Trial of Reduced Alteplase Dose for Parapneumonic Effusion (TRAPPE)

Pleural Infection Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05766124
• Other study ID #: tPALowVsStandard
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: June 1, 2024
• Est. completion date: December 31, 2027

Study information

• Verified date: May 2024
• Source: Chinese University of Hong Kong
• Contact: Ka Pang Chan, MBChB
• Phone: 35052211
• Email: chankapang[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 30
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Infections
• Pleural Infection

Intervention

Drug:
• Tissue Plasminogen Activator
Intrapleural administration of tissue plasminogen activator

Locations

Country	Name	City	State
Hong Kong	Chinese University of Hong Kong	Hong Kong
Hong Kong	Prince of Wales Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	need for additional pleural interventions	The need for additional pleural interventions (therapeutic thoracentesis, chest drain insertion, surgical referral) for failed medical treatment	90 days
Secondary	Open use of intrapleural 10mg tPA	Number of patients reverted to open intrapleural 10mg tPA after the second dose of tPA treatment	3 days
Secondary	Bleeding events	Non-significant and significant bleedings due to tPA use	90 days
Secondary	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
Secondary	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
Secondary	Pleural fluid output	The total volume of pleural fluid drainage at 24 and 72 hours after randomization	7 days
Secondary	Drain removal	The time from randomization to removal of all chest drains (in days).	90 days
Secondary	Length of hospital stay	Length of stay in acute and convalescent hospitals	90 days
Secondary	Patient reported outcomes	breathlessness visual analog scale	90 days
Secondary	Patient reported outcomes	Occurrence of pain after tPA in terms of VAS	90 days
Secondary	Patient reported outcomes	SF-36	90 days
Secondary	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
Secondary	Protocol violation	The number and reason of protocol violation in timing and dosage of intrapleural tPA administration.	3 days