ATS 2012, SAN FRANCISCO – On Tuesday afternoon, May 22, 2012, results from seven late-breaking clinical trials will be presented in session C91 at the ATS International Conference. These studies examine treatments for ventilator-associated pneumonia, cardiac surgery associated kidney injury, septic shock, idiopathic pulmonary fibrosis, smoking cessation, malignant pleural effusion and non-cystic fibrosis bronchiectasis.
Marin Kollef, MD, and colleagues conducted a Phase 3, double-blind, double-dummy study to assess the efficacy and safety of a fixed seven-day course of doripenem (one-gram four-hour infusions) versus a fixed 10-day course of imipenem in adult patients with ventilator-associated pneumonia. Numerically lower cure rates and numerically higher mortality rates were seen with the shorter seven-day course of doripenem compared with the 10-day course of imipenem, with larger differences observed in subjects with creatinine clearance ≥150 mL/min. The study was terminated early based on recommendation from an independent data monitoring committee.
In another double-blind, randomized controlled study from researchers in New Zealand and Australia, Shay McGuinness, MB, ChB, and colleagues examined whether prophylactic peri-operative infusions of sodium bicarbonate could reduce the incidence of cardiac surgery associated acute kidney injury (CSA-AKI) in a subgroup of cardiac surgery patients with pre-operative or peri-operative risk factors for the development of CSA-AKI. Bicarbonate infusion produced an increase in the pH of both blood and urine, but this did not result in a decrease in the incidence of CSA-AKI. The researchers conclude that they cannot recommend the use of peri-operative infusions of sodium bicarbonate to reduce CSA-AKI in these patients.
B. Taylor Thompson, MD, and colleagues conducted a randomized, double-blind, placebo-controlled trial to examine the efficacy and safety of drotrecogin alfa (activated, DAA) in 1,697 adult patients with septic shock, who received either DAA or placebo for 96 hours. The primary end point was all cause mortality 28 days after randomization. At 28 days, 26.4 percent of DAA patients and 24.2 percent of placebo patients had died. By 90 days, 34.1 percent of DAA patients and 32.7 percent of placebo patients had died. Odds ratios for mortality were not significantly different in eight other pre-defined subgroups, including patients at increased risk of death.
The efficacy and safety of combined prednisone, azathioprine, and N-acetylcysteine (NAC) as a treatment for idiopathic pulmonary fibrosis (IPF) were examined in a double-blind, placebo-controlled, randomized trial. Researchers Ganesh Raghu, MD, and colleagues found an increased risk of mortality and hospitalizations in patients treated with a combination of prednisone, azathioprine and NAC, compared with controls treated with placebo. The study was terminated after a mean follow-up of 32 weeks with 77 patients enrolled in the three-drug regimen arm of the study and 78 enrolled in the placebo arm.
Brian J. Smith, MBBS, and colleagues compared the effects of varenicline tartrate and counseling and counseling alone for smoking cessation in a 52-week randomized controlled trial involving 392 adult inpatients. At follow-up, the proportion of subjects who remained continuously abstinent was significantly greater in the varenicline group (31.1 percent) compared to the counseling alone group (21.4 percent, p = 0.03). Significant differences between the two study arms were seen at four, 12, and 16 weeks. The most common self-reported adverse event during the 12-week treatment phase was nausea, with 16.3 percent reporting nausea in the varenicline group compared with 1.5 percent in the counseling alone group. The efficacy and safety of patient controlled malignant pleural effusion (MPE) drainage by indwelling pleural catheter (IPC) were compared with those of usual care (chest tube and talc slurry pleurodesis) in a randomized controlled trial involving 106 patients. Researchers Helen E. Davies, MRCP, and colleagues found that IPC and talc slurry pleurodesis were comparably effective treatments for the relief of breathlessness in patients with MPE, with a similar pain profile over six weeks. Use of IPCs was associated with lower initial in-hospital stay.
Finally, in a twelve-month, randomized, double-blind, placebo-controlled trial, David J. Serisier, MBBS, DM, and colleagues examined the efficacy and safety of low-dose erythromycin ethylsuccinate in 117 non-smoking adult patients with non-cystic fibrosis bronchiectasis. Erythromycin therapy significantly reduced protocol-defined pulmonary exacerbations), with a mean annual reduction in exacerbations per patient of approximately 0.7. Erythromycin was well tolerated, with only one withdrawal due to a possible adverse event after six months of therapy.
"Late Breaking Clinical Trials Symposium" (Session C91, Tuesday, May 22, 2:00-4:30 p.m., Room 2001-2003 (West Building), Moscone Center; Abstracts 34278, 34045, 34029, 34283, 34209, 34186 and 34150)
* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.
[ 2:05 PM] A Phase 3, Double-Blind, Double-Dummy Study Assessing The Safety And Efficacy Of A Short Course Of Doripenem 1 Gram In The Treatment Of Subjects With Ventilator-Associated Pneumonia
Speakers: M. Kollef, MD1, M.I. Restrepo, MD, MSc2, H. Jolson, MD. MPH3, M. Clavel, MD4, B. Michiels, PhD5, K. Kaniga, PhD6, I. Cirillo, MS7, R. Redman, MD, FIDSA6
1St. Louis, MO/US, 2San Antonio, TX/US, 3Chevy Chase, MD/US, 4Limoges/FR, 5Beerse/BE, 6Freemont/US, 7Raritan/US
Introduction/Rationale: Doripenem is a carbapenem antibiotic approved for treatment of nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP) in many countries outside the United States. The standard dosing regimen is 500-mg 1-hour infusions every 8 hours (q8h); 4-hour infusions optimize pharmacokinetic/pharmacodynamic (PK/PD) parameters of effectiveness and are also approved for NP/VAP. It has been suggested that using higher doses with extended infusions may improve outcomes, particularly in patients infected with less susceptible bacteria, and shorter treatment courses could reduce risk for the selection of resistant bacteria. A previous phase 3 VAP study demonstrated doripenem 500-mg 4-hour infusions q8h were non-inferior to imipenem (2-3 g/day) when the length of therapy was 7-14 days and at the discretion of the investigator. This investigational study assessed a fixed 7-day course of doripenem 1-g 4-hour infusions versus a fixed 10-day course of imipenem. The rationale was that the higher doripenem dose infused over 4 hours would provide more sustained free drug-plasma concentrations above the minimum inhibitory concentration of most bacteria causing VAP than the 500-mg dose, and that a 7-day course would be non-inferior to a 10-day course of imipenem.
Methods: Adult subjects hospitalized ≥5 days, receiving mechanical ventilation, and with clinical and radiographic criteria for pneumonia were randomized 1:1 to doripenem 1-g 4-hour infusions q8h for 7 days followed by placebo for 3 days or imipenem 1-g 1-hour infusions q8h for 10 days. A bronchoalveolar lavage (BAL) or mini-BAL was performed on all subjects at baseline. Subjects whose BAL/mini-BAL culture results yielded a bacterial pathogen at ≥104 colony-forming units/mL continued receiving study drug (MITT population).
Results: The study was terminated early based on recommendation from an independent data monitoring committee; 274 of the planned 524 subjects were enrolled. Preliminary results for clinical cure and 28-day all-cause mortality rates for MITT and microbiologically evaluable (ME) subjects are provided in the table.
Conclusions: Numerically lower cure rates and numerically higher mortality rates were observed with the shorter 7-day course of doripenem 1-g compared with the 10-day course of imipenem. Larger differences were observed in subjects with creatinine clearance ≥150 mL/min than <150 mL/min. No new safety signals with the 1-g dose were found. Additional analyses of PK/PD data are planned. In countries where doripenem is approved for NP/VAP, treatment duration for VAP should be guided by the physician's assessment of individual patients and consideration should be given to administering for more than 7 days.
[ 2:25 PM] Sodium Bicarbonate Infusion To Reduce Cardiac Surgery Associated Acute Kidney Injury; A Phase II Multi-Centre, Double-Blind, Randomized Controlled Trial, [Publication Page: A6857]
Speakers: S. McGuinness, MB ChB1, R.L. Parke, MHSc (hons)1, R. Bellomo, MBBS,MD2, F. Van Haren, MD,PhD3
1Auckland/NZ, 2Melbourne, VIC/AU, 3Canberra/AU
Cardiac surgery associated acute kidney injury (CSA-AKI) occurs in up to 50% of patients and is associated with increased mortality and morbidity. A previous 100 patient pilot study suggested that prophylactic peri-operative infusions of sodium bicarbonate could reduce the incidence of CSA-AKI and thus could have a beneficial effect on patient outcomes. Before embarking on a large phase III trial of this treatment we completed a multi-centre phase II trial.
Between February 2009 and June 2011 427 patients scheduled for cardiac surgery using cardiopulmonary bypass were enrolled. All patients had pre-operative and/or peri-operative risk factors for the development of CSA-AKI (table1). Patients received an infusion of either sodium bicarbonate or placebo (sodium chloride), commencing at the start of anaesthesia, in a dose of 0.5mEq/Kg/hr for the first hour then 0.2mEq/kg/hr for 23hrs.
The primary study outcome was the number of patients who developed CSA-AKI, defined as an increase in creatinine of at least 25% from baseline to peak value within the first 5 post-operative days. Secondary outcomes included acid-base status, length of mechanical ventilation, ICU and hospital length of stay (LOS) and mortality.
215 patients were randomized to receive sodium bicarbonate and 212 to receive sodium chloride. Treating clinicians and study personnel were blinded to the allocation. There were no significant differences in the baseline characteristics of the two groups. There were significant differences in both the plasma and urinary pH between the groups (table2).
Overall 44% of patients developed CSA-AKI by the above definition; however there was no significant difference between the groups (Bicarbonate group 45%, Saline group 44%). There was no significant difference in ventilation hours (22.9hrs (mean): Bicarbonate 20.8, Saline 24.9), ICU LOS (2.25days (mean): Bicarbonate 2.23, Saline 2.28) or hospital LOS (13.1days (mean); Bicarbonate 13.4, Saline 12.8). Overall ICU mortality was 2.8% (Bicarbonate 3.3%, Saline 2.4%) and 90 Day mortality 3.3% (Bicarbonate 3.7%, Saline 2.8%).
This study demonstrates that, using the criteria described, we are able to select a sub-group of cardiac surgical patients at high risk of developing CSA-AKI. Although the bicarbonate infusion produced an increase in the pH of both blood and urine this did not result in a decrease in the incidence of CSA-AKI. On this basis we cannot recommend the use of peri-operative infusions of sodium bicarbonate to reduce CSA-AKI in these patients and do not believe further investigation of this therapy is justified.
Am J Respir Crit Care Med 185;2012:A6857
[ 2:45 PM] Efficacy And Safety Of Drotrecogin Alfa (Activated) In Adult Patients With Septic Shock: Results Of The PROWESS-SHOCK TRIAL, [Publication Page: A6858]
Speakers: B.T. Thompson, MD1, M. Ranieri, MD2
1Boston, MA/US, 2Turin/IT and the PROWESS-SHOCK Steering Committee and Investigators
Background: Although licensed for clinical use, treatment of patients with septic shock with drotrecogin alfa (activated) (DAA) remained controversial.
Methods: We conducted a randomized, double-blind, placebo-controlled, international multicenter trial. Patients with infection, systemic inflammation and shock receiving fluids and vasopressors above a threshold dose for four hours were assigned to receive either DAA (24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary end point was all cause mortality 28 days after randomization.
Results: Among 1697 patients randomized, 852 were assigned to DAA and 845 to placebo. The groups had similar demographic, illness severity and microbiologic characteristics at baseline. The primary outcome was obtained for 846 patients assigned DAA and 834 assigned placebo. At 28 days, 223 (26.4%) patients assigned to DAA and 202 (24.2%) assigned placebo had died; (relative risk of death [RR] with DAA 1.09; 95 percent confidence interval [CI], 0.92-1.28 P=0.30). By 90 days, 287/842 (34.1%) patients assigned DAA and 269/822 (32.7%) assigned placebo had died (RR 1.04; CI 0.91-1.19; P=0.56). For patients with severe protein C deficiency (≤ half LLN) at baseline, 98/342 (28.7%) assigned DAA had died at 28 days compared with 102/331(30.8%) assigned placebo, (RR 0.93; CI 0.74-1.17, P=0.54). Odds ratios for mortality were not significantly different in eight other pre-defined subgroups, including patients at increased risk of death. Serious bleeding during the treatment period occurred in 10 patients assigned DAA and 8 assigned placebo (P=0.81).
Conclusion: DAA did not reduce mortality at 28 or 90 days in patients with septic shock. (ClinicalTrials.gov: NCT00604214)
Am J Respir Crit Care Med 185;2012:A6858
[ 3:05 PM] A Double-Blind, Placebo-Controlled, Randomized Trial Of Combined Prednisone, Azathioprine And N-Acetylcysteine In Idiopathic Pulmonary Fibrosis, [Publication Page: A6859]
Speakers: G. Raghu, MD1, K.J. Anstrom, PhD2, T.E. King, Jr., MD3, J.A. Lasky, MD4, F.J. Martinez, MD, MS5
1Seattle, WA/US, 2Durham, NC/US, 3San Franscisco, CA/US, 4New Orleans, LA/US, 5Ann Arbor, MI/US IPF Clinical Research Network (IPFnet)
Background: Combined prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis (IPF). A true placebo-controlled study of this regimen in an IPF population has never been conducted and the safety and efficacy of this three-drug regimen is unknown.
Methods: We performed a randomized, double-blind, placebo-controlled trial of combined prednisone, azathioprine and NAC (three-drug regimen), or NAC alone compared with placebo for all the three drugs (1:1:1 ratio) in IPF patients with mild-moderate impairment in pulmonary function. The primary outcome measure was the change in longitudinal measurements of forced vital capacity over a 60-week treatment period.
Results: A planned interim analyses of the data revealed increased mortality (8 deaths vs. 1 death; p-value = 0.01) and hospitalizations (23 vs. 7; p-value < 0.001) in the subjects randomized to the three-drug regimen compared to placebo. These observations, and a low probability of benefit, prompted the independent Data and Safety Monitoring Board to recommend termination of the three-drug arm of the study after 77 subjects were enrolled into the three-drug regimen and 78 were enrolled into the placebo group. The mean follow-up was 32 weeks.
Conclusions: An increased risk of mortality and hospitalizations was observed in patients with IPF treated with a combination of prednisone, azathioprine and NAC when compared with placebo controls. These findings provide evidence against the three-drug regimen (prednisone, azathioprine and NAC) as a treatment for IPF patients.
Am J Respir Crit Care Med 185;2012:A6859
[ 3:25 PM] Superiority Of Varenicline Tartrate And Counselling Over Counselling Alone For Smoking Cessation: A 52 Week Randomised Controlled Trial For Inpatients, [Publication Page: A6860]
Speakers: B.J. Smith, MBBS; FRACP; Dip Clin Epid & Bio1, K.V. Carson, Dip Lab Med2, M. Peters, FRACP MBBS3, R. Fitridge, FRACP MBBS2, A. Esterman, PHD DLSHTM BSC MSC4, J. Litt, FRACP MBBS5, S. Koblar, FRACP MBBS5, J. Jannes, fracp mbbs1, A. Veale, fracp mbbs1, S. Goldsworthy, bpharm1, D. Edwards, bsc6, N. Labiszewski, bssc1, M. Brinn, bsc (hons)1
1Woodville, SA/AU, 2Woodville/AU, 3Sydney, NSW/AU, 4Adelaide, SA/AU, 5Adelaide/AU, 6Eastwood, SA/AU
RATIONALE: Smoking cessation interventions in outpatient settings have been demonstrated to be cost effective. Given the evidence of superior benefits with varenicline over nicotine replacement therapy, we aimed to evaluate this when initiated during the opportunity provided by the inpatient setting, in combination with counselling, for smokers admitted with smoking related events.
METHODS: Adult patients (n=392, 20-75 years) admitted with smoking related illnesses recruited under the disciplines of cardiology (n=195), respiratory (n=122), neurology (n=46) and vascular (n=29) from The Queen Elizabeth, Lyell McEwin and Royal Adelaide Hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling (VT+C), which is individualised phone call '5A' (Ask, Assess, Advise, Assist, Arrange) based support (n=196) or Quitline-counselling alone, (n=196). The primary abstinence metric was continuous smoking abstinence (less than 5-cigarettes) between weeks 2 and 52.
RESULTS: For the primary analysis population (intention-to-treat), the proportion of subjects who remained continuously abstinent were significantly greater in the VT+C arm (31.1%, n=61) compared to counselling alone (21.4%, n=42; RR 1.45, 95%CI 1.03 to 2.03, p=0.03) at 52-weeks follow-up. Mean number of phone calls in the VT+C arm was 3.8 and in the counselling alone arm 4.1. Secondary analyses demonstrated significant differences between the VT+C arm and counselling alone arm at 4-weeks (p=0.001), 12-weeks (end of VT+C treatment) (p=0.02) and 26-weeks (p=0.02) follow-up. The most common self reported adverse event during the 12-week treatment phase was nausea with 16.3% in the VT+C group compared with 1.5% in the counselling alone group. Other adverse events include insomnia (5.1% vs. 2.0%), headache (6.1% vs. 1.5%), vomiting (4.1% vs. 0.5%) and abnormal dreams (6.1% vs. 1.0%) in the VT+C and counselling alone groups respectively. Thirteen deaths occurred during the study period, of which n=6 were in the VT+C arm compared with n=7 in the counselling alone arm. All of these subjects had known or developed underlying co-morbidities.
CONCLUSIONS: The combined use of VT+C for the inpatient setting has produced a sustained smoking cessation benefit at 52-week follow-up, and should be considered for proactive implemented in smokers admitted with smoking related illnesses. The most commonly reported side-effect was nausea; however it is important to acknowledge that the target population are inpatients admitted with serious illness episodes. As such a combination of their illness and amendments or other new additions to their medications may also increase the likelihood of adverse events.
Am J Respir Crit Care Med 185;2012:A6860
[ 3:45 PM] The Second Therapeutic Intervention In Malignant Effusion Trial (TIME2): A Randomised Controlled Trial To Assess The Efficacy And Safety Of Patient Controlled Malignant Pleural Effusion Drainage By Indwelling Pleural Catheter Compared To Chest Tube And Ta, [Publication Page: A6861]
Speakers: H.E. Davies, MRCP1, E.K. Mishra, MRCP2, J.M. Wrightson, MRCP MB BChir2, A. Stanton, MB BS3, A. Guhan, MB BS4, C. Davies, MB BS5, J. Grayez, MB BS2, R. Harrison, MB BS6, A. Prasad, MB BS7, N. Crosthwaite, RGN2, Y.C.G. Lee, MBChB, PhD8, R. Miller, MB BS9, B. Kahan, MSc9, N.M. Rahman, DPhil, MSc2
1Cardiff/UK, 2Oxford/UK, 3Swindon/UK, 4Middlesbrough/UK, 5Reading/UK, 6North Tees/UK, 7High Wycombe/UK, 8Perth, WA/AU, 9London/UK Oxford Respiratory Trials Unit
Introduction: Malignant pleural effusions (MPEs) cause disabling breathlessness. Treatment options include indwelling pleural catheter (IPC) drainage or chest tube and talc slurry pleurodesis (usual care). This is the first direct, randomised comparison of these techniques as initial therapy and assessing patient reported outcomes. Methods: Randomised controlled trial of IPC versus usual care (chest tube and talc slurry pleurodesis) (randomised 1:1) in patients with symptomatic MPE requiring drainage. IPCs were inserted as day cases, followed by initial large volume drainage, patient education and subsequent home drainage. Usual care involved admission for chest tube insertion and talc slurry pleurodesis in patients with good lung re-expansion following a pre-defined protocol. The primary outcome was participant completed daily visual analogue scale (VAS) scores of breathlessness and chest pain over 42 days post intervention (100mm line, 0mm = no breathlessness/chest pain, 100mm = maximum breathlessness/pain). Follow up was for 1 year. Mean difference in VAS was analysed using a mixed-effects linear regression model adjusted for minimisation variables. Secondary outcomes included length of hospital stay and requirement for further pleural procedures. Results: 106 patients were randomised. Baseline variables were well matched (table 1). Dyspnoea improved in both treatment arms, with no significant difference in dyspnoea intensity (mean VAS: IPC 24.7mm (SD 18.9), usual care 24.4mm (SD 17.0), difference 0.16mm, 95% CI -6.82 to 7.15, p=0.96). Dyspnoea decreased by mean 37mm (SD 27.1) IPC arm and 30.2mm (SD 27.7) usual care arm. Chest pain decreased from baseline in both arms (mean VAS: IPC 20.5mm (SD 18.2), usual care 17.6mm (SD 16.0), difference 5.4mm, 95% CI -3.0 to 13.8, p=0.21). Chest pain decreased by mean 8.2mm (SD 27.6) IPC arm and 4.4mm (SD 27.6) usual care arm. Preliminary unadjusted analysis demonstrated lower initial hospital stay in the IPC group (median days in hospital 0 (IQR 0-1) versus 4 (IQR 2-6)).Twenty-nine IPCs were removed (56%). Three (6%) IPC patients had further pleural procedures compared to 12 (22%) usual care patients. Eight (15%) pleural infections occurred in the IPC arm compared to 1 (2%) in the usual care arm. Discussion: IPC and talc slurry pleurodesis are comparably effective treatments for the relief of breathlessness in patients with MPE. The pain profile of IPC and usual care is similar over the course of 6 weeks. Use of IPCs is associated with lower in-hospital stay during initial treatment.
Am J Respir Crit Care Med 185;2012:A6861
[ 4:05 PM] The Bronchiectasis And Low-Dose Erythromycin Study (BLESS), [Publication Page: A6862]
Speakers: D.J. Serisier, MBBS DM FRACP1, S.D. Bowler, MBBS FRACP1, M. McGuckin, PhD2, A. Chen, B Sci2, R. Lourie, MBBS2, M.L. Martin, BN1
1South Brisbane, QLD/AU, 2South Brisbane/AU
Introduction: There are no therapies with proven efficacy in non-cystic fibrosis (CF) bronchiectasis (BE). The empiric use of prophylactic macrolide antibiotics is increasingly commonplace in the absence of adequate supportive evidence. This practice is not without risk, especially for azithromycin which can rapidly induce macrolide resistance in oropharyngeal flora, with attendant risks for population macrolide resistance. Erythromycin may offer similar macrolide benefits, with a lower risk of inducing resistance.
Methods: Twelve-month, randomised, double-blind, placebo-controlled trial of low-dose erythromycin ethylsuccinate (400 mgs, equivalent to 250 mgs erythromycin base, bd) in non-smoking adult subjects with non-CF BE, no prior maintenance macrolide use and a history of at least 2 discrete infective exacerbations in the preceding 12 months. The primary outcome measure was the mean rate of protocol-defined pulmonary exacerbations (PDPE's) per patient per year, comparing erythromycin and placebo arms, by intention to treat.
Results: Six-hundred and seventy-nine (679) subjects were screened, 562 excluded and 117 randomised (mean ±SD age 62.3± 10 years, FEV1 % predicted 68.1 ± 18.6 %, 29.1% Pseudomonas-colonised). One-hundred and seven (107) completed the 48 week treatment period, although all subjects were included in the analysis. Erythromycin therapy significantly reduced PDPE's (OR 0.64, 95% CI 0.48 to 0.86, p=0.02), corresponding to a mean annual reduction in exacerbations per patient of approximately 0.7. Erythromycin therapy was well tolerated with only one withdrawal due to a possible adverse event (possible QTc prolongation) after 6 months of therapy. There was one withdrawal due to adverse event from the placebo group (nausea).
Conclusions: Low-dose erythromycin is safe, well-tolerated and significantly reduces the incidence of pulmonary infective exacerbations in macrolide-naïve, adult non-CF BE subjects. Future studies will define the risks of development of macrolide resistance in commensal oropharyngeal flora, enabling a true assessment of the risk:benefit ratio of long-term erythromycin therapy in non-CF BE.
Am J Respir Crit Care Med 185; 2012:A6862
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