Hypertension
Conditions
Keywords
Melatonin, Hypertension, Blood Pressure, Cardiovascular, Sleep, Nighttime, Nocturnal, Catecholamines, Sympathetic Nervous System, Endothelial function, African American
Brief summary
This purpose of this study is to test the effect of oral melatonin supplementation (8 mg per night for 4 weeks) on nighttime blood pressure in African Americans with a history of elevated nighttime blood pressure.
Detailed description
The main outcome of interest is the mean nighttime blood pressure. The investigator is also trying to see the mechanism of action of melatonin on blood pressure by analyzing data from sleep studies to see if melatonin lowers blood pressure by providing a better quality of sleep or is that independent of the quality of sleep. The investigator is also looking into the effect of melatonin on sympathetic nervous system by measuring urinary catecholamines. Finally, the investigator is looking into changes in vascular biology markers (P-selectin and e-selectin) on melatonin.
Interventions
DRUGMelatonin
Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine compound. Subjects will receive 8 mg time-release melatonin pills, orally, once per night for 4 weeks.
DRUGPlacebo
Subjects received placebo pills (3 pills of 8 mg each) to be taken orally once per night for 4 weeks.
Sponsors
National Center for Complementary and Integrative Health (NCCIH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
* Males or females ages 18 to 64 * Prior history of elevated nighttime blood pressure (BP) ((systolic blood pressure (SBP) \>115 mmHg)) * Taking no more than 2 antihypertensive medications * African-American race (self-defined by the participant)
Exclusion criteria
* Secondary forms of hypertension * Presence of other diseases requiring treatment with BP lowering medications * Known cardiovascular disease (including history of angina pectoris, heart failure, presence of a cardiac pacemaker, history of myocardial infarction or revascularization procedure, or cerebrovascular disease, including stroke and transient ischemic attacks) * Diabetes mellitus (type 1 or 2) * Cancer/Malignancy other than nonmelanoma skin cancer * Primary renal disease * Serum creatinine \> 1.5 mg/dL in men or \> 1.4mg/dL in women * Severe anemia * Liver enzymes \> 2.5 times upper limits of normal * Hepatitis B, Hepatitis C, or HIV positive as assessed by questionnaire * Current treatment with or regular use of calcium channel blocking agents, cyclooxygenase-2 or COX2-inhibitors, oral contraceptives, estrogen, sildenafil, vardenafil, tadalafil, antidepressants, corticosteroids, or warfarin * Current use of melatonin or any sleep aids containing melatonin. * Regular consumption (1 or more times per week) of any of the following of Vitamin methyl B12, St. Johns Wort, Feverfew, black and white mustard seeds, wolf berry seed * Severe Sleep apnea * Night work * Women who are pregnant, breast-feeding, attempting conception, or planning to attempt conception over the next 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Nighttime Systolic Blood Pressure (SBP) | At the end of 4 weeks | The nighttime systolic blood pressure (SBP) was recorded using an ambulatory blood pressure (ABP) monitor. The measurements occurring from the onset of self-reported sleep to the end of self-reported sleep were recorded. Means of multiple measurements were reported. |
| Mean Nighttime Diastolic Blood Pressure (DBP) | At the end of 4 weeks | The nighttime diastolic blood pressure (DBP) was recorded using an ambulatory blood pressure (ABP) monitor. The measurements occurring from the onset of self-reported sleep to the end of self-reported sleep were recorded. Means of multiple measurements were reported |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daytime Systolic Blood Pressure (SBP) | At the end of 4 weeks | The daytime systolic blood pressure was calculated as the average systolic blood pressure during daytime period based on 24hour ambulatory blood pressure monitoring. Means of multiple measurements were reported |
| Mean Daytime Diastolic Blood Pressure (DBP) | At the end of 4 weeks | The daytime diastolic blood pressure was calculated as the average diastolic blood pressure during the daytime period based on 24 hour ambulatory blood pressure monitoring. Means of multiple measurements were reported |
| Mean Daytime Mean Arterial Pressure (MAP) | At the end of 4 weeks | Daytime mean arterial pressure (MAP) is the average blood pressure in the subject's arteries during one cardiac cycle (one complete heartbeat) during the day. It is calculated using the formula, MAP = 1/3(SBP-DBP)+DBP; where SBP is the systolic blood pressure and DBP is the diastolic blood pressure. Means of multiple measurements were reported. |
| Mean Daytime Heart Rate (HR) | At the end of 4 weeks | Daytime heart rate is the number of the pulsations of the heart per unit of time during the day. It is measured in beats per minute (bpm). Ambulatory blood pressure monitoring was used to calculate the heart rate. Means of multiple measurements were reported |
| Urinary Dopamine Excretion Rate | At the end of 4 weeks | The rate of urinary dopamine excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight. |
| Urinary Noradrenaline Excretion Rate | At the end of 4 weeks | The rate of urinary noradrenaline excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight. |
| Mean Nighttime Mean Arterial Pressure (MAP) | At the end of 4 weeks | Nighttime mean arterial pressure (MAP) is the average blood pressure in the subject's arteries during one cardiac cycle (one complete heartbeat) at night. It is calculated using the formula, MAP = 1/3(SBP-DBP)+DBP; where SBP is the systolic blood pressure and DBP is the diastolic blood pressure. Means of multiple measurements were reported |
| Plasma E-Selectin | At the end of 4 weeks | E-Selectin is a marker of endothelial function. Levels of e-selectin were measured from stored plasma using enzyme-linked immunosorbent assay (ELISA). |
| Plasma P-Selectin | At the end of 4 weeks | P-Selectin is a marker of endothelial function. Levels of p-selectin were measured from stored plasma using enzyme-linked immunosorbent assay (ELISA). |
| Total Sleep Time | At the end of 4 weeks | The total sleep time will be measured by polysomnography (PSG) using an Embla polysomnograph. The nocturnal total sleep time (TST) or the the total number of minutes in any stage of sleep during the major nocturnal sleep period was measured by PSG. |
| Nocturnal Dipping of Blood Pressure | At the end of 4 weeks | Nocturnal dipping is the mean nighttime to mean daytime systolic and diastolic blood pressure ratios, or the percentage drop in nocturnal SBP compared to day time SBP. Night was defined as 10:00 PM through 5:59 AM. This ratio is calculated by the ambulatory blood pressure readings. |
| Percentage of Participants With Melatonin-related Side Effect. | After 4 weeks of treatment | — |
| Urinary Adrenaline Excretion Rate | At the end of 4 weeks | The rate of urinary adrenaline excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight. |
| Mean Nighttime Heart Rate (HR) | At the end of 4 weeks | Nighttime heart rate is number of pulsations of the heart per unit of time during nighttime sleep. It is measured in beats per minute (bpm). Ambulatory blood pressure monitoring was used to calculate the heart rate. Means of multiple measurements were reported |
Countries
United States
Participant flow
Recruitment details
80 patients were screened. 43 patients stopped study participation prior to randomization either due to screen failure or because the decided not to pursue the study procedures. 37 patients were randomized. There was 1 dropout, and 36 patients completed both arms of the study.
Pre-assignment details
After signing the ICF and going through screening procedures, 43 patients stopped study participation prior to randomization either due to screen failure or because the decided not to pursue the study procedures.
Participants by arm
| Arm | Count |
|---|---|
| All Participants African American subjects with mild to moderate essential hypertension and an elevated nighttime blood pressure \>115 mmHg received 8mg of time release melatonin or placebo for the first 4 weeks and were then switched to receive either placebo or 8mg of time release melatonin for an additional 4 weeks without any wash out period in between. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 (4 Weeks) | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 36 | 18 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Mean Nighttime Diastolic Blood Pressure (DBP)
The nighttime diastolic blood pressure (DBP) was recorded using an ambulatory blood pressure (ABP) monitor. The measurements occurring from the onset of self-reported sleep to the end of self-reported sleep were recorded. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Nighttime Diastolic Blood Pressure (DBP) | 76 mmHg | Standard Error 1.7 |
| Placebo | Mean Nighttime Diastolic Blood Pressure (DBP) | 76.2 mmHg | Standard Error 1.8 |
Comparison: The null hypothesis is that there is no interaction between the order of randomization and primary outcomes.p-value: 0.75ANOVA
Primary
Mean Nighttime Systolic Blood Pressure (SBP)
The nighttime systolic blood pressure (SBP) was recorded using an ambulatory blood pressure (ABP) monitor. The measurements occurring from the onset of self-reported sleep to the end of self-reported sleep were recorded. Means of multiple measurements were reported.
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Nighttime Systolic Blood Pressure (SBP) | 126.6 mmHg | Standard Error 2.4 |
| Placebo | Mean Nighttime Systolic Blood Pressure (SBP) | 125.3 mmHg | Standard Error 2.5 |
Comparison: The null hypothesis is that there is no interaction between the order of randomization and primary outcomes.p-value: 0.075ANOVA
p-value: 0.75ANOVA
Secondary
Mean Daytime Diastolic Blood Pressure (DBP)
The daytime diastolic blood pressure was calculated as the average diastolic blood pressure during the daytime period based on 24 hour ambulatory blood pressure monitoring. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Daytime Diastolic Blood Pressure (DBP) | 85.7 mmHg | Standard Error 1.6 |
| Placebo | Mean Daytime Diastolic Blood Pressure (DBP) | 86.2 mmHg | Standard Error 1.7 |
p-value: 0.89ANOVA
Secondary
Mean Daytime Heart Rate (HR)
Daytime heart rate is the number of the pulsations of the heart per unit of time during the day. It is measured in beats per minute (bpm). Ambulatory blood pressure monitoring was used to calculate the heart rate. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Daytime Heart Rate (HR) | 81 beats per minute | Standard Error 1.9 |
| Placebo | Mean Daytime Heart Rate (HR) | 84.6 beats per minute | Standard Error 1.9 |
p-value: 0.01ANOVA
Secondary
Mean Daytime Mean Arterial Pressure (MAP)
Daytime mean arterial pressure (MAP) is the average blood pressure in the subject's arteries during one cardiac cycle (one complete heartbeat) during the day. It is calculated using the formula, MAP = 1/3(SBP-DBP)+DBP; where SBP is the systolic blood pressure and DBP is the diastolic blood pressure. Means of multiple measurements were reported.
Time frame: At the end of 4 weeks
Population: 40 subjects enrolled the study. 4 subjects did not complete the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Daytime Mean Arterial Pressure (MAP) | 102.2 mmHg | Standard Error 1.7 |
| Placebo | Mean Daytime Mean Arterial Pressure (MAP) | 102.1 mmHg | Standard Error 1.8 |
p-value: 0.97ANOVA
Secondary
Mean Daytime Systolic Blood Pressure (SBP)
The daytime systolic blood pressure was calculated as the average systolic blood pressure during daytime period based on 24hour ambulatory blood pressure monitoring. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Daytime Systolic Blood Pressure (SBP) | 135.13 mmHg | Standard Error 2.2 |
| Placebo | Mean Daytime Systolic Blood Pressure (SBP) | 133.9 mmHg | Standard Error 2.2 |
p-value: 0.64ANOVA
Secondary
Mean Nighttime Heart Rate (HR)
Nighttime heart rate is number of pulsations of the heart per unit of time during nighttime sleep. It is measured in beats per minute (bpm). Ambulatory blood pressure monitoring was used to calculate the heart rate. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Nighttime Heart Rate (HR) | 75.4 beats per minute | Standard Error 2 |
| Placebo | Mean Nighttime Heart Rate (HR) | 76.2 beats per minute | Standard Error 2.1 |
p-value: 0.21ANOVA
Secondary
Mean Nighttime Mean Arterial Pressure (MAP)
Nighttime mean arterial pressure (MAP) is the average blood pressure in the subject's arteries during one cardiac cycle (one complete heartbeat) at night. It is calculated using the formula, MAP = 1/3(SBP-DBP)+DBP; where SBP is the systolic blood pressure and DBP is the diastolic blood pressure. Means of multiple measurements were reported
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Mean Nighttime Mean Arterial Pressure (MAP) | 92.9 mmHg | Standard Error 1.9 |
| Placebo | Mean Nighttime Mean Arterial Pressure (MAP) | 92.6 mmHg | Standard Error 2 |
p-value: 0.79ANOVA
Secondary
Nocturnal Dipping of Blood Pressure
Nocturnal dipping is the mean nighttime to mean daytime systolic and diastolic blood pressure ratios, or the percentage drop in nocturnal SBP compared to day time SBP. Night was defined as 10:00 PM through 5:59 AM. This ratio is calculated by the ambulatory blood pressure readings.
Time frame: At the end of 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Nocturnal Dipping of Blood Pressure | 5.6 percentage ratio in night/day SBP | Standard Error 1.23 |
| Placebo | Nocturnal Dipping of Blood Pressure | 6.14 percentage ratio in night/day SBP | Standard Error 1.3 |
Secondary
Percentage of Participants With Melatonin-related Side Effect.
Time frame: After 4 weeks of treatment
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Melatonin | Percentage of Participants With Melatonin-related Side Effect. | 47.2 percentage of total number of patients |
| Placebo | Percentage of Participants With Melatonin-related Side Effect. | 50 percentage of total number of patients |
Secondary
Plasma E-Selectin
E-Selectin is a marker of endothelial function. Levels of e-selectin were measured from stored plasma using enzyme-linked immunosorbent assay (ELISA).
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Plasma E-Selectin | 38.6 ng/ml | Standard Error 2.1 |
| Placebo | Plasma E-Selectin | 38.9 ng/ml | Standard Error 2.1 |
p-value: 0.96ANOVA
Secondary
Plasma P-Selectin
P-Selectin is a marker of endothelial function. Levels of p-selectin were measured from stored plasma using enzyme-linked immunosorbent assay (ELISA).
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Plasma P-Selectin | 97.02 ng/ml | Standard Error 7.6 |
| Placebo | Plasma P-Selectin | 82.7 ng/ml | Standard Error 7.6 |
p-value: 0.25ANOVA
Secondary
Total Sleep Time
The total sleep time will be measured by polysomnography (PSG) using an Embla polysomnograph. The nocturnal total sleep time (TST) or the the total number of minutes in any stage of sleep during the major nocturnal sleep period was measured by PSG.
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Total Sleep Time | 399.8 minutes | Standard Error 11 |
| Placebo | Total Sleep Time | 412.2 minutes | Standard Error 11.1 |
p-value: 0.52ANOVA
Secondary
Urinary Adrenaline Excretion Rate
The rate of urinary adrenaline excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight.
Time frame: At the end of 4 weeks
Population: 40 patients were enrolled in the study. 4 subjects did not complete the study. 36 patients completed the study and were their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Urinary Adrenaline Excretion Rate | 2.75 ng/ml/min | Standard Error 0.6 |
| Placebo | Urinary Adrenaline Excretion Rate | 2.02 ng/ml/min | Standard Error 0.6 |
p-value: 0.11Friedman
Secondary
Urinary Dopamine Excretion Rate
The rate of urinary dopamine excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight.
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Urinary Dopamine Excretion Rate | 140.9 ng/ml/min | Standard Error 13.2 |
| Placebo | Urinary Dopamine Excretion Rate | 137.8 ng/ml/min | Standard Error 13 |
p-value: 0.71Friedman
Secondary
Urinary Noradrenaline Excretion Rate
The rate of urinary noradrenaline excretion was measured by the Enzyme-Linked Immunosorbent Assay (ELISA) method from urine samples collected overnight.
Time frame: At the end of 4 weeks
Population: 37 subjects enrolled the study. 1 subject did not complete the two arms of the study. 36 subjects completed the study in a crossover design, being their own controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin | Urinary Noradrenaline Excretion Rate | 17.5 ng/ml/min | Standard Error 3 |
| Placebo | Urinary Noradrenaline Excretion Rate | 19.0 ng/ml/min | Standard Error 3 |
p-value: 0.38Friedman