Thommi 2012.

Methods	Double‐blind, placebo‐controlled, cross‐over design inappropriate for outcome. Truncated prior to crossover for meta‐analysis.
Participants	37 male, 21 female, age range 21 to 90 years. All received broad‐spectrum antibiotics.
Interventions	Intervention group: daily alteplase 25 mg in 100 mL normal saline intrapleurally. Control group: 100 mL normal saline intrapleurally Most participants received 28F intercostal catheters, some with 14‐16F catheters attached to suction. The tube was clamped for 1 hour then placed on suction. Treatment result assessed on day 4. Treatment was deemed successful if the CT pleural fluid volume decreased by at least 50% compared with pre‐alteplase CT. Participants who failed treatment were then crossed over to the alternative group and administered the other therapy (alteplase 25 mg daily for 3 days or placebo). Participants who failed both arms of the trial were then offered surgical decortication. Further follow‐up CT was performed as 6 weeks.
Outcomes	Primary outcome Treatment success as defined as a minimum 50% reduction in CT pleural fluid volume compared with pre‐treatment CT. This parameter was used pre and post crossover and repeated at 6 to 12 weeks. Secondary outcomes Death Serious adverse events Hospital length of stay
Notes	Parapneumonic effusions and empyema. Inappropriate trial design, truncated for meta‐analysis prior to cross‐over. Funding: A restricted grant was sponsored by Genetech, Inc. for this trial. Monies was distributed to the Institutional Review Board at Methodist hospital and to the Pharmacy department per participant. Monies were also distributed per participant to the physician co‐investigators, nursing staff and Physicians Assitsant(s) that were involved in following the participants' care and collecting the data. Genetech did not have any input in any part of the protocol, in participant care or collection of data. Genetech was informed whenever a participant entered the trial and the drug alteplase was supplied free of charge to the participant. Genetech was not involved in writing up the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Hospital pharmacist randomised participants by a fixed‐allocation randomisation process using a computer‐based random sequence generator.
Allocation concealment (selection bias)	Low risk	Central control (pharmacist with no participant contact).
Blinding (performance bias and detection bias) All outcomes	Low risk	All investigators were blinded and the pharmacist had no contact with the participant.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All investigators were blinded, specifics not mentioned. Principal investigator sole assessor of pleural fluid outcomes (only reported outcomes).
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant number of post‐randomisation withdrawals.
Selective reporting (reporting bias)	Unclear risk	Planned primary outcome described as a 40% reduction in surgical intervention between alteplase and placebo groups. Note: all participants refused surgery. All "failures" (i.e. participants without 50% reduction in fluid volume) were offered surgery but no more details available. The secondary end point was a 50% difference in resolution of dyspnoea, sepsis syndrome and pneumonia between the 2 groups. Note: all participants refused surgery. Success instead reported as proportion of participants with at least 50% reduction in pleural fluid volume on radiologic examination. No description of proportion of participants with resolution of sepsis syndrome documented. Breathlessness mentioned as secondary outcome measure in protocol; not reported. However these outcomes (except treatment failure) were not included in the review, and so they have no effect on the review results.
Other bias	Unclear risk	Cross‐over study design inappropriate for a binary outcome such as requirement for surgery or death. This had no effect on the review, however, as we only used data from the first phase (i.e. before participants were crossed over).