Trial of Reduced Alteplase Dose for Parapneumonic Effusion (TRAPPE)

NCT ID: NCT05766124

Last Updated: 2025-12-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-11-01
• Study Completion Date: 2028-06-30

Brief Summary

Objectives: A pilot study to assess the feasibility of randomizing patients to receive low (2.5mg) and standard (10mg) doses of intrapleural tissue plasminogen activator (tPA) in unresolved pleural infection, as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT.

Hypothesis: The proposed randomized protocol comparing intrapleural low and standard doses of intrapleural tPA will be feasible and acceptable.

Design and subjects: A pilot, single-centre, two-arm, double-blinded, randomized controlled trial (RCT) which includes subjects with unresolved 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 or after 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 will be feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 3 months of follow-up. Important secondary outcomes include survival at 90 days and without the need for surgical intervention, 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. Clinical and safety outcomes will be reported descriptively for each group, with simple between-group estimates given the limited sample size. The resulting estimates of recruitment rates, adherence, follow-up completeness, and variability and event rates for key clinical and bleeding outcomes will be used, together with external data, to inform the design and sample size considerations of a 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.

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. We hypothesize that a standardized regimen with pre-defined clinical criteria is essential in guiding the decision of dose escalation in a RCT. Therefore, in this pilot study, we aim to test the feasibility, robustness in clinical practice and physician acceptance before incorporating it in a full-scale multicenter RCT

Conditions

Pleural Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Low dose tPA

Patients with pleural infection and will receive a starting dose of tPA at 2.5mg

Group Type: EXPERIMENTAL

Tissue Plasminogen Activator

Intervention Type: DRUG

Intrapleural administration of tissue plasminogen activator

Standard dose tPA

Patients with pleural infection and will receive a starting dose of tPA at 10mg

Group Type: ACTIVE_COMPARATOR

Tissue Plasminogen Activator

Intervention Type: DRUG

Intrapleural administration of tissue plasminogen activator

Interventions

Tissue Plasminogen Activator

Intrapleural administration of tissue plasminogen activator

Intervention Type: DRUG

Other Intervention Names

Alteplase

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chinese University of Hong Kong

OTHER

Sponsor Role: lead

Responsible Party

Ka Pang Chan

Clinical Lecturer

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David SC Hui, MD

Role: STUDY_DIRECTOR

Chinese University of Hong Kong

Locations

Chinese University of Hong Kong

Hong Kong, Hong Kong, Hong Kong

Site Status: RECRUITING

Prince of Wales Hospital

Hong Kong, Hong Kong, Hong Kong

Site Status: RECRUITING

Countries

Hong Kong

Central Contacts

Ka Pang Chan, MBChB

Role: CONTACT

Phone: 35052211

Email: chankapang@cuhk.edu.hk

Facility Contacts

Ka Pang Chan, MBChB

Role: primary

David SC Hui, MD

Role: backup

Ka Pang Chan, MBChB

Role: primary

David SC Hui, MD

Role: backup

Other Identifiers

TRAPPE

Identifier Type: -

Identifier Source: org_study_id