A Phase 2 Randomized Controlled Study of Tralokinumab in Subjects with Idiopathic Pulmonary Fibrosis.

RATIONALE: IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. OBJECTIVES: Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF. METHODS: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. MEASUREMENTS AND MAIN RESULTS: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively. CONCLUSIONS: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab.

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.

A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. METHODS: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry. RESULTS: Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p = 0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

Negative pressure ventilation as a bridge to lung transplant.

Recent years have witnessed evolution of lung allocation strategies to prioritize sicker recipients. In the pre-transplant period, this has translated into increased utilization of invasive extracorporeal or mechanical ventilatory support as a bridge to lung transplantation. The morbidity associated with these strategies warrants consideration to less invasive respiratory support modalities. Herein, we present a case highlighting successful bridge to lung transplantation with a relatively non-invasive negative pressure ventilator.

Survival after in-hospital cardiopulmonary resuscitation.

BACKGROUND: The use of postarrest variables to predict survival after discharge following in-hospital cardiopulmonary resuscitation has not been definitive. This study evaluates whether the duration of cardiopulmonary resuscitation (CPR) and other variables affect discharge rates and survival rates after discharge. METHODS: Prospective cohort survival data and arrest variables were collected, including initial observed rhythm, duration of CPR, time of arrest, and number of arrests. Arrests on unmonitored general medical units, monitored telemetry units, and critical care units were included. Outcome measures were: survival after CPR, 24 hours post-CPR, survival to discharge, and to six months postdischarge. RESULTS: At both discharge and six months after discharge, ventricular fibrillation and ventricular tachycardia were associated with better survival rates than other initial rhythms (P < 0.001). There were significantly higher survival rates (P < 0.001) for those receiving CPR for < or =10 minutes as compared with those receiving CPR >10 minutes. Multiple versus single arrests and monitored versus unmonitored arrests approached significance. The time of day of the arrest was not a significant factor. CONCLUSIONS: Duration of CPR >10 minutes was predictive of significantly decreased survival to discharge and six months postdischarge. Low six-month survival rates may reflect the relatively high proportion of initial rhythms other than ventricular in the study group.

Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR.

OBJECTIVE: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. METHODS: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed. RESULTS: Of 46 patients (initiated on full dose: n=28; initiated on half dose: n=18), 35 (76%) completed 24weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV1 was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: -0.4 [-1.9, 1.1]; p=0.6249). Compared with the 24weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p=0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: -8.52 [24.91] days; p=0.0369) through study week 24. CONCLUSIONS: Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV1<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV1<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.

Emerging drugs in lung transplantation.

The balance between immunosuppression to ensure graft tolerance while preventing emergence of infectious complications is key in lung transplantation. Although opportunistic infection may appear to be the most important of these complications, malignancies and severe drug toxicities significantly affect the short- and long-term outcomes of the patients. The present practice is combination therapy using drugs with complementary immunosuppressive action, to achieve synergistic immunosuppression with the lowest possible toxicity. Components of immunosuppression include induction and maintenance regimens. Primary graft failure remains an important cause of mortality and morbidity in the immediate post-transplant period. Acute rejection is a common complication after lung transplant, but responds well to augmented immunosuppression and immunomodulation. Chronic rejection still is the major cause of mortality in patients who survive the initial year post-transplantation. Several new drugs have shown promise in decreasing the rate of loss of graft function. This review discusses the current and emerging therapeutic regimens.

Management of Scedosporium apiospermum in a pre- and post-lung transplant patient with cystic fibrosis.

Although the predominant type of infection seen in the cystic fibrosis lung remains bacterial, fungal organisms are being isolated more frequently and are associated with a high mortality rate in lung transplant recipients. We present a case of a patient with CF with sputum cultures positive for Scedosporium apiospermum prior to a successful lung transplant. She remains without evidence of infection 18 months later following treatment with a combination of triazoles and terbinafine.

Reconstruction of pulmonary venous conduit with CorMatrix in lung transplant.

Anomalous pulmonary vein anatomy is infrequently encountered during reconstructive lung surgery, especially lung transplantation. Complications of pulmonary venous anastomosis carry high morbidity and mortality. We report a case of anomalous pulmonary vein reconstruction with a decellularized porcine small intestinal submucosa-derived extracellular matrix during bilateral lung transplantation in an 18-year-old woman with cystic fibrosis.