Clinical effectiveness of low-dose theophylline compared with placebo
In this chapter, we report the results of people with COPD being treated for 1 year with low-dose theophylline compared with placebo. A total of 1578 participants were randomised to theophylline or placebo; 11 post-randomisation exclusions resulted in 1567 participants being eligible to initiate trial medication and for whom baseline characteristics have been reported (see Chapter 3). Follow-up data were unavailable for 31 (2%) participants (theophylline, n = 16; placebo, n = 15); therefore, the results presented for the ITT analysis are based on 1536 participants (theophylline, n = 772; placebo, n = 764). shows the Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the ITT analysis. In total there were 1489 person-years of follow-up data: 747 person-years in the theophylline group and 742 person-years in the placebo group ().
The CONSORT flow diagram for the ITT analysis. a, Reasons for ineligibility were as follows: 16 did not meet the inclusion criteria for established COPD diagnosis or had a predominant respiratory disease other than COPD, 10 had not had two exacerbations (more...)
Exacerbation outcomes (ITT analysis)
Intention-to-treat analysis
Primary outcome: total number of exacerbations of chronic obstructive pulmonary disease necessitating a change in management
In total, 633 out of 772 (82.0%) participants allocated to theophylline had at least one exacerbation, with 1727 exacerbations in the group overall. Among participants allocated to placebo, 609 out of 764 (79.7%) had at least one exacerbation and there were 1703 exacerbations in the group overall. The mean number of exacerbations per participant was 2.24 (SD 1.99) in those allocated to low-dose theophylline and 2.23 (SD 1.97) in those allocated to placebo. The adjusted IRR for exacerbation was 0.99 (95% CI 0.91 to 1.08), indicating no difference in the exacerbation rate during the 12-month follow-up period between those on low-dose theophylline and those on placebo (see ).
The primary outcome was exacerbation treated with antibiotics and/or OCSs, but we also conducted analyses relating treatment with low-dose theophylline to differing levels of treatment for COPD exacerbations, that is antibiotics only, OCSs only or antibiotics and OCSs (see Appendix 5, Table 39). In the adjusted model, for exacerbations treated with antibiotics only, the IRR was 0.94 (95% CI 0.78 to 1.14); for exacerbations treated with OCSs only, the IRR was 0.88 (95% CI 0.62 to 1.25); and for exacerbations treated with antibiotics and OCSs, the IRR was 1.02 (95% CI 0.92 to 1.14).
Among participants allocated to low-dose theophylline, 106 (13.7%) had at least one exacerbation requiring hospital admission, with a total of 134 hospital admissions in the group. Among participants allocated to placebo, 130 (17.0%) had at least one exacerbation requiring hospital admission, and there were 185 admissions in total. A comparison of the proportion of participants with at least one exacerbation requiring hospital admission was not significant at the 5% level (13.7% in the theophylline arm vs. 17.0% in the placebo arm; p = 0.074). In the adjusted model, the IRR for exacerbations of COPD requiring hospital treatment was 0.72 (95% CI 0.55 to 0.94), suggesting that low-dose theophylline resulted in a reduction in the number of exacerbations requiring hospital admission when compared with placebo (see ). However, further exploration of the data showed that, in the theophylline group, only three participants had three or more exacerbations necessitating treatment in hospital (12 exacerbations in total), compared with 13 participants in the placebo group having three or more exacerbations necessitating hospital treatment (51 exacerbations in total). Therefore, a small excess of participants (n = 10) allocated to placebo who had three or more exacerbations requiring treatment in hospital accounted for 39 of the 51 excess admissions in the placebo group ().
Number of exacerbations requiring hospital admission
Secondary outcomes
Time to first exacerbation
The date of onset of the first exacerbation after commencing trial medication was not available for 27 of the 1242 participants who had at least one exacerbation; therefore, this analysis was based on 1509 participants in the ITT population [294 who had no exacerbation and 1215 (80.5%) who had an exacerbation]. Of the 756 participants allocated to theophylline, 617 (81.6%) had at least one exacerbation, with a median time to first exacerbation of 219 days (7.2 months) after randomisation. In the placebo group, 598 out of 753 (79.4%) participants had at least one exacerbation, with a median time to first exacerbation of 227 days (7.5 months). In a Cox regression analysis, the adjusted HR for the time to first exacerbation was 1.01 (95% CI 0.90 to 1.13), suggesting no significant difference between the treatment groups in terms of the time to first exacerbation (from point of randomisation) during the 12-month follow-up period (see ).
Total number of emergency hospital admissions (including those not related to chronic obstructive pulmonary disease)
Hospital admission data were available for 1517 of the 1536 participants in the ITT population (theophylline, n = 762; placebo, n = 755). A similar proportion of participants had at least one hospital admission for non-COPD-related causes. Among the participants allocated to low-dose theophylline, this proportion was 10.4% (79/762); among those allocated to placebo, it was 12.2% (92/755). In total, there were 116 hospital admissions among participants allocated to theophylline and 119 among those allocated to placebo. The adjusted IRR was 0.99 (95% CI 0.71 to 1.38), suggesting no significant difference in the rate of emergency (unscheduled) hospital admissions between the groups ().
Secondary clinical outcomes (ITT analysis)
Mortality (all cause and respiratory related)
There were 33 deaths (from all causes) during the 12-month follow-up period: 19 (2.5%) in the low-dose theophylline group and 14 (1.8%) in the placebo group. Respiratory-related disease accounted for seven deaths in theophylline group and eight deaths in the placebo group. Relative to the placebo group, the adjusted HR for death from all causes in the theophylline group was 1.38 (95% CI 0.69 to 2.76), and for respiratory-related causes it was 0.85 (95% CI 0.30 to 2.40). Therefore, there was no evidence of a significant difference between treatment groups for mortality outcomes (see ).
Total number of episodes of pneumonia
In total, there were 23 episodes of pneumonia reported during the follow-up: 14 in participants allocated to theophylline and nine in participants allocated to placebo (1.8% in the theophylline arm vs. 1.2% in the placebo arm). The proportion of admissions for pneumonia was not found to significantly differ between treatment groups (p = 0.307). The unadjusted odds ratio (OR) was 1.55 (95% CI 0.67 to 3.62); however, in the light of the small event counts, no adjustments were made (see ).
Total dose of inhaled corticosteroids
The total daily dose of ICSs at baseline was available for 1532 of the 1536 members of the ITT population (two missing from each treatment group). The mean total daily beclomethasone-equivalent ICS dose at baseline was 1662 µg (SD 677 µg) in those allocated to theophylline and 1680 µg (SD 691 µg) in those allocated to placebo. During the 12-month follow-up, 215 participants changed their medication: 104 (13.5%) theophylline participants and 111 (14.6%) placebo participants (p = 0.550). The mean total daily beclomethasone-equivalent dose at the end of follow-up was 1606 µg (SD 694 µg) in those allocated to theophylline and 1622 µg (SD 714 µg) in those allocated to placebo, resulting in an adjusted difference of –12.4 µg per day (95% CI –81.4 to 56.6 µg) for theophylline compared with placebo (see ). This lower dose at the end of follow-up in those taking theophylline was not significantly different from the dose for those taking placebo. Both groups showed a slight reduction in total daily dose from baseline to end of follow-up, but a comparison of the adjusted mean dose change between treatment groups was not significant (p = 0.852).
Lung function (% predicted forced expiratory volume in 1 second and forced vital capacity)
In the ITT analysis, lung function was found to be similar between the treatment groups with mean % predicted FEV1 (FEV1%) at the end of the 12-month follow-up of 51.5% (SD 20.4%) for participants allocated to low-dose theophylline (n = 533) and 52.1% (SD 21.7%) for participants allocated to placebo (n = 489). The overall difference in FEV1% predicted (across the 12-month period) was –0.56% (95% CI –2.42% to 1.30%) between the groups. A similar pattern was observed for % predicted FVC, with an overall significant difference of –0.28% (95% CI –2.33% to 1.76%) ().
Lung function (ITT analysis)
Modified Medical Research Council dyspnoea scale
details the responses to the mMRC breathlessness scale at baseline and at 6 and 12 months for each treatment group. The proportions of participants in each category are relatively similar in both groups at each time point. The overall adjusted OR () from the mixed-effects ordinal logistic regression for theophylline relative to placebo is 1.20 (95% CI 0.88 to 1.63), indicating a slight increase in odds of higher mMRC score in theophylline participants than in the placebo participants, but the increase is not significant.
The mMRC dyspnoea scale (ITT analysis)
The ORs for the mMRC dyspnoea scale (ITT analysis)
The COPD Assessment Test
The CAT scores were very similar between groups at baseline () and remained similar throughout the 12-month treatment period, with a mean score of 21.4 (SD 8.2) for participants allocated to low-dose theophylline (n = 633) and 21.4 (SD 8.6) for participants allocated to placebo (n = 615). A comparison of the profile of the CAT scores across the three time points (i.e. 0, 6 and 12 months) showed an adjusted difference of 0.01 (95% CI –0.65 to 0.68), suggesting no significant difference between the groups of the impact of COPD on the participants’ lives.
Participant-reported outcomes (ITT analysis)
Hull Airways Reflux Questionnaire
The HARQ assesses respiratory symptoms associated with airway reflux, and was completed by a subset of participants. Participants for whom HARQ data were available were more likely to be female and younger than those who had no HARQ data (see Appendix 5, Table 37). Data were available for 199 (26.0%) participants allocated to theophylline and 203 (26.9%) allocated to placebo at baseline. The HARQ scores were very similar between treatment groups throughout the trial and at the 12-month follow-up; for participants allocated to low-dose theophylline, the mean HARQ score was 24.1 (SD 15.7), based on 184 participants, and for those allocated to placebo, it was 24.2 (SD 15.9), based on 172 participants. A comparison of the profiles of HARQ scores across the three time points (i.e. 0, 6 and 12 months) revealed an adjusted difference of –1.10 (95% CI –3.46 to 1.26), suggesting no significant difference between the groups in reflux-associated respiratory symptoms measured by the HARQ (see ).
Safety outcomes (safety population)
The safety population comprised all participants who were randomised and included in the trial (n = 1567) and initiated their trial medication. Five out of 788 (0.6%) participants allocated theophylline did not initiate medication; 9 out of 779 (1.2%) participants in the placebo group did not initiate placebo. The safety population consisted of 1553 (99.1%) participants (theophylline, n = 783; placebo, n = 770).
Serious adverse events
Overall, 211 (13.6%) participants had at least one SAE, 103 (out of 783, 13.2%) in the low-dose theophylline group and 108 (out of 770, 14.0%) in the placebo group. A total of 276 SAEs were reported in individuals in the safety population. These were balanced between the treatment groups, with 141 in participants allocated to theophylline and 135 in placebo participants. SAEs were classified using System Organ Classes (SOCs).95
details, for each SOC code and for each treatment group, the number of participants experiencing at least one SAE of that code, and the total number of SAEs of that SOC code. No significant differences were observed in the SAE profile of the two treatment groups. The most common SAE SOC code was for ‘cardiac disorders’ [2.8% (2.3% in the theophylline arm and 3.4% in the placebo arm)]. SAEs with a coding of ‘respiratory, thoracic and mediastinal’ occurred in 2.5% of participants (2.3% in the theophylline arm and 2.7% in the placebo arm). A borderline significantly higher proportion of participants in the theophylline group (2.7%) reported a gastrointestinal SAE than in the placebo group (1.3%) (p = 0.051). No pregnancies were reported. Line listings are provided in Appendix 6.
Serious adverse events (ITT analysis)
Adverse reactions
Information on adverse reactions was available for 1408 participants (theophylline, n = 709; placebo, n = 699), with 648 (46%) suffering at least one AR (theophylline, n = 341; placebo; n = 307). There were 1701 ARs in total: 883 in those allocated to low-dose theophylline and 818 in those allocated placebo. presents these ARs in more detail, with total number available for analysis for each AR, number of participants with at least one AR of that type and the percentage in each group. The five most common ARs were nausea (10.9% in the theophylline arm and 8.0% in the placebo arm; p = 0.059), insomnia (9.3% in the theophylline arm and 8.9% in the placebo arm; p = 0.790), dizziness (8.1% in the theophylline arm and 9.6% in the placebo arm; p = 0.290), gastro-oesophageal reflux (9.4% in the theophylline arm and 7.5% in the placebo arm; p = 0.217) and headache (9.0% in the theophylline arm and 7.7% in the placebo arm; p = 0.383). In addition, the proportion reporting tachycardia was slightly higher in the placebo group (3.5%) than in the theophylline group (1.9%) (p = 0.058). There were no other observed significant differences in ARs between treatment groups.
Adverse reactions (ITT analysis)
Subgroup analysis (intention to treat)
Appendix 5, Table 40 details the results of the subgroup analysis for the prespecified subgroups. Given the exploratory nature of the analyses, we present 99% CIs. displays this information, alongside the p-values for the interaction in the adjusted model. There was no evidence at the 1% level of statistical significance that any effect of low-dose theophylline differed between subgroups of age, sex, smoking status, BMI, COPD treatments, exacerbation history, COPD severity, baseline ICS dose or use of maintenance OCSs.
Forest plot of estimates from the subgroups. Vertical dashed line represents no effect (IRR = 1), vertical solid line indicates the overall treatment effect for exacerbation (IRR = 0.992). a, Upper limit of CI truncated (more...)
Treatment adherence/compliance
Adherence/compliance was defined as having taken ≥ 70% of expected doses of trial tablets. In the ITT population (n = 1536), 1180 (76.8%) participants fulfilled the definition of adherent/compliant (and made up the per-protocol population). In the theophylline-allocated group, 181 out of 772 (23.4%) participants were classed as non-adherent/non-compliant; three of these never initiated treatment, 171 were non-persistent with (i.e. ceased) trial medication and seven persisted with trial medication but from returned medication it was evident that they were non-adherent/non-compliant (). In addition, 32 out of 591 low-dose theophylline participants fulfilled the adherent/compliant definition despite not persisting with the trial medication, usually very late in the treatment period (). In the placebo group, 175 out of 764 (22.9%) participants were classed as non-adherent/non-compliant; six never initiated medication, 159 were non-persistent with trial medication and 10 persisted with trial medication but medication returns demonstrated poor implementation (see ). A further 34 participants were non-persistent with medication but fulfilled the definition of adherent/compliant because they ceased trial medication late into the treatment period (see ). In summary, the per-protocol population comprises 1180 participants (591 from the theophylline arm and 589 from the placebo arm) and there were 1146 person-years of follow-up data (see ). A comparison of the proportion who were non-adherent/non-compliant (23.4% in the theophylline arm vs. 22.9% in the placebo arm) was not significant (p = 0.802). In total, 203 out of 772 participants in the theophylline arm were non-persistent with medication, compared with 193 out of 764 in the placebo arm (unadjusted IRR 1.05, 95% CI 0.84 to 1.32).
Reasons for stopping medication (of those who started)
Reasons for stopping medication
presents the reasons for stopping medication among the ITT population by SOC code. The most common reason for stopping medication was gastrointestinal disorders (theophylline, n = 46; placebo, n = 32), followed by surgical and medical procedures (theophylline, n = 19; placebo, n = 21). Although the surgical and medical procedures group included some participants who had discontinued ICSs containing inhalers, the majority of this group comprised participants advised to discontinue the trial drug by a clinician after presenting with a wide range of illnesses. In total, 46 participants discontinued the trial medication because they felt no benefit (theophylline, n = 25; placebo, n = 21), and in 64 cases no reason was given (theophylline, n = 28; placebo, n = 36), with a further 29 ceasing for social circumstances (theophylline, n = 15; placebo, n = 14). There were no obvious differences between the two treatment groups in the reasons why trial medication was discontinued, but no formal statistical testing was undertaken.
Per-protocol analysis
The per-protocol population comprised the 1180 participants of the ITT population who met the trial definition of adherence with the trial medication. The per-protocol analysis comprised 591 participants allocated to low-dose theophylline and 589 allocated to placebo ().
The CONSORT flow diagram for the per-protocol analysis.
Primary outcome: total number of exacerbations of chronic obstructive pulmonary disease necessitating a change in management
In the per-protocol population, 591 theophylline-allocated participants had a mean of 2.20 (SD 1.96) exacerbations, compared with a mean of 2.14 (SD 1.92) exacerbations among the 589 placebo participants. There were 1298 exacerbations in the theophylline group and 1258 in placebo group. The adjusted IRR for COPD exacerbation was 1.00 (95% CI 0.91 to 1.10), indicating no difference in the exacerbation rate during the 12-month follow-up period for those on low-dose theophylline compared with those receiving placebo who were adherent/compliant with the trial medication ().
Exacerbation outcomes (per-protocol analysis)
Secondary outcomes
Total number of exacerbations of chronic obstructive pulmonary disease resulting in hospital admission
In the per-protocol population, 76 out of 591 (13%) participants allocated to theophylline had at least one COPD exacerbation necessitating hospital admission; there were 92 admissions in the group overall. Among participants allocated to placebo, 88 out of 589 (15%) had at least one admission and there were 126 admissions overall. The mean number of COPD exacerbations necessitating hospital admission was 0.16 (SD 0.45) among the 591 compliant participants in the theophylline group and 0.21 (SD 0.61) among the 589 compliant participants in the placebo group. In the adjusted model, the IRR for COPD exacerbations necessitating hospital admission was 0.70 (95% CI 0.50 to 0.97), suggesting a significant reduction in the number of exacerbations necessitating hospital admission in the low-dose theophylline group compared with the placebo group (see ).
Time to first exacerbation
The information for the time to first exacerbation was missing for 19 of the 1180 per-protocol participants; therefore, this analysis was based on 1161 participants. Among participants allocated to theophylline, 468 out of 578 (81.0%) had at least one exacerbation, with a median time to first exacerbation of 221 days (7.3 months) after randomisation. In the placebo group, 459 out of 583 (78.7%) participants had at least one exacerbation, with a median time to first exacerbation of 232 days (7.7 months). In a Cox regression analysis, the adjusted HR for time to first exacerbation was 1.02 (95% CI 0.90 to 1.16), suggesting no difference between the treatment groups in terms of time to first exacerbation (from point of randomisation) during the 12-month follow-up period (see ).
Total number of emergency hospital admissions (non-chronic obstructive pulmonary disease related)
Hospital admission data were available for 1176 out of 1180 participants in the per-protocol population. Overall, 111 participants had at least one admission (theophylline, n = 45; placebo, n = 66), with 66 admissions in the theophylline group and 85 admissions in the placebo group. The adjusted IRR for admission was 0.82 (95% CI 0.54 to 1.24), suggesting no significant difference in the rate of non-COPD-related emergency hospital admissions between participants compliant with low-dose theophylline and those compliant with placebo ().
Secondary clinical outcomes (per-protocol analysis)
Mortality (all cause and respiratory related)
There were 22 deaths (from all causes) during the 12-month follow-up period in the per-protocol population: 13 (2.2%) in participants taking theophylline and nine (1.5%) in participants taking placebo. These deaths were respiratory related in five cases in each of the theophylline and placebo groups. The unadjusted HR for deaths from all causes was 1.45 (95% CI 0.62 to 3.38); for deaths from respiratory-related causes, the HR was 1.00 (95% CI 0.29 to 3.46) for theophylline relative to placebo (see ). Therefore, there was no evidence of a significant difference between treatment groups for mortality outcomes in the per-protocol population. No adjustments were made because of small event counts.
Total number of episodes of pneumonia
There were 14 episodes of pneumonia: nine (out of 591, 1.5%) among low-dose theophylline-adherent/compliant participants and five (out of 589, 0.9%) among placebo-compliant participants. The unadjusted IRR was 1.81 (95% CI 0.60 to 5.44) and no adjustments were made because of small event counts (see ).
Total dose of inhaled corticosteroids
The total daily dose of ICS at baseline was available for 1176 of the 1180 members of the per-protocol population. During the 12-month follow-up, 171 participants changed their medication: 78 (13.2%) theophylline participants and 93 (15.8%) placebo participants (p = 0.210). The mean total daily beclomethasone-equivalent dose at the end of follow-up was 1617 µg (SD 693 µg) in those allocated to theophylline and 1605 µg (SD 704 µg) in those allocated to placebo, resulting in an adjusted daily beclomethasone-equivalent difference of 12.5 µg (95% CI –65.9 to 90.9 µg) between theophylline and placebo (see ); this difference was not significantly different. Both groups showed a slight reduction in total daily dose from baseline to end of follow-up, but a comparison of the adjusted mean dose change between treatment groups revealed that the difference was not significant (p = 0.979).
Lung function (% predicted forced expiratory volume in 1 second and forced vital capacity)
In the per-protocol analysis, lung function profile was similar in both treatment groups. The mean % predicted FEV1 at the end of the 12-month follow-up period was slightly lower in the compliant/adherent theophylline group than in the placebo group [51.3% (SD 20.3%) (n = 455) vs. 52.6% (SD 21.8%) (n = 432)], giving an overall difference between the groups of –1.33% (95% CI –3.47% to 0.80%) (). A similar pattern was observed for % predicted FVC, with an overall difference of –0.65% (95% CI –2.96% to 1.67%). This was a larger reduction than that observed in the ITT analysis, but remained non-significant.
Lung function (per-protocol analysis)
Modified Medical Research Council dyspnoea scale
and detail the responses to the mMRC dyspnoea scale at baseline, 6 months and 12 months for each treatment group in the per-protocol population. In the unadjusted model, the OR for higher mMRC dyspnoea score in theophylline participants compared with placebo participants is 1.54 (95% CI 1.05 to 2.26); the adjusted OR is 1.39 (95% CI 0.97 to 1.98).
The mMRC dyspnoea scale (per-protocol analysis)
The ORs for the mMRC dyspnoea scale (per-protocol analysis)
The COPD Assessment Test
The CAT scores were very similar between treatment groups at baseline () and remained similar through to 12 months, with a mean score of 21.0 (SD 8.2) for theophylline-adherent/compliant participants (n = 534) and 20.9 (SD 8.7) for placebo participants (n = 527) in the per-protocol population. A comparison of the profile of the CAT scores across the three time points (0, 6 and 12 months) showed an adjusted difference of 0.29 (95% CI –0.45 to 1.04), suggesting that the impact of COPD on participants’ lives did not significantly different between the groups of the per-protocol population.
Patient-reported outcomes (per-protocol analysis)
Hull Airway Reflux Questionnaire
At 12 months, the mean HARQ score was 23.0 (SD 15.6) among 153 theophylline-adherent/compliant participants and 24.4 (SD 15.8) among 141 placebo-adherent/compliant participants. A comparison of the profile of the HARQ scores across the three time points (0, 6 and 12 months) showed an adjusted difference of –1.62 (95% CI –4.25 to 1.01), suggesting no significant difference between the per-protocol treatment groups in reflux-associated respiratory symptoms measured by the HARQ (see ).
Sensitivity analysis
We undertook a sensitivity analysis for the primary outcome and a number of secondary outcomes that excluded the 33 participants who died during the 12-month follow-up period. This left 1503 participants in the ITT population (753 theophylline and 750 placebo). Appendix 5, Tables 41 and 42, give the details of these analyses.
Primary outcome
After excluding participants who died, the adjusted IRR for COPD exacerbations was 0.99 (95% CI 0.91 to 1.07) (see Appendix 5, Table 41), indicating that restricting the result to those who were alive for the full 12-month follow-up did not change the result of the original ITT analysis (IRR 0.99, 95% CI 0.91 to 1.08).
Secondary outcomes
Hospital admissions
Excluding the 33 deaths from the analysis of COPD exacerbations necessitating hospital admission, the adjusted IRR was 0.73 (95% CI 0.55 to 0.97) in the remaining 1503 members of the ITT population, which is very similar to the treatment estimate observed for all 1536 members of the ITT population (IRR 0.72, 95% CI 0.55 to 0.94). Data on admission to hospital for non-COPD reasons were available for 1485 people, after excluding those who died. The adjusted IRR for admission for theophylline relative to placebo was 1.03 (95% CI 0.73 to 1.43), compared with 0.99 (95% CI 0.71 to 1.38) in the full ITT population.
Other
Excluding the 33 deaths made very little difference to the estimates of treatment effect on lung function (FEV1 or FVC) or to the patient-reported outcomes of CAT and HARQ scores (see Appendix 5, Table 42). For FEV1, the adjusted difference was –0.58% (95% CI –2.46% to 1.29%) compared with –0.56% (95% CI –2.42% to 1.30%). For FVC, the adjusted difference was –0.37% (95% CI –2.43% to 1.69%) compared with –0.28% (95% CI –2.33% to 1.76%) for the ITT population. For the CAT score, the treatment difference was 0.02 (95% CI –0.65 to 0.69) compared with 0.01 (95% CI –0.65 to 0.69) in the original ITT population. The HARQ analysis gave an adjusted difference of –0.89 (95% CI –3.27 to 1.50) compared with –1.10 (95% CI –3.46 to 1.26) of the original ITT population. In summary, excluding the 33 deaths made little or no difference to the estimates of treatment effect in the ITT population.
Summary
There was no evidence that, overall, low-dose theophylline significantly reduced the number of COPD exacerbations requiring treatment compared with placebo. There was some evidence that low-dose theophylline reduced exacerbations that necessitated hospital admission, with most benefit being evident in a small [1% (13/1556)] subgroup of patients frequently hospitalised with COPD. The total number of emergency hospital admissions (non-COPD related) did not significantly differ between groups, and nor did total episodes of pneumonia or mortality. Lung function was similar across the 12-month follow-up in the two groups. The impact of the disease on patients was measured by the CAT, mMRC dyspnoea scale and HARQ; no significant differences were found. The safety profile of low-dose theophylline was similar to placebo. There was no evidence that the treatment effect differed in any of the prespecified subgroups.
