Journal Club The ELITE Trial. Sandra Katalinic, Pharmacy Resident University Hospital of Northern British Columbia April 28, 2010

Transcription

1 Journal Club The ELITE Trial Sandra Katalinic, Pharmacy Resident University Hospital of Northern British Columbia April 28, 2010

2 Overview Journal article Title, journal, authors, funding Abstract Introduction Methods Results Discussion Critique or evaluation General interpretation Recommendation

3 Title Treatment of Early Pseudomonas aeruginosa Infection in People with Cystic Fibrosis: The ELITE Trial Authors: Felix Ratjen, Anne Munck, Pearl Kho, Gerhild Angyalosi Journal Background Thorax Part of BMJ Journal family Publication Timeline Published online June 19, 2007

4 Authors Dr. Felix Ratjen: Member of editorial board of Am J of Resp and Crit Care Med, Ped Pulm and Journal of Cystic Fibrosis Research focus on CF Has published multiple CF articles in Eur Resp J, Am J Resp Care Med, Lancet Anna Munck Background Published multiple CF papers in: J Hepatology, Ped Pulm, Journal of Cystic Fibrosis European CF Society member of the board Pearl Kho (works for novartis) Published CF related articles in Journal of Cystic Fibrosis, Thorax

5 Funding Sources Sponsored by Novartis Pharma also involved in data collection, analysis and interpretation Chiron involved in initiation and study design Conflicts of Interest Background Pearl Kho, Gerhild Angyalosi work for Novartis

6 Abstract Thorax 2010;65:286e291.

7 Summary Introduction Discusses CF pathophys and susceptibility to respiratory infections Difficulty of treating pseudomonas lung infections in this population Acknowledges studies regarding use of inhaled antibiotics in prevention / delaying of chronic infection Data on the most efficacious dose/ regimen is lacking Requires larger / better studies

8 Purpose Introduction The early inhaled tobramycin for eradication (ELITE) trial was designed to assess the short and long term efficacy and safety of [inhaled tobramycin] 300 mg/5 ml twice daily for 28 and 56 days in the treatment of early onset P aeruginosa infection in patients with CF.

9 Null hypothesis Methods The efficacy of a 28 day regimen of inhaled tobramycin does not significantly differ from the efficacy of a 56 day regimen in the time to recurrence of p. aeruginosa infection Research hypothesis There is a significant difference in the efficacy of a 28 day regiment of inhaled tobramycin as compared to a 56 day regimen in the time to recurrence of p. aeruginosa infection

10 Methods Design Open-label two-arm randomised multicentre study 21 centres in Germany, France, Netherlands, UK, Spain and Austria Approved by the ethics committees/ institutional review boards at each centre Followed the Declaration of Helsinki and Good Clinical Practice Each patient and/or their parent / legal guardian gave written informed consent

11 Setting Methods 21 centres in Germany, France, Netherlands, UK, Spain and Austria November 2003 January 2008

12 Methods Population a) Inclusion criteria Aged 6 months Confirmed CF (clinical signs of CF sweat chloride >60 meq/l by quantitative pilocarpine iontophoresis or genotype with two identifiable mutations consistent with CF) First or early infection with P aeruginosa

13 Methods Population b) Exclusion criteria History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycosides Signs or symptoms of acute pulmonary disease (eg, pneumonia, pneumothorax) History of hearing loss Any investigational drug within 30 days Loop diuretics within 7 days before enrolment Macrolide antibiotics as a maintenance therapy for 12 days during the 28 days before screening/ baseline

14 Methods Screening/recruitment Patients receiving regularly attend outpatient clinics had microbiological testing q3mo An early or positive Pseudomonas aeruginosa culture at routine hospital visit = eligibility Received 28 days of therapy with inhaled tobramycin randomized Not random sampling, aimed to duplicate clinical practice (most pseudomonal colonization found during check-ups)

15 Treatment allocation Methods After 28 days, patients randomized 1:1 to stop treatment or continue 28 more days Randomization process not described No concealment of tobramycin (i.e. Inhaled placebo)

16 Blinding Methods Open label study no blinding done Interventions Tobramycin inhalational solution 300mg/5ml BID via jet nebulizer (4-6ml/min) x 28 or 56 days

17 Study definitions Methods Early infection: new detection of P aeruginosa in a respiratory culture after: Negative cultures for 1 year if 4 negative cultures were available OR up to 2 years with four negative cultures + no abx treatment Efficacy evaluable population - received 1 dose of tobramycin, were randomised, had documented P aeruginosa infection at screening and micro-biological assessments at 1 month after last dose of tobra Safety population received at least one dose of drug

18 Outcome measures Methods Outcome measures stated a) Primary median time to recurrence of any strain of P. aeruginosa b) Secondary proportion of patients free of P. aeruginaosa 1 month after the end of treatment, time to recurrence of any strain via deep throat swab or sputum; # patients with same or new genotype of psuedomonas + recurrence; length of hospital admissions for respitory indications

19 Outcome measures Methods Exploratory outcomes Safety assessment

20 Methods Study procedures (Broad overview) Patients given 28 days inhaled tobramycin Randomized to either stop treatment or continue for 28 days more Monthly study visits for 1 year post intervention then q3 months until positive pseudomonas culture obtained This culture treated at their MD s discretion

21 Statistical considerations a) Sample size calculation o o o o o o Methods Modelled to provide precision for the measurement of time to recurrence Based on simulations using 50-75/treatment group Median time to recurrence 6-9 months for 28day group 9-12 months for 56 day group 90% power, two tailed p-value, significance Estimated 120 enrolled for 100 to be randomized

22 Methods Statistical considerations Time to recurrence of P aeruginosa = Kaplane-Meier method A log-rank test = differences between treatment groups The relative risk of recurrence and 95% Cis = Cox proportional hazard model Comparisons between the treatment groups for the other efficacy variables = Cochrane-Mantele-Haenszel test Spirometry variables, AEs and other safety variables were analysed = descriptive statistics.

23 Trial Flow Diagram Enrollment Allocation Number assessed for eligibility n =? METRO n = 90 Number randomized n = 172 VANCO n = 82 Reasons not enrolled? All received intervention? Follow-up 13% not included in final analysis

24 Trial Flow Diagram RSS 2001

25 Baseline Characteristics Study conducted between Table of baseline characteristics given Any statistically significant differences between groups? Co-interventions Results No cointerventions stated

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27 Analysis Results ITT vs Per Protocol analysis not explicitly stated Primary outcome used the efficacy evaluable population Other efficacy analyses the safety population was used, which included all patients who received at least one dose of study medication.

28 Trial Flow Diagram RSS 2001

29 Results CURE Rate Study Group 28 day 56 day Nonrandomized P-value Median time to recurrence P. aeruginosa free (sputum / throat swab) 1mo post mo (n = 34) 66 (n = 41) AE s 3 mo 32 (73%) n=44 AE s >3mo 21 (60%) n= mo (n = 31) (n = 36) (58%) n = 43 7 (20%) n=35 19 (53%) n=

30 Efficacy Proportion of P. aeruginosa free patients and time to recurrence are comparable in both groups 1 month after end of study drug Safety Results Most common <3mo = cough; >30mo 28 day = dysphonia, 56 day = cough; no statistical significance calculate No significant changes in SrCr in either group Tobra day 28 Vs 56: 1.4 (1.2; 0e5.8) mg/ml vs 1.3 (1.1; 0e3.7) mg/ml) suggesting no accumulation of tobramycin over time

31 Discussion Summary (from authors) Authors acknowledge lack of studies evaluating optimal regimen and choice of inhaled abx Other studies have included patients with previous pseudomonas infection Acknowledge that other therapies including inhaled colistin and PO cipro can delay pseudomonal infection in CF as well Inhaled tobra 80 mg q12h x12 months has shown similar success Advanced disease, mucoid plugs may deposition into lung and increase failure rate

32 Discussion Summary (from authors) Authors claim high success rate Limitations: Collecting proper sputum culture in children Smaller sample size than planned

33 Discussion Summary (from authors) Authors suggest no additive benefit with 56 day treatment Can keep patient free from infection for up to 27 months

34 Title and Abstract Title should state that this is an RCT for easier screening Abstract is structured into headings, but provides limited data compared to full text gives false impression Introduction Critique Some scientific background provided on epidemiology, impact of disease, treatment options No null or alternate (research) hypothesis explicitly stated

35 Methods Critique Study was randomized, multicentre but not blinded Strange technique, starting after intervention given Was randomization done by computer/vs human? Investigator vs blinded person Selection bias? Unclear if consecutive patients sampled, or if it was based on convenience Randomization based on titres? Clinically relevant / practical?

36 Critique Methods Population OK because CF mostly affects children Can we extrapolate to adults? Baseline similar except vaccination rate (Vaccine not available here) Pseudomonal infections more common in older patients Pseudomonal culture based on throat swab low positive predictive value but says they are good Sensitivities?

37 Methods Critique Reasonable diagnostic criteria for CF Inclusion criteria seemed reasonable considering goal of paper List of reasons for drop out given on flow chart Sample calculation done, but not attained Should have randomized 100, only 88 randomized Very small population, only 18 in each group finished protocol Are results valid?

38 Methods Critique Did not tell us dose of tobra used, only concentration Sampling tobra levels? Using inhaled makes no sense if trying to assess efficacy/toxicity Not blinded; Blinding seems easy, why not done? $? Adherence tested via returned ampoules

39 Results Critique Trial flow diagram provided, but confusing Low recruitment rate, potential selection bias Small trial, only 18 pts in each group completed protocol This patient population not even evaluated Important imbalances in baseline characteristics Vaccines could this affect severity of disease

40 Results Critique No data on concurrent use of potential confounding co-interventions Other antibiotics (oral / inhaled / IV?) or interventions not mentioned Primary analysis was based on an efficacy analysis of patients receiving drug, not explicitly stated if ITT or per protocol Purpose of paper is to evaluate 28 vs 56 day therapy on time to recurrence Evaluating a population that received at least one dose why not evaluate those that completed the course?

41 Results Critique

42 Discussion Critique Discuss some important study limitations, which are a threat to the validity of study Fail to discuss concerns around external validity (generalizability) of results to other CF populations Stated conclusion not consistent with quality of data

43 General Interpretation Can we extrapolate this data to adult patients? Can we use it on patients already colonized with pseudomonas? (i.e. not first or early infection) Looked at various other bugs cultured this can be a sign of pt s health? Immune suppression? Higher incidence in 28 day regimen. Why full protocol not assessed? RSS 2001

44 Summary General Interpretation Significant methodological limitations Lots of missing information A larger, well-designed study is required to confirm an optimal duration of inhaled antibiotics for CF patients My be difficult considering frequency of CF Studies in adult patients also warranted CF patients now living longer

45 Summary Recommendation Consider using inhaled tobramycin in CF patients who: Have colonization with P. aeruginosa (cultured) Have a strain of P. aeruginosa susceptible to tobramycin Have multiple / frequent exacerbations (>3/yr) Use 600mg q6 12h via nebulizer x28 days * Recommendations based on other tertiary sources + journal articles

46 Questions?