Primary outcome
A primary outcome was attributed to 1136 of the 1150 included participants (99%), with 14 participants (1%) completely lost to follow-up. The occurrence of the primary outcome at any time up to 4 weeks after randomisation (number of participants not requiring further intervention for the symptomatic ureteric stone) was 307 out of 378 (81.2%) in the tamsulosin group and 304 out of 379 (80.2%) in the nifedipine group, compared with 303 out of 379 (79.9%) for those randomised to placebo. These primary results are described in more detail in using both raw and adjusted analyses. The full logistic regression model is detailed in Appendix 7.
Primary outcome: stone passage at 4 weeks (defined as number of participants not requiring further intervention)
We also recorded the number of participants having an intervention planned between 4 weeks and 12 weeks on the 12-week CRF. A further 27 (7.1%) participants in the tamsulosin group, 25 (6.4%) in the nifedipine group and 28 (7.4%) in the placebo group were recorded as having had an intervention between these time points.
Secondary outcomes
Estimated time to stone passage
The outcome for time to passage of stone as measured by clinical report, and confirmed by imaging, was available for 237 (21%) participants and showed no difference between groups ().
Pain
Participants scored the severity of pain during the day of completion of the baseline and 4-week questionnaire using the NRS.53,54 The duration of pain and use of analgesic medication was recorded as the number of days pain medication was used on the 4-week participant questionnaire. The results are shown in .
Health status
Generic health profile as measured by the SF-36 and EQ-5D at baseline and 4 weeks and 12 weeks after randomisation is shown in and .
Quality-of-life scores measured at baseline, 4 weeks and 12 weeks. Graphs summarise mean and SD for SF-36 physical component summary (PCS) and mental component summary (MCS), median and 25th to 75th centiles for the EQ-5D.
On both the EQ-5D and the SF-36 physical component summary, participants had impaired HRQoL at baseline which returned to population average (SF-36) or full health (EQ-5D) levels by 12 weeks. There was no evidence of a difference between any groups when comparing MET to placebo or tamsulosin to nifedipine at either of the time points. Owing to the high proportion of missing data, the robustness of these results was tested using multiple imputation and pattern mixture models. Younger participants and those with higher baseline SF-36 physical and mental component summary scores were less likely to respond at 4 weeks and 12 weeks. Multiple imputation models gave practically identical treatment effect estimates but with slightly tighter CIs for all treatment effect estimates in . The results were also robust when varying the pattern of missing data for all but implausible scenarios; for example, missing data in MET group were no different from observed data, but in the placebo group the missing data were over one-third of a SD lower (i.e. 3 points on the SF-36 physical component summary) than observed data. This was the case for all treatment effects summarised in .
Duration of hospitalisation
The number of participants with further hospital admissions was low and similar in all the groups (see Table 21). The average stay of additional hospital admissions up to 12 weeks after randomisation was 0.17 days (SD 0.64 days) in the tamsulosin group, 0.23 days (SD 1.06 days) in the nifedipine group and 0.25 days (SD 1.13 days) in the placebo group.
Significant clinical events
Participant discontinuation of trial medication was reported from responses to a single question on the 4-week participant questionnaire. Discontinuation rates solely as a result of side effects were 10% (25/247) for tamsulosin, 17% (40/241) for nifedipine and 6% (15/231) for placebo (). Serious adverse reactions (defined as SAEs that were thought to be possibly or definitely related to trial medication) were recorded by sites using a SAE form. The event rates are shown in with further details of the reactions reported in .
Discontinuation and serious adverse reaction rates
Details of reported serious adverse reactions
Subgroup analysis
We explored the potential moderating effect of several factors previously reported in the literature by analysing the following subgroups:
sex
stone size (≤ 5 mm, > 5 to 10 mm)
stone location (upper, mid, lower ureter).
Use of analgesia was considered as a subgroup analysis. However, as 98% of participants had used analgesia prior to randomisation it was therefore felt that any subgroup analysis would be uninformative.
Results of the subgroup analysis are summarised graphically using forest plots in and for MET versus placebo and tamsulosin versus nifedipine, respectively. The forest plots present ORs and 99% CIs. There was no evidence of any subgroup by treatment interaction. The p-values for the interaction terms were 0.59 for sex, 0.23 for stone size, and 0.12 for upper and 0.04 for mid ureter (with lower ureter as the reference location) for stone location comparing MET versus placebo. For tamsulosin versus nifedipine, these p-values were 0.39 for sex, 0.13 for stone size, 0.54 for upper ureter and 0.70 for mid ureter. The full breakdown of primary outcome by subgroup is summarised in Appendix 8.
Subgroup analysis: stone size and stone location on stone passage (MET vs. placebo).
Subgroup analysis: stone size and stone location on stone passage (tamsulosin vs. nifedipine).
