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1 Supplementary Online Content Rahman NM, Pepperell J, Rehal S, et al. Effect of opioids vs NSAIDs and larger vs smaller chest tube size on pain control and pleurodesis efficacy among patients with malignant pleural effusion: the TIME1 randomized clinical trial. JAMA. doi: /jama eappendix 1. Pleurodesis Standard Operating Procedures eappendix 2. Data Quality and Numbers of Patients in Analyses eappendix 3. Per Protocol Analysis Results eappendix 4. Subgroup Analyses for Pain and Pleurodesis Failure eappendix 5. Adverse Events eappendix 6. Time in Hospital and Time With Drain in Situ eappendix 7. Additional Data for Figure 3 (Pain Analysis) eappendix 8. Details of Pleurodesis Failure by % Opacity on Chest X-Ray eappendix 9. Missing Data on VAS Scores by Time Point for Primary Outcome This supplementary material has been provided by the authors to give readers additional information about their work.

2 eappendix 1. Pleurodesis Standard Operating Procedures Oxford Respiratory Trials Unit Standard Operating Procedure (TIME1) Talc Slurry Pleurodesis via chest drain SOP Title: TIME 1 Author: Dr N M Rahman Reviewer: Dr H Davies Authoriser: Dr RJO Davies Version number and date: Version th November 2008 Purpose: To describe (1) when talc slurry pleurodesis is indicated for patient participating in the TIME1 trial and (2) how to administer talc slurry via the chest tube Scope of this SOP: The scope of this SOP will relate to all patients participating in the TIME1 trial (who are undergoing non-thoracoscopic talc pleurodesis) Responsible personnel: Research doctors and doctors involved in care of the patients on the hospital ward Procedure Timing When pleural fluid drainage is <150ml / 24hrs and / or when a good radiological result is seen (to be decided at the local clinicians discretion). Data required Chest X-ray PA (and lateral if possible) Patient pleural fluid monitoring chart Method 1. Discuss indication for talc pleurodesis with patient 2. Outline benefit of pleurodesis Reduces likelihood of pleural effusion recurrence 3. Explain potential side effects Fever, chest pain Rarely respiratory failure as a result of adult respiratory distress syndrome 4. Obtain written informed consent 5. Consider pre-medication Opioid analgesia: orally (e.g. oramorph 5-10mg) / intravenous (IV): mg morphine sulphate Sedation: midazolam 1-2mg IV (Take care in the elderly patient and those with respiratory failure)

3 6. Prepare a trolley with: Procedure pack 50ml Leur-lock syringe 2 x 20ml Leur-lock syringes 2 green needles 60mls normal saline 15ml 2% lignocaine local anaesthetic or 30mls 0.25% bupivucaine 4g sterile talc powder (high grade) 7. Administer intra-pleural local anaesthetic (15mls of 2% lignocaine) 8. Clamp drain and leave for 5-10 minutes during this time prepare talc pleurodesis slurry by adding the 4g talc powder to 40ml of normal saline (use the 50ml syringe) 9. Administer sterile talc slurry followed by drain flush with the remaining 20ml normal saline 10. Clamp chest drain for 1 hour following talc slurry and then open and leave tube on free drainage 11. In the event of any increasing breathlessness during this one hour period, the drain may be unclamped and fluid allowed to drain off. 12. Apply suction starting at 5cm H 2 O and increased incrementally to 20cm H 2 O if tolerated by the patient over the following 4 hour period 13. Ensure TIME1 related analgesia is prescribed on the drug chart and tell patient to let nursing staff know if pain worsens or he/she feels more breathless 14. Ensure that VAS scores are collected by the patient

4 eappendix 2. Data Quality and Numbers of Patients in Analyses Primary outcomes Pain (VAS) score 24F 12F Opiate NSAID Number included in analysis 56 (98%) 54 (95%) 155 (97%) 153 (96%) Pleurodesis failure At 4 weeks 51 (89%) 50 (88%) 152 (95%) 145 (91%) At 12 weeks 40 (70%) 42 (74%) 135 (84%) 129 (81%) Number included in analysis 50 (88%) 50 (88%) 150 (94%) 144 (90%) Table 2.1 Primary outcomes (ITT) Pain (VAS) score Number included in analysis Pleurodesis failure At 4 weeks At 12 weeks Number included in analysis 24F (n=263) 254 (97%) 247 (94%) 222 (84%) 244 (93%) 12F 54 (95%) 50 (88%) 42 (74%) 50 (88%) Opiate 155 (97%) NSAID 153 (96%) Table 2.2 Secondary comparison on primary outcome (ITT; including both thoracoscopic and nonthoracoscopic population) Primary outcomes 24F (n=52) 12F (n=44) Opiate (n=146) NSAID (n=147) Pleurodesis failure At 4 weeks 47 (90%) At 12 weeks 36 (69%) Number included in analysis 46 (88%) 42 (95%) 36 (82%) 42 (95%) 140 (96%) 127 (87%) 140 (96%) 139 (95%) 123 (84%) 137 (93%) Table 2.3 Primary outcome (PP)

5 Secondary outcomes Rescue medication taken during hospital stay Number included in analysis Pleural procedure (clinician assessed) up to 12 weeks post randomisation 24F 57 Number included in analysis 56 (98%) Time from randomisation to pleurodesis failure up to 6 months 4 weeks 51 (89%) 12 weeks 40 (70%) 6 months 29 (51%) Number included in analysis 51 (89%) Pain (VAS) scores Number included in analysis at 4 weeks 32 (56%) Number included in analysis at 12 weeks 25 (44%) All-cause mortality up to 12 months Number included in analysis Days from randomisation to hospital discharge 57 Number included in analysis 56 (98%) Table 2.4 Secondary outcomes (ITT) 12F (88%) 42 (74%) 31 (54%) 51 (89%) 32 (56%) 21 (37%) (98%) Opiate (99%) 152 (95%) 135 (84%) 112 (70%) 152 (95%) 117 (73%) NSAID (97%) 145 (91%) 129 (81%) 109 (68%) 146 (91%) 109 (68%) 96 (60%) 88 (55%) (99%) (98%)

6 eappendix 3. Per Protocol Analysis PP analysis 24F 12F Opiate NSAID Pleurodesis failure at 12 weeks - n (%) 10/46 (22%) 9/42 (21%) 25/140 (18%) 29/137 (21%) Difference in proportions and 90% CI -0.4% (-15% to 14%) -3% (-11% to 5%) p-value (for non-inferiority) Table 3.1. Per protocol analysis pleurodesis failure. 24F 12F Opiate NSAID PP analysis Pleurodesis failure at 12 45/235 9/42 weeks - n (%) (19%) (21%) Difference in proportions -2% and 90% CI (-14% to 9%) p-value (for non-inferiority) 0.03 Table 3.2. Per protocol analysis - pleurodesis failure (secondary comparison: both thoracoscopic and non-thoracoscopic patients)

7 eappendix 4. Subgroup Analyses for Pain and Pleurodesis Failure Analgesia regimen: a) Mesothelioma vs. no mesothelioma: The interaction test comparing opiates (control) vs. NSAID for the average pain score up to 5 days is not statistically significant at the 5% level (P=0.31). The interaction test comparing opiates (control) vs. NSAID for pleurodesis failure up to 12 weeks failed to converge. This is because there are a total of 9 patients that have mesothelioma compared with 109 who do not. b) Thoracoscopic procedure vs. non-thoracoscopic procedure (including all patients): The interaction test comparing opiates (control) vs. NSAIDS for the average pain score up to 5 days is not statistically significant at the 5% level (P=0.17). The interaction test comparing opiates (control) vs. NSAIDS for pleurodesis failure up to 12 weeks is not statistically significant at the 5% level (P=0.48). Drain size: a) Mesothelioma vs. no mesothelioma: The interaction test comparing 24F (control) vs. 12F (only including non-thoracoscopic patients) for the average pain score up to 5 days is not statistically significant at the 5% level (P=0.70). The interaction test comparing 24F (control) vs. 12F (only including non-thoracoscopic patients) for pleurodesis failure up to 12 weeks is not statistically significant at the 5% level (P=0.71).

8 eappendix 5. Adverse Events Adverse events summarised by severity, relatedness (as judged by local investigator adverse event clinically possible to be associated with the intervention) and treatment group (includes only non-thoracoscopic patients by tube size group): Severity Relatedness 12F (N=57) 24F (N=57) Mild Yes 26 (72%) 30 (67%) No 10 (38%) 15 (33%) Total 36 (24) 45 (24) Moderate Yes 8 (36%) 7 (27%) No 14 (64%) 19 (73%) Total 22 (16) 26 (15) Severe Yes 2 3 No 0 (0%) 0 (0%) Total 2 (2) 3 (3) Table 5.1. Adverse events by tube size group. Total is the total number of Adverse Events (number of patients). For example, there are 36 Adverse Events classed as being related with mild severity within 24 patients on the 12F group. Adverse events summarised by severity, relatedness and treatment group (analgesia comparison): Severity Relatedness NSAID (N=160) Opiate - control (N=160) Mild Yes 42 (54%) 61 (63%) No 36 (46%) 36 (37%) Total 78 (48) 97 (60) Moderate Yes 11 (34%) 13 (36%) No 21 (66%) 23 (64%) Total 32 (23) 36 (26) Severe Yes 0 (0%) 0 (0%) No 5 2 Total 5 (5) 2 (2) Table 5.2. Adverse events by analgesia group. Total is the total number of Advere Events (number of patients). For example, there are 78 Adverse Events classed as being related with mild severity within 48 patients in the NSAID group.

9 eappendix 6. Time in Hospital and Time With Drain in Situ Secondary outcomes Number of days from randomisation to hospital discharge median (IQR) Hazard ratio and 95% CI 24F 8 (5 to 13) 12F Opiate NSAID 6 (5 to 9) 5 (3 to 7) 4 (2 to 7) 1.28 (0.89 to 1.84) P-value (0.88 to 1.37) Table 6.1 Time in hospital comparing treatment groups.

10 eappendix 7. Additional Data for Figure 3 (Pain Analysis) The following table summarises the number of patients who had available VAS scores at each time point (hours), by analgesia regimen in relation to Figure 3 in the main manuscript: t (hours) Opiate NSAID 8 8 (5%) 5 (3%) (31%) 38 (24%) (74%) 122 (76%) (91%) 147 (92%) (93%) 149 (93%) (90%) 146 (91%) (89%) 145 (91%) (86%) 140 (88%) (88%) 143 (89%) (84%) 136 (85%) (69%) 118 (74%) (61%) 104 (65%) (64%) 99 (62%) (59%) 92 (58%) (52%) 75 (47%) (46%) 68 (43%) (46%) 67 (42%) (40%) 65 (41%) (35%) 56 (35%) (31%) 49 (31%) (32%) 49 (31%) (26%) 45 (28%) (22%) 35 (22%) (19%) 35 (22%) Table 7.1. Number of patients with available VAS scores at each time point for Figure 3, opiate versus NSAID comparison.

11 The following table summarises the number of patients who had available VAS scores at each time point (hours), by tube size in relation to Figure 3 in the main mansuscript: t 24F 12F 8 6 (11%) 5 (9%) (21%) 8 (14%) (60%) 41 (72%) (93%) 52 (91%) (98%) 51 (89%) (95%) 49 (86%) (89%) 49 (86%) (91%) 46 (81%) (89%) 49 (86%) (89%) 47 (82%) (88%) 46 (81%) (82%) 42 (74%) (89%) 47 (82%) (89%) 44 (77%) (84%) 39 (68%) (77%) 36 (63%) (75%) 37 (65%) (74%) 33 (58%) (68%) 31 (54%) (63%) 27 (47%) (67%) 27 (47%) (61%) 22 (39%) (51%) 19 (33%) (49%) 18 (32%) Table 7.2. Number of patients with available VAS scores at each time point for Figure 3, tube size comparison.

12 eappendix 8. Details of Pleurodesis Failure by % Opacity on Chest X-Ray Number of patients who had at least one result of pleural opacity >=50% either at week 4 or week 12 (i.e. patients with at least one result >=50% only at week 4 or week 12 after enrolment): n (%) >= 50% <50% Missing 24F 9 (15.8%) 31 (54.4%) 17 (29.8%) 12F 13 (22.8%) 28 (49.1%) 16 (28.1%) Table 8.1 Drain comparison all patients Of the 22 patients who had pleural opacity >=50 (missing means patients were missing whether or not a further pleural intervention was required): n (%) Had further pleural intervention Did not have further pleural intervention Missing 24F (n=9) 4 (44.4%) 5 (55.6%) 0 12F (n=13) 7 (53.9%) 5 (38.5%) 1 (7.7%) Table 8.2 Drain comparison large effusions Of the 59 patients who had pleural opacity <50 (missing means patients were missing whether or not a further pleural intervention was required): n (%) Had further plural intervention Did not have further pleural intervention Missing 24F (n=28) 7 (22.6%) 22 (71%) 2 (6.5%) 12F (n=31) 6 (21.4%) 22 (78.6%) 0 Table 8.3 Drain comparison <50% effusions n (%) >= 50% <50% Missing Opiate 30 (18.8%) 88 (55%) 42 (26.3%) NSAID 24 (15%) 92 (57.5%) 44 (27.5%) Table 8.4 Analgesia comparison all patients

13 Of the 54 patients who had pleural opacity >=50 (missing means patients were missing whether or not a further pleural intervention was required): n (%) Had further plural intervention Did not have further pleural intervention Missing Opiate (n=30) 15 (50%) 14 (46.7%) 1 (3.3%) NSAID (n=24) 10 (41.7%) 14 (58.3%) 0 Table 8.5 Analgesia comparison large effusions Of the 180 patients who had pleural opacity <50 (missing means patients were missing whether or not a further pleural intervention was required): n (%) Had further plural intervention Did not have further pleural intervention Missing Opiate (n=88) 11 (12.5%) 76 (86.4%) 1 (1.1%) NSAID (n=92) 17 (18.5%) 72 (78.3%) 3 (3.3%) Table 8.6 Analgesia comparison - <50% effusions

14 eappendix 9. Missing Data on VAS Scores (Primary Outcome) Day Day of tube insertion AM Total number of patients missing data (out of 320) not included in imputation model Day of tube insertion PM 8 (2.5%) Day 1 AM 4 (1.3%) Day 1 PM 8 (2.5%) Day 2 AM 4 (1.3%) Day 2 PM 2 (0.6%) Day 3 AM 0 Day 3 PM 5 (1.6%) Day 4 AM 3 (0.9%) Day 4 PM 5 (1.6%) Day 5 AM 0 Day 5 PM not included in imputation model Table 9.1 Number of missing VAS data points by time point.