Rapid Pleurodesis Through an Indwelling Pleural Catheter (RAPID)

A Randomized, Double Blinded, Controlled Trial of a Rapid Pleurodesis Protocol After Indwelling Pleural Catheter Placement for Malignant Pleural Effusions

The primary objective of the study is to evaluate whether the use of a rapid pleurodesis protocol using 10% iodopovidone immediately after tunneled pleural catheter placement improves time to IPC removal compared to patients who receive an IPC alone.

Patients will be screened throughout the year as part of the clinical referral process to the Interventional Pulmonology service at the Hospital of the University of Pennsylvania for the management of a malignant pleural effusion. Patients eligible for inclusion based on the clinical evaluation will be approached for enrollment. Written consent will be obtained. Patients will subsequently undergo placement of a IPC under MAC as per standard clinical practice followed by complete drainage of the pleural space. Patients randomized to the rapid pleurodesis protocol arm will received 20mL of 10% iodopovidone mixed with 80mL of normal saline instilled intrapleurally through the IPC. Patients randomized to the standard of care arm will have 100mL of normal saline (placebo) instilled intrapleurally through the IPC. The mixture will be allowed to dwell for 2 hours and then completely evacuated through the IPC and the patient will be discharged home. After discharge, all patients will continue to drain their IPC on a daily basis for 7 days. Following this, all patients will continue to drain their IPC on an every-other-day basis until total IPC output is less than 50ml per session over 3 consecutive sessions. At which point they will be asked to undergo a clamp trial of no drainage for 7 days followed by a reattempt at drainage. Patients without return of symptoms over those 7 days and minimal drainage afterwards (<50ml) will be seen in the office for possible IPC removal. Patients with return of symptoms during those 7 days or more than minimal drainage afterwards (>50mL) will be asked to continue drainage until total IPC output is again less than 50mL per session over 3 sessions. After a passed clamp trial, patients will be evaluated in the office with a bedside ultrasound to assess for pleural apposition in 5 of 6 designated points and the absence of pleural effusions. If all criteria are met, the IPC is removed. If there is evidence of residual effusion, continued drainage will be advised. All patients will be evaluated in the office on day 7, day 14, day 30, day 60 and day 90 after IPC placement. On each visit they will be assessed for pleural apposition with ultrasound. At day 30, 60, and 90 all patients will receive a global health related questionnaire (EORTC QLQ30) and a symptom questionnaire. At 90 days, complications rate will be assessed for the entire study period.

Subject assignment will be done using randomly generated assignment tables based on stratification by tumor type (Lung, Breast, Other) and assigned 1:1 using random permuted blocks of 4. Subjects will be blinded to their group assignment to minimize bias on follow up surveys. Physicians evaluating the patient during the initial visit and on subsequent postprocedure followup will be blinded to subject assignment. The provider responsible for placement of the catheter and delivery of the pleurodesis agent or placebo will not be involved in post procedure followup care All treatment physicians will follow prespecified protocols in deciding on adequate pleurodesis and timing of IPC removal.

Subjects in this arm will receive placebo only (100mL of normal saline) into the pleural space delivered via the newly placed tunneled intrapleural catheter

Subjects in this arm will receive the chemical pleurodesing agent of 10% iodopovidone solution delivered to the pleural space via the newly placed tunneled intrapleural catheter

The pleural space will be evacuated completely through the newly placed IPC 20mL of 10% iodopovidone and 80mL of normal saline will be instilled into the pleural space The patient will be transferred to the recovery unit Two hours after instillation the pleural space will be drained After recovery from anesthesia and complete drainage of the pleurodesis mix, the subject will be discharged Subjects will be asked to drain their effusion on a daily basis for the next 7 days and then on an every other day basis.

The pleural space will be evacuated completely through the newly placed IPC Only placebo (normal saline) will be instilled into the pleural space The patient will be transferred to the recovery unit Two hours after instillation the pleural space will be drained After recovery from anesthesia and complete drainage of the pleurodesis mix, the subject will be discharged Subjects will be asked to drain their effusion on a daily basis for the next 7 days and then on an every other day basis.

Time to IPC removal will be measured in days from the day of IPC placement to the day of IPC removal after meeting removal criteria as listed above.

The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQC30) will be used to assess global health-related quality of life. This is a 30-item questionnaire validated for use in patients with cancer. The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

We will use a 5 point Likert scale (5PLS) that has been created for the trial. Patients will be asked to indicate their degree of shortness of breath or chest pain during sitting, walking and lying down/sleeping on that specific day. Thus, a total of 6 scales will be utilized. Point 1 will be described as "no shortness of breath" or "no chest pain." Point 2 will be described as "mild shortness of breath" or "mild chest pain." Point 3 will be described as "moderate shortness of breath" or "moderate chest pain." Point 4 will be described as "severe shortness of breath" or "severe chest pain." Point 5 will be described as "Worst shortness of breath possible" or "Worst chest pain possible."

This will be measured in days from the day of IPC removal to the day of return of a clinically significant pleural effusion in the same hemithorax that originally required IPC placement. A clinically significant reaccumulation of pleural fluid will be defined as an effusion with a maximum fluid depth greater than 25% of the AP window on chest CT or 1cm thoracic ultrasound along the lateral 1/3 of the thorax that is associated with shortness of breath or chest pain

Successful pleurodesis will be defined as removal of the IPC with no clinically significant reaccumulation of pleural fluid as evaluated by chest CT or thoracic ultrasound. A clinically significant reaccumulation of pleural fluid will be defined as an effusion with a maximum fluid depth greater than 25% of the AP window on chest CT or 1cm thoracic ultrasound along the lateral 1/3 of the thorax that is associated with shortness of breath or chest pain.

Inclusion Criteria: Diagnosis of MPE as defined by A diagnosis a pleural effusion in the setting of known malignancy. AND Confirmed malignant involvement of the pleural space by fluid cytology or pleural biopsy. OR Evidence of pleural disease on radiographic imaging. OR A recurrent effusion with no other identifiable cause after thorough workup. Symptomatic from the pleural effusions (shortness of breath, cough, or chest pain) Prior thoracentesis with post procedure symptomatic relief Recurrence of symptoms with re-accumulation of pleural effusion Lung re-expansion after thoracentesis on chest imaging within last 30 days Exclusion Criteria: Malignant pleural effusion due to a hematologic malignancy ECOG >4 Any history of trapped lung Prior attempted pleurodesis on the affected site Age <18 Pregnant or lactating Known allergy to iodopovidone (Betadine) Unable or unwilling to provide consent Uncorrectable coagulopathy (INR > 1.5, aPTT > 1.5 x the upper limit of normal) or thrombocytopenia (< 50,000) Anatomic contraindication to IPC (overlying skin abnormalities) Unable or unwilling to care for IPC and adhere to drainage protocol Need for bilateral IPC placement

Antunes G, Neville E, Duffy J, Ali N; Pleural Diseases Group, Standards of Care Committee, British Thoracic Society. BTS guidelines for the management of malignant pleural effusions. Thorax. 2003 May;58 Suppl 2(Suppl 2):ii29-38. doi: 10.1136/thorax.58.suppl_2.ii29. No abstract available.

American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000 Nov;162(5):1987-2001. doi: 10.1164/ajrccm.162.5.ats8-00. No abstract available.

Davies HE, Mishra EK, Kahan BC, Wrightson JM, Stanton AE, Guhan A, Davies CW, Grayez J, Harrison R, Prasad A, Crosthwaite N, Lee YC, Davies RJ, Miller RF, Rahman NM. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012 Jun 13;307(22):2383-9. doi: 10.1001/jama.2012.5535.

Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ; BTS Pleural Disease Guideline Group. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010 Aug;65 Suppl 2:ii32-40. doi: 10.1136/thx.2010.136994. No abstract available.

Wahidi MM, Reddy C, Yarmus L, Feller-Kopman D, Musani A, Shepherd RW, Lee H, Bechara R, Lamb C, Shofer S, Mahmood K, Michaud G, Puchalski J, Rafeq S, Cattaneo SM, Mullon J, Leh S, Mayse M, Thomas SM, Peterson B, Light RW. Randomized Trial of Pleural Fluid Drainage Frequency in Patients with Malignant Pleural Effusions. The ASAP Trial. Am J Respir Crit Care Med. 2017 Apr 15;195(8):1050-1057. doi: 10.1164/rccm.201607-1404OC.

Lui MM, Thomas R, Lee YC. Complications of indwelling pleural catheter use and their management. BMJ Open Respir Res. 2016 Feb 5;3(1):e000123. doi: 10.1136/bmjresp-2015-000123. eCollection 2016.

Reddy C, Ernst A, Lamb C, Feller-Kopman D. Rapid pleurodesis for malignant pleural effusions: a pilot study. Chest. 2011 Jun;139(6):1419-1423. doi: 10.1378/chest.10-1868. Epub 2010 Oct 7.

Krochmal R, Reddy C, Yarmus L, Desai NR, Feller-Kopman D, Lee HJ. Patient evaluation for rapid pleurodesis of malignant pleural effusions. J Thorac Dis. 2016 Sep;8(9):2538-2543. doi: 10.21037/jtd.2016.08.55.

Boujaoude Z, Bartter T, Abboud M, Pratter M, Abouzgheib W. Pleuroscopic Pleurodesis Combined With Tunneled Pleural Catheter for Management of Malignant Pleural Effusion: A Prospective Observational Study. J Bronchology Interv Pulmonol. 2015 Jul;22(3):237-43. doi: 10.1097/LBR.0000000000000186.

Ahmed L, Ip H, Rao D, Patel N, Noorzad F. Talc pleurodesis through indwelling pleural catheters for malignant pleural effusions: retrospective case series of a novel clinical pathway. Chest. 2014 Dec;146(6):e190-e194. doi: 10.1378/chest.14-0394.

King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res. 1996 Dec;5(6):555-67. doi: 10.1007/BF00439229.

Sivakumar P, Douiri A, West A, Rao D, Warwick G, Chen T, Ahmed L. OPTIMUM: a protocol for a multicentre randomised controlled trial comparing Out Patient Talc slurry via Indwelling pleural catheter for Malignant pleural effusion vs Usual inpatient Management. BMJ Open. 2016 Oct 18;6(10):e012795. doi: 10.1136/bmjopen-2016-012795. Erratum In: BMJ Open. 2016 Nov 14;6(11):e012795corr1.

Neto JD, de Oliveira SF, Vianna SP, Terra RM. Efficacy and safety of iodopovidone pleurodesis in malignant pleural effusions. Respirology. 2010 Jan;15(1):115-8. doi: 10.1111/j.1440-1843.2009.01663.x. Epub 2009 Nov 23.

Agarwal R, Paul AS, Aggarwal AN, Gupta D, Jindal SK. A randomized controlled trial of the efficacy of cosmetic talc compared with iodopovidone for chemical pleurodesis. Respirology. 2011 Oct;16(7):1064-9. doi: 10.1111/j.1440-1843.2011.01999.x.

Olivares-Torres CA, Laniado-Laborin R, Chavez-Garcia C, Leon-Gastelum C, Reyes-Escamilla A, Light RW. Iodopovidone pleurodesis for recurrent pleural effusions. Chest. 2002 Aug;122(2):581-3. doi: 10.1378/chest.122.2.581.

Godazandeh G, Qasemi NH, Saghafi M, Mortazian M, Tayebi P. Pleurodesis with povidone-iodine, as an effective procedure in management of patients with malignant pleural effusion. J Thorac Dis. 2013 Apr;5(2):141-4. doi: 10.3978/j.issn.2072-1439.2013.02.02.

Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Efficacy and safety of iodopovidone in chemical pleurodesis: a meta-analysis of observational studies. Respir Med. 2006 Nov;100(11):2043-7. doi: 10.1016/j.rmed.2006.02.009. Epub 2006 Mar 30.