Amlodipine (Norvasc®), tablet, 5 mg; Nifedipine GITS (Adalat® XL 30), controlled released tablet, 30 mg
Intervention MeSH terms: Amlodipine; Nifedipine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: 24 hour blood pressure; morning blood pressure surge; amlodipine; nifedipine GITS