| Study |
Bias |
| Randomisation process |
Deviations from intended interventions |
Missing outcome data |
Measurement of the outcome |
Selection of the reported results |
Overall |
| Authors' judgement |
Support for judgement |
Authors' judgement |
Support for judgement |
Authors' judgement |
Support for judgement |
Authors' judgement |
Support for judgement |
Authors' judgement |
Support for judgement |
Authors' judgement |
Support for judgement |
| ACTRN12605000631606 |
Low risk of bias |
"Stratified block randomisation by age (3‐5, 6‐10, 11‐14), gender, centre". "Sequential study number allocated from a list according to blocking details". "...blocking details emailed to Dept of Epidemiology and Preventative Medicine, Monash Med School, Melbourne". "Study puffer number was allocated. Pre‐numbered puffers were held at RCH Brisbane pharmacy". Imbalances noted in disease characteristics (higher proportion of patients in the intervention group than the control group had persistent asthma and atopic history), but likely to be down to chance given sample size. |
High risk of bias |
Placebo inhalers were used to presume this was to blind participants and personnel from the study medication, but no explicit definition of masking procedures. No details about how they monitored or increased adherence to the intervention so unsure whether there were failures in implementing it. No details about methods to derive an unbiased estimate of the effect of adhering to intervention. |
Low risk of bias |
Have assumed that all participants who used oral steroid rescue had an exacerbation. Outcome data accounted for and a much higher number of events than those who withdrew. |
Low risk of bias |
The method of measuring the outcome was appropriate. Measurment of the outcome likely to be the same between the groups. Clear instructions for what to do in the event of worsening symptoms and called weekly by study nurse ‐ all events likely to have been recorded. The outcome assessor was the study participant (who was blinded). |
Some concerns |
Trial registered (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=630) but after participant enrollment was completed. No details about the analyses available. No published journal report. The numerical result is not likelyt to have been selected on the basis of the results from multiple outcome measurements or analyses. |
High risk of bias |
Used tool algorithm. |
| FitzGerald 2004 |
Low risk of bias |
Patients were randomised to treatment groups at visit 2 according to a blocked computer generated randomisation list for each centre. As a randomisation list was generated for each centre, this sounds like it was centrally generated. Baseline characteristics not shown for the full population, only those who had an exacerbation and started the study inhaler. Paper states that "there were no differences in patient characteristics between those who experienced an exacerbation and those who did not". |
Low risk of bias |
Methods state 'double blind' so assume this means participants. The participants themselves delivered the intervention. Participants used a computerised diary to track doses. Authors state that compliance to the intervention was high for both groups. |
High risk of bias |
Statistical analysis used the "all patients treated" (APT) approach but most did not meet the threshold to start the study inhaler and so were not included in the analysis. In the full population, Of the 148 randomised to the control group, 115 completed the study (22% dropout), and 117/142 in the intervention group completed the study (17.6% dropout) which is higher than the % who experienced an event in each group. Patients who discontinued who did not use the study inhaler might have done so for reasons relating to their disease worsening, but the CONSORT diagram does not suggest that this was the case although the most common reason is 'other' in both groups. |
Low risk of bias |
Method of measuring the outcome was appropriate. Measurement of the outcome was the same between intervention groups. The study participant (who was blinded) entered details into an electronic diary with thorough pre‐defined criteria on the outcome. |
Some concerns |
No study protocol or trial registration record is available. Clear definition of outcome and timepoints. |
High risk of bias |
Used the tool algorithm. |
| Garrett 1998 |
Low risk of bias |
Only information about the allocation is that the children were randomised by the hospital pharmacist and the investigators were blinded to this allocation. Baseline characteristics were not provided by intervention group. |
Some concerns |
Used a blinded inhaler delivered by the participant. Participants' were familiarised with the intervention and recording during the run‐in period. Authors state that 95% of all the diary entries during an exacerbation period were completed and the study protocol was followed correctly in all but five exacerbations. Authors included the data from the five exacerbations where the protocol was not followed in the analysis. Five deviations from the protocol involved the study inhaler being used for an incorrect number of days, which could have affected the outcome (additional active ingredient). Authors state that the approach was appropriate as it reflects the reality of asthma treatment and adherence. In the review, cross‐over data were included by obtaining two‐by‐two data and applying a formula to account for inter‐correlation of matched pairs (Elbourne 2002). |
High risk of bias |
Only participants who had two matching pairs of exacerbations were analysed, which was 18 out of 28 enrolled. Those who had 1 or 3+ exacerbations during the study were not included. No anlyses were reported to address bias from missing outcome data. Reported reason for excluding from analyses was that they had good health status (no exacerabtions). Those who had 1 or 3+ exacerbations during the study were not included. |
Low risk of bias |
Method for measuring the outcome was appropriate, and unlikely to differ between groups. Reported that investigators were blinded to the allocation. |
Some concerns |
No trial registration, study protocol or SAP (even though article mentions a study protocol). The numerical result is not likely to have been selected on the basis of the results from multiple outcome measurements or analyses. |
High risk of bias |
Used tool alogorithm.
Domain S = LOW RISK OF BIAS
SQ1 = NI on whether the number of participants allocated to each of the two sequences equal or nearly equal.
SQ2 = LOW ‐ Cross‐over data were included in the review by obtaining two‐by‐two data and applying a formula to account for inter‐correlation of matched pairs (Elbourne 2002).
SQ3 = LOW ‐ Sufficient time was given for carryover effects to have disappeared before outcome assessment in the second period ‐ followed for two weeks and study tated that spirometry returned to normal within 1 week |
| Harrison 2004 |
Low risk of bias |
An independent pharmacist randomly allocated individuals using computer generated random number tables. Statistical tests for imbalances not presented but group differences at baseline do not suggest a problem with randomisation. |
High risk of bias |
Study report does not explicitly state "double‐blind", but a placebo was used which implies that it was not open label, and text mentions "A range of active and placebo study inhalers was available to enable the type of inhaler and daily dose to be matched to patients’ regular inhaled corticosteroid, type of inhaler, and dose". Participants delivered the intervention themselves. There is no information on how the trialists ensured adherence to the intervention. Clear criteria given to participants as part of an action plan to guide how they should measure their symptoms and at what point they should initiate the study inhaler. However, no details about how they monitored or increased adherence to the intervention so unsure whether there were failures in implementing it. Report doesn't detail methods used to derive an unbiased estimate of the effect of adhering to intervention but the trial measured treatment failure only in those participants who started the study inhaler. |
Low risk of bias |
8.9 and 10.1% withdrew from the total intervention and placebo groups respectively which is relatively low and balanced, although the study does not report whether and how missing data were imputed. |
Low risk of bias |
Method for measuring the outcome was appropriate. Participants were given a 10‐day course of prednisolone (30 mg per day) to be taken if their asthma control deteriorated to the point that they would usually start oral corticosteroids, or if their peak flow fell by 40% from the mean run‐in value. Unlikely that the measurement of Measurement of the outcome was the same between intervention groups. Oral steroids were patient initiated and they were blinded to the contents of the study inhalers. Outcome assessors were the study participants. |
Some concerns |
No publicly available trial registration, study protocol or SAP (SAP is mentioned in the study report). Clear definition of outcome and timepoints. |
High risk of bias |
Used tool algorithm. If bias due to deviations from intended interventions was Low, would have assigned Low to overall risk of bias assessed as the only 'some concerns' was due to no trial registration or study protocol details, but this is an old trial when making these available was not standard. |
| Martinez 2011 |
Low risk of bias |
The Data Coordinating Center generated the random allocation sequence via computer software.The DCC had no contact with participants. No obvious imbalances between groups. |
Low risk of bias |
States double blind and placebo interventions were used. Those delivering the intervention were the participants. Measures were taken to ensure adherence, inc. electronic measurement, participant diaries and pump canister checks. |
Low risk of bias |
The same raw data were used in the ITT and per protocol anlayses for this review because the study's design implies all participants would have used their study inhaler. Withdrawals from the study were relatively low and even between the two groups included in this review: 11.3% in the intervention group (double ICS) and 12.5% in the control group (stable ICS). However, in some groups the number of events was similar to the number of participants with missing data, therefore their outcomes could impact the estimated effect of intervention. Authors didn't correct or assess for bias from missing outcome data. Reasons for missing data were accounted for and most were not related to the ouctome of interest (only two participants across the study were lost because they were unsatisfied with asthma control, both in the rescue beclomethasone group). |
Low risk of bias |
Method for measuring the outcome was appropriate. Measurement of the outcome would not have differed between groups. Drugs were masked A to D to mask statisticians to treatment group. |
Some concerns |
Trial registered before participant enrolment began (https://clinicaltrials.gov/ct2/show/study/NCT00394329). However, registry record contains no prospective information about statistical analyses and no protocol or SAP available. The numerical result is not likely to have been selected on the basis of the results from multiple outcome measurements or analyses. |
Low risk of bias |
Overall risk of bias assessed as low as the only 'some concerns' was due to no study protocol or SAP available. However, it was registered and no other details from the trial for this outcome gives us reason to believe that there are some concerns regarding risk of bias. |
| Oborne 2009 |
Low risk of bias |
An allocation sequence of random permuted blocks of 10 was generated using a random number table by an independent pharmacist and implemented by one of the study investigators once participants were enrolled into the trial. Mentions an investigator providing the randomization schedule and concealed allocation of masked inhalers. Inhalers were identical and participants blind to the intervention. Baseline data provided for all participants and those starting the study inhaler ‐ no issues noted. |
High risk of bias |
Placebo inhaler was used. Participants were not aware of the intervention, which they adminstered. Clear criteria give to participants as part of an action plan to guide how they should measure their symptoms and at what point they should initiate the study inhaler. However, no details about how they monitored or increased adherence to the intervention so unsure whether there were failures in implementing it. Report doesn't detail methods used to derive an unbiased estimate of the effect of adhering to intervention but the trial measured treatment failure only in those participants who started the study inhaler. |
High risk of bias |
The per protocol analysis based on only participants who started their study inhaler represents a relatively small, non‐randomized proportion of the full cohort, and there was an imbalance in the number of people in each group who did so. No analyses corrected for bias. Patients who discontinued who did not use the study inhaler might have done so for reasons relating to their disease worsening. The CONSORT diagram includes changes to inhaler therapy and other medical reasons for reasons for discontinuing the intervention. |
Low risk of bias |
Method of measuring the outcome was appropriate. Measurement of the outcome was the same between intervention groups. Investigators blinded and they were likely the assessors. |
Some concerns |
The trial was rgeistered (http://www.isrctn.com/ISRCTN46018181). It was registered after participant enrolment began but before recruitment was completed. The registry doesn't include anything about the anlyses and a protocol/SAP isn't available. Clear definition of outcome and timepoints. |
High risk of bias |
Used tool algorithm. |
| Rice‐McDonald 2005 |
Low risk of bias |
Method of sequence generation not described but "order and allocation of treatment by concealed randomisation". Does not report baseline characteristics for each intervention group. |
Low risk of bias |
A double‐blind, double‐dummy study with order and allocation of treatment by concealed randomisation. The participants administered the intervention. Compliance to the intervention was monitored by symptom and medication diaries and a four week run in tested participants compliance to the protocol as part of the inclusion criteria. Participants were contacted regularly by a nurse to judge when to initiate the study inhaler. |
High risk of bias |
Of 35 randomized participants, 13 subsequently withdrew prior to any asthma exacerbations. There is no evidence that the result was not biased by missing outcome data. The reasons for withdrawal from the trial are not associated with the intervention or outcome. However, 11 participants who were randomised and had exacerbations that went straight to oral corticosteroids (no study inhaler) were not analysed and this missingness woudl depend on its true value. |
Low risk of bias |
Method for measuring the outcome was appropriate, and unlikely to differ between groups. Treatment failure well defined. Outcome assessors were the particpants, who were blinded. |
Some concerns |
No trial registry, protocol or SAP available. The numerical result is not likely to have been selected on the basis of the results from multiple outcome measurements or analyses. |
High risk of bias |
Used tool algorithm.
Domain S (for crossover trials) = LOW
SQ S1 = the number of participants allocated to each of the sequences was nearly equal.
SQ S2 = N/A
SQ S3 = a four week washout period was used which is sufficient time for any carryover effects to have disappeared before outcome assessment in the second period. |
