Methods for therapeutic trials in COPD: lessons from the TORCH trial.

The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.

Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited.

Various statistical methods have been used to measure the impact of treatment on chronic obstructive pulmonary disease (COPD) exacerbations. Poisson regression has recently been recommended as the appropriate method but the model does not satisfactorily account for variability between patients. In contrast, use of a negative binomial model, which corresponds to assuming a separate Poisson parameter for each patient, offers a more appealing approach. The present paper reviews analysis methods, with particular focus on the negative binomial model. To illustrate the differences that arise from using different analysis methods, we have reanalysed data from two large studies which, among other objectives, investigated the effectiveness of inhaled corticosteroids in reducing COPD exacerbation rates. Using the negative binomial model to reanalyse data from the TRISTAN and ISOLDE studies, the overall estimates of exacerbation rates on each treatment arm are higher and the confidence intervals for comparisons between treatments are wider, but the overall conclusions of TRISTAN and ISOLDE regarding reduction of exacerbations remain unchanged. The negative binomial approach appears to provide a better fit to the distribution of the data than earlier methods and is currently the method of choice. Research needs to continue on further methods to improve the analysis of exacerbation data.

Diagnosis of influenza in the community: relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza.

BACKGROUND: Successful treatment of influenza depends on an accurate diagnosis of the illness and prompt intervention. However, there is a lack of data comparing clinical diagnosis vs laboratory diagnostic techniques. OBJECTIVE: To compare the clinical diagnosis of community cases of influenza with various laboratory diagnostic techniques including multiplex, reverse transcription polymerase chain reaction. METHODS: Clinical diagnosis, viral isolation, hemagglutinin inhibition serology, and multiplex, reverse transcription polymerase chain reaction were used to diagnose influenza in patients enrolled in international phase 3 studies designed to investigate the efficacy and safety of an anti-influenza drug (inhaled zanamivir). Patients clinically diagnosed with influenza were enrolled at centers across North America and Europe. RESULTS: A total of 791 (77%) of 1033 patients with laboratory results from all 3 methods were confirmed positive for influenza by 1 or more test results. For 692 patients (67%), the results of all 3 tests agreed. Total symptom scores at baseline showed a significant association toward greater severity of symptoms with an increasing number of positive test results (P<.001). An increasing number of positive test results also showed a significant correlation with a longer time to alleviation of symptoms of influenza in the placebo group (P =.001). CONCLUSIONS: During a time when influenza was known to be circulating and clinical diagnostic criteria were applied, diagnosis of influenza in these trials was accurate in approximately 77% of adults on clinical grounds alone. This highlights the need for primary care physicians to be alerted to circulating influenza and to be aware that presentation with cough and fever provide the most predictive symptoms.

Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials.

BACKGROUND: Influenza can cause significant morbidity and mortality, particularly in patients considered to be at high risk (such as the elderly and those with chronic disease) of developing influenza-related complications. Data on the efficacy of zanamivir in high-risk patients are lacking because individual studies recruited a limited number of these patients. METHODS: A retrospective pooled analysis of data from high-risk patients in studies completed before or during the 1998-1999 winter season was performed to investigate the efficacy and safety of inhaled zanamivir (10 mg twice daily for 5 days) for the treatment of confirmed influenza. All studies were randomized, double-blind, and placebo-controlled with 21- to 28-day follow-up. A total of 2751 patients was recruited. Of these, 321 (12%) were considered high risk and 154 were randomized to zanamivir. The median time to alleviation of influenza symptoms and time to return to normal activities were the main outcome measures. RESULTS: Zanamivir-treated high-risk patients had a treatment benefit of 2.5 days compared with those given placebo (P = .015). Patients treated with zanamivir returned to normal activities 3.0 days earlier (P = .022) and had an 11% reduction (P = .039) in the median total symptom score over 1 to 5 days relative to those taking placebo. In addition, zanamivir reduced the incidence of complications requiring antibiotic use by 43% relative to placebo users (P = .045). Adverse events reported were of a similar nature and frequency between the two groups. CONCLUSION: This pooled analysis shows that zanamivir is an effective and well-tolerated treatment for influenza in patients considered at high-risk of developing influenza-related complications.

Impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults.

BACKGROUND: Influenza infections commonly lead to respiratory tract complications that result in antibiotic treatment. OBJECTIVES: To determine frequency of respiratory events leading to antibiotic use following influenza illness in adolescents and adults, and to assess whether treatment with topical zanamivir prevents these complications. METHODS: Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal zanamivir, inhaled zanamivir, or corresponding placebos. Twelve percent of enrolled subjects were high-risk patients. The main outcome was the incidence of respiratory events leading to antibiotic prescriptions in patients with proven influenza. RESULTS: Influenza infections were laboratory confirmed in 2499 (66%) of 3815 patients (influenza A in 88% and B in 12%). Placebo recipients developed a respiratory event leading to antibiotic use in 17% of cases, mainly for acute bronchitis or acute sinusitis. Among zanamivir-treated patients (n = 1494) the incidence of respiratory events leading to the use of antimicrobials was 11% (relative risk [RR] compared with placebo, 0.69; 95% confidence interval [CI], 0.57-0.84). Intranasal and inhaled zanamivir seemed to reduce the number of upper (RR, 0.59; 95% CI, 0.36-0.97) and lower respiratory tract events (RR, 0.64; 95% CI, 0.38-1.08). Inhaled zanamivir reduced the number of lower respiratory tract events (RR, 0.60; 95% CI, 0.42-0.85), but the reduction in the number of upper respiratory tract events was not statistically significant (RR, 0.90; 95% CI, 0.63-1.27). CONCLUSIONS: Respiratory complications or worsening of symptoms leading to antibiotic use occurred in about 17% of adolescents or adults with influenza infection. Early treatment of influenza illness with zanamivir reduced the number of these antibiotic prescriptions. Arch Intern Med. 2000;160:3234-3240.

Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial.

BACKGROUND: Influenza infection rates are higher in children than in other age groups. This study evaluated the efficacy, safety and tolerability of a 5-day course of twice daily inhaled zanamivir, 10 mg, compared with placebo in the treatment of symptomatic influenza A and B viral infections among children 5 to 12 years of age. METHODS: This double blind, randomized, placebo-controlled, parallel group, multicenter study conducted in the Northern Hemisphere during the 1998 and 1999 influenza season enrolled 471 patients with influenza-like symptoms for < or = 36 h. Patients were randomly assigned to zanamivir (n = 224) or placebo (n = 247). Symptoms were recorded on diary cards twice daily during treatment, for 9 days after treatment and for 14 additional days (if still reporting moderate/severe cough and/or taking relief medication). FINDINGS: A total of 346 (73%) patients were influenza-positive by culture, serology or polymerase chain reaction (65% influenza A, 35% influenza B). Zanamivir reduced the median time to symptom alleviation by 1.25 days compared with placebo among patients with confirmed influenza infection (P < 0.001). Zanamivir-treated patients returned to normal activities significantly faster and took significantly fewer relief medications than placebo-treated patients. Zanamivir was well-tolerated, demonstrating adverse event profiles similar to those of placebo and no clinically significant changes in laboratory findings. Viral susceptibility testing revealed no zanamivir-resistant strains of influenza A or B. CONCLUSIONS: Zanamivir was effective in shortening the duration and severity of influenza symptoms and was well-tolerated among children 5 to 12 years of age.

Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study.

OBJECTIVES: To assess the clinical efficacy and safety of orally inhaled zanamivir in the treatment of influenza in a European primary care setting. METHODS: This was a randomized, double-blind, placebo-controlled trial in primary care and hospital clinics in 11 European countries. Patients aged > or = 12 years were recruited within 2 days of onset of typical influenza symptoms and received orally inhaled zanamivir 10 mg via a Diskhaler twice daily for 5 days or matching placebo. Influenza symptoms and temperature were recorded daily for 14 days. The primary endpoint was time to alleviation of clinically significant symptoms of influenza. Other endpoints included symptom severity, use of relief medications, time to return to normal activities, complications and investigator's assessment of symptoms. RESULTS: A total of 356 patients were recruited; 277 (78%) had laboratory-confirmed influenza and 32 (9%) were considered high-risk (i.e. elderly or with underlying medical conditions). Zanamivir significantly reduced the time to alleviation of symptoms versus placebo (median 5 days versus 7.5 days, P<0.001), a 33% reduction in duration of illness. Zanamivir significantly reduced the severity of several symptoms; improvements versus placebo were discernible after approximately 24 h. The proportion of patients who were afebrile after 24 h increased by 46% versus placebo. Similar treatment benefits were observed in the high-risk patients. Zanamivir was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: Zanamivir is effective in reducing the duration and severity of influenza illness and is well tolerated. Zanamivir should therefore be a clinically valuable intervention in the management of influenza.

Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study.

We explored the prophylactic activity of zanamivir after presumed exposure to influenza in the community. After close contacts with index cases of influenza-like illnesses, 575 subjects were randomized in 4 treatment groups: 144 received placebo, 141 received intranasal zanamivir, 144 received inhaled zanamivir, and 146 received inhaled plus intranasal zanamivir for 5 days. Of 25 subjects (4%) who developed symptomatic influenza during the 5 days of prophylaxis, 9 (36%) were in the placebo group, 8 (32%) were in the intranasal zanamivir group (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.30-2.72; P=.855), 3 (12%) were in the inhaled zanamivir group (OR, 0.27; 95% CI, 0.07-1.05; P=.058), and 5 (20%) were in the inhaled plus intranasal zanamivir group (OR, 0.52; 95% CI, 0.17-1.58; P=.247). Short-term treatment with intranasal zanamivir was ineffective. However, inhaled zanamivir treatment reduced the rate of influenza, which was 2%-3% among zanamivir recipients versus 6% among placebo recipients. Additional studies assessing a longer duration of postcontact prophylaxis are warranted.

Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections.

The efficacy and safety of zanamivir, administered 2x or 4x daily over 5 days, was evaluated in the treatment of influenza infections. A total of 1256 patients entered the study; 57% of those randomized had laboratory-confirmed influenza infection. The primary end point, "alleviation of major symptoms," was created to evaluate differences in clinical impact. In the overall population with or without influenza infection, zanamivir reduced the median number of days to reach this end point by 1 day (P=.012 2x daily vs. placebo; P=.014 4x daily vs. placebo). The reduction was greater in patients treated within 30 h of symptom onset, febrile at study entry, and in defined high-risk groups. Zanamivir reduced nights of disturbed sleep, time to resumption of normal activities, and use of symptom relief medications. It was well tolerated. These results suggest that zanamivir can significantly reduce the duration and overall symptomatic effect of influenza.

Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis.

Zanamivir, a potent, highly selective inhibitor of influenza virus A and B neuraminidase, has been evaluated in seven, similarly designed, placebo-controlled studies of the treatment of influenza. Patients with typical influenza symptoms were recruited when influenza was known to be circulating in the community. Six of these studies included a zanamivir 10 mg inhaled bd (for 5 days) treatment arm, the dose regimen submitted to regulatory agencies. Pooled analyses were conducted to evaluate efficacy more precisely in terms of the alleviation of symptoms in population subgroups and for secondary endpoints. Median time to alleviation of symptoms, the primary endpoint, was reduced from 6.0 days in the placebo group (n = 1,102) to 5.0 days in the zanamivir group (n = 1,133), P< 0.001. In febrile, laboratory-confirmed, influenza-positive (IP) patients, time to alleviation was reduced from 6.5 days to 5.0 days, a treatment benefit of 1.5 days (P < 0.001). A larger treatment benefit (3 days) was seen in IP patients who had severe symptoms at entry (n = 474, P < 0.001), compared with 1 day in patients whose symptoms were not severe (n = 1,098, P< 0.001). Similarly, a 3 day treatment benefit (P = 0.003) was observed in IP patients aged >50 years (n = 263), compared with 1 day (P < 0.001) in patients aged <50 years. In 'high-risk' IP patients (recruited into all treatment studies), there was a treatment benefit of 2.5 days (n = 305, P = 0.006). Pooled analyses of secondary endpoints showed statistically significant reductions in antibiotic use, time to return to normal activities and use of relief medication. In addition, reductions in symptom scores were apparent shortly after commencing zanamivir treatment. By the evening of the second day of treatment, the median total symptom score had fallen by 44% in zanamivir recipients compared with 33% in placebo recipients (P < 0.001). These results highlight the groups likely to show greatest benefit from zanamivir treatment, and confirm the clinical relevance of the treatment benefit.

Evaluation of different partial AUCs as indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

The performance of different partial AUCs, including partial AUC from zero to t(max) of the reference formulation (AUC(r)) and partial AUC from zero to tmax of test or reference formulation, whichever occurs earliest (AUC(e), as indirect measures of rate of absorption have been evaluated using simulated experiments. The performance of these metrics relative to C(max), t(max) and C(max)/AUC(infinity) was further assessed using the results of actual studies involving a Glaxo drug. The normalised metrics AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) have also been evaluated. Our provisional conclusions were: (1) AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) had greater statistical power than C(max) and the non-normalised partial AUCs at detecting true differences in rate of absorption. Using real data, the performance of AUC(e)/AUC(infinity) was poor, however, the performance of AUC(r)/AUC(infinity) was good; (2) C(max)/AUC(infinity) was more precisely estimated than AUC(r)/AUC(infinity) or AUC(e)/AUC(infinity) and may be a superior metric for assessing absorption rates of highly variable drugs.

Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group.

BACKGROUND: The sialic acid analogue zanamivir (GG167) is a selective inhibitor of influenza A and B virus neuraminidases. These viral enzymes are essential for the release of virus from infected cells, and they may also reduce the inactivation of virus by respiratory secretions. When administered experimentally directly to the respiratory tract, zanamivir has potent antiviral effects. We assessed the therapeutic activity of zanamivir in adults with acute influenza. METHODS: We conducted separate randomized, double-blind studies in 38 centers in North America and 32 centers in Europe during the influenza season of 1994-1995. A total of 417 adults with influenza-like illness of < or =48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by inhalation plus placebo spray, or placebo by both routes. Treatments were self-administered twice daily for five days. RESULTS: Of 262 patients with confirmed influenza-virus infection (63 percent of all patients), the median length of time to the alleviation of all major symptoms was one day shorter (four days vs. five days) in the 88 patients given inhaled and intranasal zanamivir (P=0.02) and the 85 patients given inhaled zanamivir alone (P=0.05) than in the 89 patients given placebo. Among the infected patients who were febrile at enrollment and among those who began treatment within 30 hours after the onset of symptoms, the median time to the alleviation of major symptoms was four days in both zanamivir groups and seven days in the placebo group (P< or =0.01). Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group. The topically administered zanamivir was well tolerated. CONCLUSIONS: In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early.

Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed?

We investigated the hypothesis that distributions of continuous pharmacokinetic variables are positively skewed in nature and that logarithmic transformation of these variables restores normality. The distributions of common continuous noncompartmental pharmacokinetic variables were investigated for four different Glaxo Wellcome compounds, administered by three different routes of administration: ranitidine (po), sumatriptan (sc), ondansetron (iv), and bismuth, from ranitidine bismuth citrate (po). The distributions of all the investigated noncompartmental pharmacokinetic variables were adequately described by a log-normal distribution, whereas statistically significant departures from normality occurred in the majority of cases. Thus, unless there is strong and consistent evidence for a departure from log-normality, the parametric statistical analysis of common noncompartmental pharmacokinetic variables should be carried out after a priori log transformation.

The effect of ondansetron on the pharmacokinetics and pharmacodynamics of temazepam.

The objective of this study was to determine the effects of ondansetron on the pharmacokinetics of temazepam and on pharmacodynamics relevant to its use as oral premedication. Twenty-four healthy volunteers (12 of each sex) were administered the following oral treatments in a randomised, double-blind crossover design: temazepam 20 mg plus placebo; or temazepam 20 mg plus ondansetron 8 mg. Blood samples were taken for plasma temazepam assay at intervals up to 32 h after administration. In addition, a brief battery of psychomotor tests was administered 1 h prior to dosing and 1 and 4 h after dosing. Analysis of the derived pharmacokinetic parameters showed no differences between the treatments described above. Analysis of data from the dynamic measures likewise showed no difference between the treatments. It was concluded that the co-administration of ondansetron did not influence the pharmacokinetics or pharmacodynamic actions of temazepam.

The log transformation is special.

The logarithmic (log) transformation is a simple yet controversial step in the analysis of positive continuous data measured on an interval scale. Situations where a log transformation is indicated will be reviewed. This paper contends that the log transformation should not be classed with other transformations as it has particular advantages. Problems with using the data themselves to decide whether or not to transform will be discussed. It is recommended that log transformed analyses should frequently be preferred to untransformed analyses and that careful consideration should be given to use of a log transformation at the protocol design stage.

Evaluation of different metrics as indirect measures of rate of drug absorption from extended release dosage forms at steady-state.

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.

Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

As indirect measures of rate of drug absorption (metrics), maximum plasma concentration (Cmax) is confounded by extent of drug absorption and the time to reach Cmax (tmax) is a discrete variable, dependent on blood sampling frequency. Building on the work of Endrenyi et al., we have compared different metrics, including Cmax/area under the curve of concentration versus time from time zero to infinity (AUC infinity), partial AUC from zero to tmax (AUCp), and Cmax.tmax with simulated experiments. Importantly, the performance of these metrics was assessed with the results of actual pharmacokinetic studies involving Glaxo drugs. The results of the simulated and real experiments were consistent and produced the following unambiguous findings: (1) Cmax/AUC infinity is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent; (2) Cmax/AUC infinity is more sensitive than Cmax at detecting differences in rate of absorption when they exist; and (3) the treatment ratios for AUCp, AUCp/AUC infinity, and Cmax.tmax are very imprecisely estimated and are of no practical value as measures of rate of absorption. Of the metrics examined, Cmax/AUC infinity is the most sensitive and powerful indirect measure of rate of drug absorption in comparative pharmacokinetic studies involving immediate-release dosage forms and should be used instead of Cmax in bioequivalence testing.