Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children?
We evaluated the efficacy, safety, and dose–response relationship of fosinopril in children aged 6 to 16 years with hypertension or high-normal blood pressure with an associated medical condition requiring treatment. The study was a prospective, double-blind, placebo-controlled trial conducted in 78 clinical sites in the United States, Russia, and Israel. There were 4 phases: a screening phase of 10 days maximum, a 4-week dose–response phase, a placebo withdrawal phase of 2 weeks maximum, and a 52-week open-label safety phase. The primary objective of the dose–response phase was to determine whether low (0.1 mg/kg), medium (0.3 mg/kg), or high (0.6 mg/kg) doses of fosinopril based on established adult dosing affect trough seated systolic blood pressure. During the dose–response phase, all 3 doses were equally effective in lowering systolic blood pressure. During the placebo withdrawal phase, there was an adjusted mean systolic blood pressure increase of 5.2 mm Hg for the placebo group and 1.5 mm Hg for the fosinopril group, a net withdrawal effect of 3.7 mm Hg (P=0.013). Fosinopril was well tolerated; serious adverse events occurred infrequently and were generally not attributed to fosinopril. Because children appear to be more sensitive to lower doses of fosinopril than adults, starting doses for children should be ≤0.1 mg/kg.
Systemic hypertension occurs in an estimated 1% to 2% of the pediatric population,1–5 and the prevalence is increasing because of the epidemic of childhood obesity and insulin resistance.6–7 Thus, there is a growing need for data on antihypertensive medications in children. Few antihypertensive medications have been studied in children, and many of the trials that were done lacked appropriate controls, were of retrospective design, or had inadequate numbers of patients.8 This is of particular concern because a substantial number of children with hypertension have underlying systemic diseases that might influence metabolism, dosing, efficacy, and safety.
Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension in children. There are only 2 published well-controlled trials of ACE inhibitor use in hypertensive children.9,10 This study was designed to evaluate the efficacy, safety, and dose–response relationship of fosinopril in hypertensive children. Fosinopril is a phosphorus-containing ACE inhibitor that is hydrolyzed to pharmacologically active fosinoprilat, a potent ACE inhibitor cleared almost equally by renal and hepatic routes. This balanced elimination route has potential benefit to patients with impaired kidney function. This study is the largest multicenter, prospective, double-blind, controlled trial of ACE inhibitor use in children to date.
The study procedures were approved by the institutional review boards at each institution. Informed parental consent and patient assent were obtained. Enrolling sites included 45 in the United States, 4 in Israel, and 11 in Russia (see Appendix). Eligible patients were aged 6 to 16 years with either hypertension or high-normal blood pressure (BP) with an associated clinical condition such as diabetes mellitus. Hypertension was defined as having 3 sequential systolic BP (SBP) or diastolic BP (DBP) measurements >95th percentile for gender, age, and height, as defined by the Task Force on High Blood Pressure Control in Children.11 High-normal BP meant having SBP or DBP >90th percentile but ≤95th percentile. BP measurements were obtained with the device for indirect noninvasive automatic mean arterial pressure (Dinamap, Critikon). Patients already receiving antihypertensive medication were eligible provided that medication was washed-out for up to 10 days.
The study periods included a maximum 10-day screening period followed by a fosinopril test dose of 0.1 mg/kg (Period A); a 4-week randomized dose-ranging phase of low (0.1 mg/kg), medium (0.3 mg/kg), and high (0.6 mg/kg) doses of fosinopril (Period B); a maximum 2-week randomized placebo withdrawal phase (Period C); and a 52-week open-label safety study (Period D; Figure). During Period D, fosinopril could be titrated from 0.1 mg/kg to 0.6 mg/kg to achieve target BP control (defined by SBP and DBP <90th percentile for age, gender, and height). Adjunctive antihypertensive agents were allowed only during Period D. The maximum dose permitted during all phases was 40 mg, the recommended adult dosage of fosinopril. Subjects weighing >60 kg were given 10, 20, or 40 mg daily in the low-, medium-, and high-dose groups, respectively.
The primary efficacy measure was the change in trough SBP from baseline in patients treated with low-, medium-, and high-dose fosinopril in Period B. The secondary efficacy measures were: (1) change from baseline in trough DBP for low-, medium-, and high-dose fosinopril-treated patients after Period B; (2) change in trough SBP or DBP from the end of Period B to the end of Period C in fosinopril-treated patients (all 3 levels combined) compared with placebo-treated patients; (3) percent of patients with both SBP and DBP <90th percentile at the end of Period B; and (4) safety evaluation of adverse events and laboratory abnormalities. The proportional contrast coefficients used to determine sample size for the dose–response phase assumed that the true response in SBP is linear in dose and differs by 6.0 mm Hg between the high and low doses with a standard deviation of 12 mm Hg.12 A sample size of 62 subjects per dose level provides 80% power to detect a change from baseline in SBP across the 3 dose regimens with a 2-sided test of contrast at the 0.05 level.
Comparisons between regimen groups (Period B) and treatment groups (Period C) were carried out for SBP and DBP by ANCOVA by baseline measurement. Additional analysis included adjustment of the primary ANCOVA model for baseline variables such as renal disease and hematologic parameters. Effects of fosinopril on BP in relation to patient weight were also examined.
In all, 376 patients were screened. Of these, 255 met eligibility criteria and received the fosinopril test dose. One patient experienced an adverse event (anisocoria); another’s SBP dropped >20 mm Hg. A total of 253 patients were randomly assigned to double-blind therapy. Baseline demographics were similar in the 3 treatment regimens (Table 1).
Dose–Response Period (Period B)
Of 253 patients that entered Period B, 14 did not complete it: 3 patients did not tolerate uptitration of the study drug after 1 week of double-blind treatment (they were then enrolled in the open-label phase [Period D]), 6 patients or their parents withdrew consent, 1 patient did not comply, 1 patient experienced an adverse event (hyperkalemia), 1 patient had an unspecified laboratory abnormality, and 2 patients were lost to follow-up.
In the primary (intent-to-treat) analysis of SBP change from baseline to Week 4 of Period B, the adjusted mean changes from baseline were −10.9 (low dose), −11.3 (medium dose), and −11.9 mm Hg (high dose; Table 2). The test for trend across these fosinopril treatment groups did not show a dose–response relationship (P=0.53). For DBP, the adjusted mean changes from baseline were −4.5 (low dose), −4.2 (medium dose), and −5.1 mm Hg (high dose). Again, there was no evidence of a fosinopril dose–response relationship (P=0.52).
At Week 4 of Period B, the proportions of patients who reached target BP were 45% (low dose), 47% (medium dose), and 42% (high dose). There was no evidence of a dose–response relationship. Even after adjustment for renal, hematologic, and demographic covariates, no dose–response relationship emerged. In addition, study data were analyzed for 2 weight groups: <60 kg and ≥60 kg. After adjustment for weight and body surface area, there was still no evident dose–response relationship.
Randomized Withdrawal Period (Period C)
Of 235 patients in Period C, 13 ended participation prematurely. Six patients became hypertensive and were directly enrolled in Period D, and 7 withdrew completely (1 moved outside the study area, 1 could not make the scheduled visits, 1 had a predose BP within the 90th percentile, and 1 withdrew at the institutional review board’s request because it was later found that the patient did not meet inclusion criteria.)
Both the placebo group and the group remaining on any fosinopril had increased SBP and DBP (Table 3). For both variables, however, the increase was greater for the placebo group. The adjusted mean increases in SBP were 5.2 mm Hg for placebo and 1.5 mm Hg for fosinopril, a net withdrawal effect of 3.7 mm Hg (P=0.013). The adjusted mean increases in DBP were 1.7 mm Hg (placebo) and 0.1 mm Hg (fosinopril), a net effect of 1.6 mm Hg (P=0.104).
Of placebo patients, 32% (95% confidence interval, 0.24 to 0.41) reached target BP at Week 2 of Period C; of the combined fosinopril groups, 43% (95% confidence interval, 0.34 to 0.53) did. Fosinopril patients received a relative benefit of 1.35 compared with those who received placebo (proportion normalized on fosinopril/proportion normalized on placebo).
Open-Label Period (Period D)
Of 209 patients in Period D, 174 (83%) successfully reached target BP. For analysis purposes, doses were rounded to either 0.1, 0.3, or 0.6 mg/kg. Doses ≥0.1 and <0.3 mg/kg were considered low, ≥0.3 and <0.6 mg/kg were medium, and ≥0.6 mg/kg were high.
Of 174 responders, 84.5% were in the low-dose group, 12.6% were in the medium-dose group, and 2.8% were in the high-dose group. All 174 achieved BP control with ≤40 mg/d. With all fosinopril doses combined, mean SBP reduction from baseline to trough at 52 weeks was 13 mm Hg. For trough DBP the mean reduction was 8.3 mm Hg at 52 weeks. The proportions of patients reaching target BP ranged from 40% to 60%. The effects are comparable or superior to those achieved during Period B. The benefits of fosinopril were maintained long-term; after more than a year, there was no evidence fosinopril lost its effectiveness.
The safety and tolerability of fosinopril was evaluated based on clinical adverse events, laboratory abnormalities, changes from baseline in standard safety laboratory analysis, and changes in physical examinations. No deaths occurred during the study. Five patients discontinued the study because of adverse events. None of the patients with a renal etiology for hypertension (20.9%) discontinued because of adverse events. One patient developed anisocoria after receiving the fosinopril test dose, which was “probably unrelated” to the study treatment per the investigator’s assessment. One patient on 0.3 mg/kg fosinopril developed hyperkalemia (serum potassium concentration of 6.6 mmol/L), “probably related” to the study treatment. One patient on placebo in Period C developed an increased serum bilirubin concentration, “possibly related” to study treatment. Two patients discontinued treatment during Period D because of elevated creatine kinase (CK) levels. There were 2 adverse events in patients who continued in the study: 1 patient exhibited “psychiatric negativism” before treatment, and 1 patient taking 0.1 mg/kg fosinopril in Period B developed transient torticollis.
During Period C, the incidence of adverse events was similar between placebo (33.9%) and combined fosinopril treatment groups (34.3%). During Period D, the following events were reported in ≥3% patients: headache (20.1%), nasopharyngitis (9.6%), cough (9.1%), pharyngitis (8.6%), and nonspecific abdominal pain (6.2%). None of these events were persistent or severe.
Elevated serum creatinine was the most frequently occurring laboratory abnormality (8.9% fosinopril patients versus 4.1% placebo). All elevations were transient and did not exceed the upper limit of the normal.
Several patients had serum CK levels elevated ≥3× the upper limit of normal during double-blind and open-label therapy (7 patients in Period B, 11 in Period C [6 placebo and 5 fosinopril], 13 in Period D). These elevations were transient with no clinical evidence of related myalgia. Most patients with CK elevation >3× the upper limit of normal also had elevated baseline CK levels, making an association with fosinopril unclear.
The US Food and Drug Administration Modernization Act of 1997 and the Best Pharmaceuticals for Children Act of 2002 have increased the standards for pharmaceutical trials in children. These initiatives offer extension of patent exclusivity for approved clinical trials of mediations with pediatric indications. As a result of this legislation, there has been an increase in clinical trials in childhood hypertension. Fosinopril is included on the Food and Drug Administration Pediatric Priority List of drugs for which additional pediatric information may produce health benefits in the pediatric population (http://www.fda.gov/cder/pediatric/peddrugsfinal.htm).
Rationale for dose selection was based on a recent pharmacokinetic study of fosinoprilat in children that showed a strong positive bivariate correlation with age, body weight, and body surface area for peak plasma concentration and area under the curve (http://www.fda.gov/cder/foi/esum/2003/19915s037.pdf). The fosinopril doses used in this study were selected by determining the per-kilogram dose of fosinopril for a 70-kg adult for both the lowest (0.14 mg/kg) and highest (0.57 mg/kg) doses approved for the treatment of hypertension. Using these per-kilogram doses as a reference, the low dose for this study was 0.1 mg/kg, the medium dose 0.3 mg/kg, and the high dose 0.6 mg/kg.
In adults, there is a dose–response relationship with fosinopril treatment for both SBP and DBP up to doses of 40 mg/d. The 10-mg dose is not consistently different from placebo.12 In this study, the absence of a dose–response effect in children could be because there is no such effect or because all doses were too high. In the withdrawal phase, the placebo group had greater SBP increases than the fosinopril group, indicating all 3 fosinopril doses were effective in reducing SBP. The unexpected sensitivity to lower doses of fosinopril suggests that starting doses for children should be ≤0.1 mg/kg.
Fosinopril was generally well tolerated in children. Serious adverse events occurred infrequently and were rarely attributed to fosinopril. There were few study discontinuations because of adverse events.
The incidence of pediatric hypertension is increasing. Thus, efficacy and safety data of antihypertensive drugs in this population are needed. Children aged 6 to 16 years with hypertension or high-normal BP with concomitant illness or risk factors treated with 0.1 to 0.6 mg/kg fosinopril demonstrated substantial mean decreases in SBP and DBP. Doses were extrapolated from adult data, but no dose–response relationship was evident. Withdrawal of fosinopril resulted in a partial increase in BP, especially in SBP, where a statistically significant difference of 3.7 mm Hg existed between patients who underwent treatment withdrawal compared with no withdrawal. Responder rates were 40% to 60% for the short-term and long-term treatment periods. There was no evidence of decreased effectiveness during long-term treatment. Fosinopril is safe and well tolerated, with an adverse event profile similar to that observed in adults with hypertension.
Israel: Daniel Landau, Soroka Medical Center, Beer Sheva; Daniel Lotan, Sheba Medical Center, Tel Hashomer Hospital, Ramat Gan; Avi-Shalom Pomeranz, Sapir Medical Center, Meir Hospital, Kfar Sava; Irit Weisman, Western Galilee Hospital, Nahariya. Russia: Elena Basargina, Children’s Health Research Center, Moscow; Igor Briazgounov, Children’s Health Research Center, Moscow; Ludmila Kozlova, Smolensk State Medical Academy; Leonid Makarov, Moscow Institute of Pediatry and Children Surgery; Galina Rimarchuk, Moscow Regional Clinical Research Institute; Galina Samsygina, Russian State Medical University, Moscow; Maria Shkolnikova, Moscow Institute of Pediatry and Children Surgery; Eugeny Shlyakhto, Cardiology Research Institute, St. Petersburg; Yury Titkov, Central Medico-Sanitary Department, St. Petersburg; Ludmila Zharkova, Smolensk State Medical Academy; Dmitry Zotov, City Children’s Out-Patient Clinic #35, St. Petersburg. United States: Donald Batisky, Pediatric Clinical Trials International, Columbus, Ohio; Stuart Berger, Children’s Hospital of Wisconsin, Milwaukee; Andrew Brem, Rhode Island Hospital, Providence; Leonardo Canessa, Children’s Medical Center, Dayton, Ohio; Carol Cottrill, Pediatric Cardiology, PSC, Lexington, Ky; Robert Cunningham, Cleveland Clinic Foundation, Ohio; Stephen Daniels, Children’s Hospital Medical Center, Cincinnati, Ohio; Craig Fleishman, Nemours Cardiac Center, Orlando, Fla; Joseph Flynn, Montefiore Medical Center, Bronx, NY; Paul Saenger, Montefiore Medical Center, Bronx, NY; Raul Gaona, Pro Research Group, San Antonio, Tex; Jeremy Gitomer, Marshfield Clinic, Wis; Ann Guillot, Vermont Childrens Hospital, Childrens Specialty Center, Burlington; Coral Hanevold, Medical College of Georgia Health, Inc, Augusta; Boyde Harrison, Winston Physicians Services, LCC, Haleyville, Ala; Lydia Hazan, Impact Clinical Trials, Los Angeles, Calif; Ronald Hogg, Medical City Dallas Hospital, Tex; Tracy Hunley, Vanderbilt Children’s Hospital, Nashville, Tenn; Randall Jenkins, Northwest Pediatric Kidney Specialists, Portland, Ore; Mark Johnson, St. Louis Children’s Hospital, Mo; Prapti Kanani, Children’s Hospital of Pittsburgh, Pa; Howard Knapp, Deaconess Billings Clinic, Billings, Mont; Linda Lear, Bluegrass Community Research, Inc, Lexington, Ky; Susan Massengill, Carolinas Medical Center, Charlotte, NC; Tej Mattoo, Children’s Hospital of Michigan, Detroit; Daniel McKenney, East Carolina University School of Medicine, Greenville, NC; Susan Mendley, University of Maryland Medical Center, Baltimore; Kenneth Miller, Nephrology and Hypertension Consultants, Park Ridge, Ill; James Musgrave, Kapiolani Medical Center for Women, Honolulu, Hawaii; Naomi Neufeld, Neufeld Medical Group, Inc, Los Angeles, Calif; Victoria Norwood, University of Virginia School of Medicine, Charlottesville; Ana Paredes, Miami Children’s Hospital, Fla; Ronald Portman, University of Texas Health Science Center, Houston; Eric Quivers, Children’s National Medical Center, Washington, DC; Jorge Ramirez, Nemours Children’s Clinic, Orlando, Fla; William Riley, Driscoll Children’s Hospital, Corpus Christi, Tex; Daeyoung Roh, Nephrology Associates Medical Group, Inc, Riverside, Calif; Bertrand Ross, Children’s Hospital of the King’s Daughters, Norfolk, Va; Stephen Sanders, Duke University Medical Center, Durham, NC; Thomas Scholz, University of Iowa College of Medicine, Iowa City; George Schwartz, University of Rochester Medical Center, NY; Melville Singer, Children’s Hospital of Orange County P.S.F., Inc, Orange, Calif; Elaine Urbina, Tulane University Health Sciences Center, New Orleans, La; Marcela Vergara, Schneider Children’s Hospital, New Hyde Park, NY; Thomas Wells, Arkansas Children’s Hospital, Little Rock.
Bristol-Myers Squibb Company generously supported this study.
- Received March 23, 2004.
- Revision received April 8, 2004.
- Accepted June 25, 2004.
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