Comparison of Outcomes Between Low and Standard Dose Intrapleural tPA for Pleural Infection

Study Overview
=================
Brief Summary
-----------------
Objectives: A pilot study to compare the therapeutic and safety profiles between low(2.5mg) and standard(10mg) doses of intrapleural tissue plasminogen activator(tPA) in uncontrolled pleural infection. The study design will be tested for its trialability. Hypothesis: 2.5mg tPA has comparable therapeutic efficacy and less bleeding complications to 10mg tPA. Design and subjects: A pilot, single-centre, two-arm, double-blinded, randomized controlled trial(RCT) which includes subjects with uncontrolled pleural infection, with follow-up till 90 days after hospital discharge. Interventions: Recruited subjects will be randomized in 1:1 ratio to receive a maximum of 6 doses of intrapleural tPA starting at either 2.5mg or 10mg. A clinical decision is allowed at the third dose to continue with the assigned dose or escalate to 10mg to complete the course based on the clinical response, without breaking the blinding. Main outcome measures: The primary outcome is survival at 90 days and without the need for surgical intervention. Secondary outcomes include the need for additional pleural interventions, number of decisions to choose 10mg intrapleural tPA at the third dose, clinical and radiographic response after the treatment course, safety profiles especially bleeding complications, and the number and reason for protocol violation. Data analysis and expected results: Data will be analyzed on an intention-to-treat basis for all randomized subjects. The clinical outcomes will be compared with a regression model built to adjust for confounding covariates. The data on therapeutic efficacy and bleeding complications will inform the power calculation of sample size in subsequent full-scale multicentred RCT incorporating the current study design.

Detailed Description
-----------------
Pleural infection, including complicated parapneumonic effusion and empyema, is a common complication secondary to pneumonia, and its presence predicts a need of hospitalization, longer hospital stay and higher mortality (10 - 20%). Timely and effective treatment is required to lower the related morbidity and mortality. The cornerstone of management for pleural infection involves adequate drainage of infected pleural fluid and adequate antibiotics coverage. However, this only works in 70% of cases. Complete evacuation of pleural fluid can become challenging even with an adequately large-bore chest drain, due to its viscous nature and extensive septations partitioning the infected fluid into multiple locules in the pleural space. Although surgical decortication in these refractory cases was once believed to be the definitive treatment, it is now considered as the last resort of treatment due to a high anaesthetic risk whilst uncontrolled sepsis, high rate of chronic post thoracotomy pain (50%) and unavoidable bleeding. The advent of intrapleural therapy using tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has revolutionized the care in pleural infection, as shown in the pivotal MIST-2 trial. Their synergistic effect targeting the pus viscosity and pleural adhesions can greatly improve the drainage of pleural fluid, which avoided the need for surgery in more than 90% of patients. The optimal dose of intrapleural tPA remains undefined. The dose of 10mg used in the MIST-2 trial was chosen empirically and had not been subjected to conventionally dose-escalation assessment or long-term pharmacovigilance follow-up. In such case any major adverse effects can be a hindering factor of using this medication at the standard dose. An occurrence rate of bleeding complication between 1.8 and 12% using the dose of 10mg tPA has been reported by several large-scale studies. Clinically significant bleeding warrants additional intervention including pack cell transfusion, radiological interventions and even surgical haemostasis. This risk is therefore one of the driving forces urging for finding a safer and lower effective dose. A dose-dependent bleeding risk of intravenous tPA has been established, and such linkage may probably exist for intrapleural tPA. Alemán C et al has reported that a double dose of intrapleural tPA was associated with a doubling of serious bleeding complications (28% for 20mg and 12% for 10mg). Therefore, it appears logical and safe that a lower dose of intrapleural tPA may reduce the bleeding risk. Several studies have reported that a lower dose (< 10mg) of intrapleural tPA remains efficacious in pleural infection. In an animal study, a median tPA dose of 3.75mg (range 0.375 - 20mg) was required for the treatment of fibrinous pleuropneumonia in horses, with an average weight 4 to 10 times higher than humans. A multi-centered dose de-escalation study by Popowicz et al has confirmed that a combination of 5mg tPA together with 5mg DNase is safe and effective. They employed a pragmatic approach to begin therapy with a lower tPA dose (5mg) and return to the conventional dose (10mg) if lack of clinical response is observed. The reduced tPA dose was well tolerated with a bleeding complication comparable to previous studies using 10mg tPA. A similar cohort study, ADAPT-2, assessed the clinical outcomes of an even lower starting dose of intrapleural tPA at 2.5mg. The lower dose remained efficacious, with only 2 patients (2.9%) required surgery and a low rate of bleeding complication (2.9%) compared with 4.2% in the landmark MIST-2 trial. The lower dose of tPA, with a potentially lower bleeding risk, provides an attractive alternative especially in patients who require therapeutic anticoagulation and those with acquired coagulopathy due to overwhelming sepsis. A standard dose (10mg) can be employed at any time in an attempt to break non-communicating locules if clinical improvement could not be achieved by a low dose tPA, while it is not practical to do the other way round if clinical efficacy is observed with standard dose tPA. Till now, there is no high quality data comparing the treatment efficacy and bleeding complications between low dose (< 10mg) with standard dose (10mg) in pleural infection. It was reflected by a heterogeneous practice in choosing the optimal dose of intrapleural tPA from a recent international survey among practicing physicians expert in pleural medicine. The respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if a median 80% (interquartile range 50-80%) of patients could be successfully treated at that dose. We hypothesize that a lower starting dose (2.5mg) of intrapleural tPA remains as efficacious as standard dose (10mg) with a lower bleeding risk. However, using an unchanged low dose of tPA throughout the course of treatment may put the patients in disadvantage of subjecting them to the need for surgery if failed treatment. Previous dose de-escalation studies employed a low starting dose of intrapleural tPA and allowed an escalation to the standard dose in the midway of treatment course depending on the clinical progress at the discretion of treatment physicians and this practice is also preferred from the international survey. The same study design will therefore be adopted in the current study.

Official Title
-----------------
A Pilot Study Comparing the Clinical Efficacy and Bleeding Risk Between Low Dose and Standard Dose Intrapleural Tissue Plasminogen Activator for Pleural Infection

Conditions
-----------------
Pleural Infection

Intervention / Treatment
-----------------
* Drug: Tissue Plasminogen Activator


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical features suggesting uncontrolled pleural infection with incomplete drainage of pleural effusion, at least 1 day after insertion of pleural drain (French size 12 or above) and administration of antibiotics. Intend to administer intrapleural fibrinolytic Written informed consent obtained Exclusion Criteria: Previously received intrapleural tPA to the ipsilateral pleural space for the current episode of pleural infection. Known sensitivity to tPA or DNase. A coincidental stroke, major haemorrhage or major trauma. Frank bleeding or evidence of puncture to the intercostal artery during chest drain insertion. Ongoing frank bleeding from the ipsilateral pleural space. Has had puncture of a non-compressible vessel in the previous 14 days. Has had major surgery in the previous 14 days. Has had unprovoked gastrointestinal bleeding or intracranial haemorrhage in the last 3 months. Active use of anticoagulation (except prophylaxis for deep vein thrombosis) or dual-antiplatelet agents. Active use of any systemic fibrinolytic therapy or any airway DNase therapy. On long-term macrolide antibiotics (as they may interact with DNase). Uncorrectable bleeding diathesis or baseline INR > 1.5. Has had a previous pneumonectomy (either on the same or contralateral side). Presence of active bronchopleural fistula. Age less than 18 years old. Patients who are pregnant or lactating (females of childbearing potential must have a negative pregnancy test before randomisation). Expected survival less than three months from a different pathology to this empyema (e.g. metastatic lung carcinoma). Use of agents under research or not registered in the 30 days prior to the study. Inability to give informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Recruited subjects will be randomized in 1:1 ratio to receive a course of maximum of 6 doses intrapleural tPA (Actilyse®, 50mg ampoule, Boehringer Ingelheim) with starting dose at either low dose (2.5mg) or standard dose (10mg) in addition to fixed dose deoxyribonuclease. The first dose of intrapleural tPA will be given at the time of randomization. At the third dose of tPA, the attending physician will be allowed to continue with the assigned dose of tPA or escalate to 10mg tPA for the remaining four doses based on the clinical response, without knowing the previous doses and not breaking the blinding. This study will follow patients through their hospital stay and at outpatient visits at 30 and 90 days.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose tPA<br>Patients with pleural infection and will receive a starting dose of tPA at 2.5mg | Drug: Tissue Plasminogen Activator<br>* Intrapleural administration of tissue plasminogen activator<br>* Other names: Alteplase;|
| Active Comparator: Standard dose tPA<br>Patients with pleural infection and will receive a starting dose of tPA at 10mg | Drug: Tissue Plasminogen Activator<br>* Intrapleural administration of tissue plasminogen activator<br>* Other names: Alteplase;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success | survival at 90 days and without the need for surgical intervention following the initial dose of tPA/DNase (at randomization) (14 | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| need for additional pleural interventions | The need for additional pleural interventions (therapeutic thoracentesis, chest drain insertion, surgical referral) for failed medical treatment | 90 days | 
| Open use of intrapleural 10mg tPA | Number of patients reverted to open intrapleural 10mg tPA after the second dose of tPA treatment | 3 days | 
| Bleeding events | Non-significant and significant bleedings due to tPA use | 90 days | 
| Time to clinical stability | The time from randomisation to clinical stability (including the resolution of fever; fall of WBC, CRP; change of radiographic appearance) | 90 days | 
| Sonographic changes on thoracic ultrasound | Reduction in area of pleural opacity occupied by pleural effusion by CXR and thoracic ultrasound (TUS) at different time points compared to immediately before tPA/DNase injection: days 1, 3 and 7 following randomization, at the completion of antibiotic therapy. Where a CXR or TUS is not available at the completion of antibiotic therapy, a CXR or TUS within 30 days after completion of the antibiotic course or the last available CXR or TUS during treatment was assessed | 90 days | 
| Pleural fluid output | The total volume of pleural fluid drainage at 24 and 72 hours after randomization | 7 days | 
| Drain removal | The time from randomization to removal of all chest drains (in days). | 90 days | 
| Length of hospital stay | Length of stay in acute and convalescent hospitals | 90 days | 
| Patient reported outcomes | breathlessness visual analog scale | 90 days | 
| Patient reported outcomes | Occurrence of pain after tPA in terms of VAS | 90 days | 
| Patient reported outcomes | SF-36 | 90 days | 
| Clinician experience with the clinical decision of dose escalation | Clinicians' comfortableness in deciding the dose of intrapleural tPA from 3rd dose onwards, in a 5-point Likert scale | 3 days | 
| Protocol violation | The number and reason of protocol violation in timing and dosage of intrapleural tPA administration. | 3 days |