The placebo-controlled phase of these 10 trials ranged from 2 weeks to 4 weeks. Trial size ranged from 85–295 patients, and a total of 1707 patients entered the placebo-controlled phase of the trials (). There were 685 patients randomized to placebo and 1022 randomized to active drug. The trials enrolled patients from 6–17 years of age. The majority of patients in the studies were white (55.5%) and male (62.1%).
Over the course of the placebo-controlled phase of the 10 studies, the median diastolic blood pressure decreased 5.6 mm Hg in the active drug treatment group and 3.0 mm Hg in the placebo group (P<0.001). Median systolic blood pressure decreased 8.5 mm Hg in the active drug treatment group and 5.0 mm Hg in the placebo group (P<0.001). For patients receiving low, medium, and high doses of anti-hypertensive drugs, the median changes in diastolic blood pressure were −3.9 (IQR −9.0, 1.5), −4.7 (−10.3, 0.3), and −7.8 (−14.0, −1.3) mm Hg, respectively (). For patients receiving low, medium, and high doses of anti-hypertensive drugs, the median changes in systolic blood pressure were −6.3 (−13.0, 0.0), −8.0 (−15.0, −1.0), and −10.3 (−17.5, −4.0) mm Hg, respectively.
During the placebo-controlled phase of the trial, 263/685 (38.4%) of the patients in the placebo arm and 402/1022 (39.3%) of the patients in the active drug arm had a least 1 AE (P=0.72). The mean number of AEs/patient was 0.76 in the placebo cohort (519 AEs total) and 0.83 in the active drug cohort (851 AEs total) (P=0.37). The mean number of AEs/patient in the low-dose, medium-dose, and high-dose groups were 0.79, 1.07, and 0.61, respectively. No difference was observed in the percentage of patients in either group suffering an AE in 21 different body system MedDRA categories ().
Patients in Each Cohort Suffering an AE in 1 of 21 System Organ Class MedDRA Categories
We examined the number of AEs occurring in 10 categories of AEs that are common to antihypertensive medications (). No significant differences in the number of AEs between patients receiving placebo and active drug were noted in any of these categories. There were 3 reported episodes of hypotension (2 episodes in 1 patient) in the group of patients receiving active drug and no episodes in patients receiving placebo. Hypertension was recorded as an AE in only 4 patients over the 10 studies (). Three (1.2%) of these patients received placebo, and 1 (0.3%) received active drug.
Number of Reported Pediatric Adverse Events (% of AEs)
One patient receiving placebo (0.1%) and 4 patients (0.4%) receiving active drug suffered a SAE (P=0.65). The patient receiving placebo suffered a rejection of a transplanted kidney. A patient receiving irbesartan experienced an episode of diabetic ketoacidosis, and a second patient had a syncopal event. A patient receiving lisinopril experienced 2 separate SAEs (gastroenteritis and pyuria). Finally, a patient receiving losartan broke a clavicle after a fall. None of these SAEs were felt by the investigators to be related to study drug. The AE’s relationship to study drug was determined by the investigators at each of the study sites. All of the 167 AEs identified as definitely related to study drug were from the amlodipine trial ().
Investigator Perception of Relationship of Adverse Event to Study Drug
The reason for subject dropout was available for 8 of the 10 studies. The total number of dropouts from beginning of study to end of placebo-controlled phase was 149/1355 (11.0%). However, only 30/1355 (2.2%) patients left the study due to AEs. There were 76 dropout subjects identified in the published reports of the 5 trials for which we had dropout data versus 81 identified in the original data. In a regression model using treatment received during placebo-controlled phase (drug vs. placebo), sex, body mass index, and age to predict a patient experiencing an AE, we observed no effect for treatment (P=0.82) or sex (P=0.88). Higher body mass index and younger age were associated with increased risk of AEs (P=0.025 and <0.001, respectively).