Open-label Drug Research Articles

Inhaled corticosteroids do not prevent the development of asthma

Question In children with early wheezing, does the use of inhaled corticosteroids (ICS) prevent loss of lung function or reduce the incidence of asthma later in childhood? Design Randomized, double-blind, controlled study. Setting South Manchester, United Kingdom. Participants 1073 children were followed prospectively, of whom 333 were eligible, and 200 began treatment. One hundred and seventy-three completed follow-up at 5 years of age. Intervention Fluticasone propionate 100 μg twice daily in young children who were randomized after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 μg twice daily was added to the treatment. Outcomes Children’s lung function (specific airways resistance [sRaw], forced expiratory volume in 1 second [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). Main Results The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI −2.5-13.4]) vs for treatment 5.0% [−2.2-12.2], P = .87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73–1.73], P = .60) or the proportion needing the open-label drug. Conclusions The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and it did not prevent lung function decline or reduce airway reactivity. Commentary Asthma is characterized by chronic airway inflammation and obstructive lung physiology that frequently cause symptoms in early childhood. Studies in school-aged children with mild to moderate asthma demonstrated that inhaled corticosteroid (ICS) therapy improves asthma symptoms and airway hyperreactivity, but it does not improve lung function.1The Childhood Asthma Management Program Research GroupLong-term effects of budesonide or nedocromil in children with asthma.N Engl J Med. 2000; 343: 1054-1063Crossref PubMed Scopus (1297) Google Scholar Therefore, it has been hypothesized that an earlier intervention with anti-inflammatory therapy may be able to alter the natural course of asthma and prevent the decline in lung function over time. The IFWIN study instituted ICS therapy in preschool children after their second wheezing episode and failed to show any difference in lung function or asthma diagnosis at 5 years of age compared with placebo. This agrees with two recent studies (PEAK2Guilbert T.W. Morgan W.J. Zeiger R.S. Mauger D.T. Boehmer S.J. Szefler S.J. et al.Long-term inhaled corticosteroids in preschool children at high risk for asthma.N Engl J Med. 2006; 354: 1985-1997Crossref PubMed Scopus (884) Google Scholar and PAC3Bisgaard H. Hermansen M.N. Loland L. Halkjaer L.B. Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing.N Engl J Med. 2006; 354: 1998-2005Crossref PubMed Scopus (477) Google Scholar) that also did not demonstrate improvement in pulmonary function with chronic or intermittent ICS therapy in children with early wheezing. These studies suggest that the predisposition to asthma may be set very early in life and/or that development of asthma is insensitive to the effects of corticosteroids. These early treatment approaches are complicated by the high incidence of wheezing in preschool children, and the fact that these “early wheezers” are a heterogeneous population from which only a subgroup will progress to chronic asthma. Despite these findings, it is important to point out that the evidence remains strong that ICS therapy improves control of asthma symptoms in preschool children. Therefore, judicious use of ICS in early childhood is still warranted in those with chronic wheezing in accordance with established guidelines for the treatment of childhood asthma.

Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study

Wheezing and asthma often begins in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. Some researchers suggest that treatment with inhaled corticosteroids at the first signs of wheezing in childhood could prevent the development of asthma later in life. However, other investigators have reported that although such treatment could help control symptoms, the benefits can disappear within months of stopping treatment. We tested our hypothesis that to prevent loss of lung function and worsening asthma later in childhood, anti-inflammatory treatment needs to be started early in life. We did a randomised, double-blind, controlled study of inhaled fluticasone propionate 100 mug twice daily in young children who were followed prospectively and randomised after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 mug twice daily was added to the treatment. Children were followed-up to 5 years of age, at which point we gave their parents or guardians questionnaires, and measured the children's lung function (specific airways resistance [sR(aw)], forced expiratory volume in 1s [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN86717853. We followed 1073 children prospectively, of whom 333 were eligible, and 200 of these began treatment (130 male, median age 1.2 years [range 0.5-4.9]; 101 placebo, 99 treatment); 173 (85 treatment, 88 placebo) completed the follow-up at age five years. The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI -2.5 to 13.4]) vs for treatment 5.0% [-2.2 to 12.2], p=0.87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73-1.73], p=0.60), or the proportion needing the open-label drug (43 [42.57%] placebo, 41 [41.41%] treatment). The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and did not prevent lung function decline or reduce airway reactivity.

Cross-Over Trial of Intensive Monotherapy With Atorvastatin and Combined Therapy With Atorvastatin and Colestimide for Japanese Familial Hypercholesterolemia

In familial hypercholesterolemia (FH), low-density lipoprotein-cholesterol (LDL-C)-lowering therapy is important to avoid predisposition to coronary artery disease. This study investigated the advantages of combined therapy with atorvastatin and colestimide vs intensive monotherapy with atorvastatin. The trial used a randomized cross-over design consisting of 2 16-week periods of open-label drug therapy. Among the 24 initial patients, 17 heterozygous FH patients (age: 54.1 years; 5 males) were enrolled after 20 mg/day atorvastatin failed to achieve their target level. The patients received 20 mg/day atorvastatin and 3 g/day colestimide or 40 mg/day atorvastatin. Fifteen patients completed the trial and their LDL-C reduced from 5.07 +/- 1.10 mmol/L to 3.76 +/- 0.90 mmol/L with the combined therapy and to 3.81 +/- 0.50 mmol/L with the intensive monotherapy. Although the 2 therapies showed comparable mean effects for decreasing LDL-C, similar adverse reaction and cost, each therapy was predominantly more effective in some patients than in others. The triglyceride and high-density lipoprotein cholesterol levels were similar in both therapies. To achieve the therapeutic target of LDL-C level for refractory FH, the LDL-C-lowering therapy selected can be either intensive monotherapy or combined therapy as the next to standard statin therapy.

Open label study of intranasal sumatriptan (Imigran) for footballer’s headache

Objective: To study the efficacy and practicality of treating headache in professional footballers with intranasal sumatriptan. Methods: An open label drug trial was performed in elite Australian footballers using intranasal...

Comparison of Blood Pressure Control With Amlodipine and Controlled‐Release Isradipine: An Open‐Label, Drug Substitution Study

An open-label drug substitution study showed that controlled-release isradipine (Dynacirc-CR) can be safely substituted for amlodipine on a mg-for-mg basis in patients with mild-to-moderate hypertension. When controlled-release isradipine was substituted for amlodipine, blood pressure was more effectively controlled, and edema rates were reduced. When subjects resumed amlodipine therapy, the previous gain in blood pressure reduction and lessening of edema vanished. The basis for this more favorable pattern of efficacy and side-effects with controlled-release isradipine, although mechanistically unresolved, may relate to a lesser degree of sympathetic nervous system activation.

The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283)

Dapsone hydroxylamine formation is thought to be the cause of the high rates of adverse reactions to dapsone in human immunodeficiency virus (HIV)-infected individuals. Therefore we studied the effect of the commonly coadministered drugs fluconazole, clarithromycin, and rifabutin on hydroxylamine formation in individuals with HIV infection. HIV-infected subjects (CD4 + > or =200 cells/mm 3 ) were enrolled in a 2-part (A or B) open-label drug interaction study. In part A, subjects (n = 12) received dapsone (100-mg tablet once daily) alone for 2 weeks and then, in a randomly assigned order, received dapsone and either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 11) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. On the last study day of each 2-week period, plasma and urine were collected over ascorbic acid for 24 hours. In part A, fluconazole decreased the area under the plasma concentration-time curve, percent of dose excreted in 24-hour urine, and formation clearance of the hydroxylamine by 49%, 53%, and 55% (n = 12, P < .05), respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on hydroxylamine area under the plasma concentration-time curve or percent excreted in 24-hour urine but increased formation clearance of the hydroxylamine by 92% (n = 12, P < .05). Dapsone clearance was increased by rifabutin or rifabutin plus fluconazole (67% and 38%, respectively) (n = 12, P < .05) but was unaffected by fluconazole or clarithromycin. In part B, hydroxylamine production was unaffected by clarithromycin but was affected by fluconazole in a manner identical to that in part A. On the basis of these data and with the assumption that the exposure to the hydroxylamine is a determinant of dapsone toxicity, we predict that coadministration of fluconazole should decrease the rate of adverse reactions to dapsone in persons with HIV infection but that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary in light of the increase in dapsone clearance.

Rationale for a non-inferiority clinical trial design focused on subpopulations

Although double-blind, placebo-controlled clinical trials are utilized extensively to characterize the efficacy and safety of new treatment options, the characteristics of the trial participants often do not most cases, one or more patient subgroups (whether defined by race, ethnicity, co-morbidity, concomitant medication, age, or gender) will be under-represented. Understanding treatment responses in these subpopulations is a vital component of the overall therapeutic profile of a medication. Several different approaches to subgroup analyses within a single trial have been described. In addition, meta-analytic and data pooling approaches utilize results from multiple clinical trials of similar design to increase the number of patients within a targeted subgroup. If the results from exploratory analyses are suggestive of a clinically relevant difference in treatment response for a particular subgroup, then implementation of a prospectively designed clinical trial may be warranted. In this commentary, we discuss the design and results of various studies that include subgroup analyses. In addition, we describe a novel study design with a non-inferiority subpopulation analysis (NISA) that may provide new insights with respect to subgroup analyses. The NISA study design relies on characterization of the dominant group of patients recruited to date in placebo-controlled trials. In the NISA study, the group of patients with those same characteristics is referred to as the Core group. The other key features of the NISA design include non-inferiority analyses comparing subgroups to the Core group and study conditions closely aligned with routine clinical practice (heterogeneous study population and open-label drug administration without placebo). Limitations of the NISA design include the requirement of previously conducted placebo-controlled trials, the inability to compare treatment response to placebo, and that NISA has yet to be validated in practice. We also describe the implementation of the NISA study design in two ongoing clinical trials. After completion of these two studies, the practical value of the NISA design can be more thoroughly evaluated.

Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study

Objective To measure the efficacy of sulfadoxine-pyrimethamine treatment of falciparum malaria in Malawi from 1998 to 2002, after a change from chloroquine to sulfadoxine-pyrimethamine as first line treatment in that...

Efficacy and safety of sustained-release (SR)-isradipine in hypertensive patients treated with SR-amlodipine. An open-label drug substitution study

Efficacy and safety of sustained-release (SR)-isradipine in hypertensive patients treated with SR-amlodipine. An open-label drug substitution study

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

The effect of open label UT15 or bosentan on hospitalisation days in patients with pulmonary arterial hypertension (PAH)

Two novel therapies, bosentan (endothelin antagonist) and UT15 (prostacycline analogue), have been shown in randomised trials to be efficacious in patients with PAH of varying etiologies. Following end of randomised trial, 49 Class III-IV patients (bosentan n 12 and UT15 n 37), were entered to open label therapy at a single centre and survived to followup 30 Sept 2001, allowing comparison of the effect of these two therapies on hospitalisation. Etiology of PAH was primary (24), scleroderma/SLE (7), Eisenmengers (7), embolic (7) and other (4). There were 29 females, 20 males: mean age at start of open label drug 49 16 years. Mean time from symptoms to diagnosis was 15 17 months for bosentan, and 33 98 months for UT15, reflecting the inclusion of Eisenmengers in the UT15, but not bosentan trial. Hospitalisation days, adjusted for months of followup were compared for the time from symptom onset to start open label drug, and from start open label drug to the followup date. Results: Time from symptom onset to start drug was shorter for bosentan than UT15 (46 40 months vs 78 122 months, p 0.05), and time on drug to followup was also shorter (6.5 0.5 months vs 15.9 7.2 months, p 0.001). When hospital days were adjusted for duration of disease, the mean total days/month for the index disease before and after start open label bosentan were 0.186 and 0.051 (76% reduction), and for UT15 0.146 and 0.182 (25% increase). For all cause hospitalisation, including index disease, but also ulceration and amputation, mean total hospital days/ month before and after start open label bosentan were 0.188 and 0.064 (66% reduction), and for UT15 0.207 vs 0.321 (55% increase). In addition, 17% of bosentan and 70% of UT15 patients were admitted to commence drug, resulting in trial-related hospital days of 0.58 1.38 vs 2.54 2.08, p 0.0044 respectively. Conclusions: Bosentan, but not UT15, appears to reduce timeadjusted hospitalisation rates in patients with PAH, both for the index disease and for inter-related causes. 290

The effects of postal and telephone reminders on compliance with pravastatin therapy in a national registry: results of the First Myocardial Infarction Risk Reduction Program

Background: Noncompliance with cardiovascular therapy and prevention initiatives is well documented. Objectives: The purpose of the First Myocardial Infarction (MI) Risk Reduction Program, an open-label drug registry involving mainly primary-care patients at increased risk of a first MI, was to examine the effects of postal and telephone reminders, as well as demographic and other baseline characteristics, on patient self-reported compliance with pravastatin treatment. A second objective was to determine whether regimen adherence was associated with the adoption of other lifestyle modifications recommended to decrease the risk of coronary artery disease. Methods: Patients with risk scores of ≥4 on a scale of −1 to +16 for men and −1 to +17 for women on the First Heart Attack Risk Test were considered to be at increased risk of a first MI and eligible for enrollment in the registry program. An elevated total cholesterol level despite dietary interventions was an additional inclusion criterion. Patients were prospectively randomized (4:1) to either an intervention involving postal and telephone reminders (about coronary risk reduction and medication compliance), which were sent during the first 2 months of pravastatin treatment, or usual care. Both groups received reminder postcards at 4 and 5 months, in addition to counseling by physicians about coronary risk reduction. At 3 and 6 months (or study discontinuation), patients completed and mailed to the program-coordinating center questionnaires concerning compliance with care, including current use of prescribed pravastatin, as well as self-reported adoption of other lifestyle modifications, such as changing eating habits, losing weight, increasing physical activity, and/or quitting smoking. Compliance with pravastatin therapy and with these coronary risk—reducing behaviors was also assessed by physicians at the 3-month follow-up visit. Results: A total of 10,335 patients were in the intervention group, and 2765 received usual care. The 2 groups were well balanced at baseline with respect to age, race, and total cholesterol values. Neither early reminders nor baseline patient characteristics were significantly associated with reported pravastatin compliance rates, which were ∼79% overall. However, according to self-reports at 6 months, regimen compliance was associated with the adoption of other coronary risk—reducing behaviors. Conclusions: The results of this study suggest that early telephone and postal reminders do not improve compliance with drug treatment or with recommended coronary risk—reducing behaviors.

Tacrine and nursing home placement

To the Editor: We read with interest the article Long-term tacrine (Cognex, Parke-Davis, Morris Plains, NJ) treatment: effects on nursing home placement and mortality.1 While the analysis is of great interest to many in the field of Alzheimer's disease, and the authors point out several limitations of the dataset, a further cautionary note is warranted because of the potential biases when utilizing a dataset consisting of a highly selected subgroup of patients on open-label drug. With respect to the analysis for nursing home placement or mortality performed during the 30-week double-blind phase, there are a number of …

Events in the cardiac arrhythmia suppression trial (CAST): Mortality in patients surviving open label titration but not randomized to double-blind therapy

The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial (CAST) and who were not randomized to double-blind therapy and in 942 patients, who were randomized to double-blind placebo therapy. The patients randomized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate (4% vs. 8.5%). However, at baseline, nonrandomized patients were dissimilar from patients randomized to placebo in the following ways: older; lower left ventricular ejection fraction; greater use of digitalis, diuretic drugs and antihypertensive agents; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems, including runs of ventricular tachycardia and left bundle branch block. A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonrandomized patients and clinically equivalent patients randomized to placebo. Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonrandomized patients: female gender (4.7, p less than 0.05) and electrocardiographic events (ventricular tachycardia, proarrhythmia, widened QRS complex, heart block, bradycardia) during open label titration (7.0, p less than 0.005). However, some potentially important differences between men and women were not included in the Cox regression model. Of the nonrandomized patients, approximately 70% were not randomized because of lack of suppression of ventricular premature depolarizations or adverse events, or both, and the remaining 30% because of patient or private physician request with no indication of another reason.(ABSTRACT TRUNCATED AT 250 WORDS)

Events in the cardiac arrhythmia suppression trial (CAST): Mortality in the entire population enrolled

To test the hypothesis that suppression of ventricular arrhythmias by antiarrhythmic drugs after myocardial infarction improves survival, the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. Suppression was evaluated before randomization during an open label titration period. Patients whose arrhythmias were suppressed were randomized in the main study and those whose arrhythmias were partially suppressed were randomized in a substudy. Overall survival and survival free of arrhythmic death or cardiac arrest were lower [corrected] in patients treated with encainide or flecainide than in patients treated with placebo. However, the death rate in patients randomized to placebo therapy was lower than expected. This report describes the survival experience of all patients enrolled in CAST and compares it with mortality in other studies of patients with ventricular arrhythmias after myocardial infarction. As of April 18, 1989, 2,371 patients had enrolled in CAST and entered prerandomization, open label titration: 1,913 (81%) were randomized to double-blind, placebo-controlled therapy (1,775 patients whose arrhythmias were suppressed and 138 patients whose arrhythmias were partially suppressed during open label titration); and 458 patients (19%) were not randomized because they were still in titration, had died during titration or had withdrawn. Including all patients who enrolled in CAST, the actuarial (Kaplan-Meier) estimate of 1-year mortality was 10.3%. To estimate the "natural" mortality rate of patients enrolled in CAST, an analysis was done that adjusted for deaths that might be attributable to encainide or flecainide treatment either during prerandomization, open label drug titration or after randomization. Because the censoring procedure excluded patients treated with encainide or flecainide after randomization, the mortality estimate will be less than the unadjusted mortality estimate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)