| 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 |
| Subgroup 1.5.1 Serious adverse events |
| 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. Outcome reported as as counts on a bar chart so unclear whether participants or events are the unit of analysis, and whether the events were counted in the full population or only those starting the inhaler. For the purposes of including data in the review, data were included as people with full population denominators. Most participants started the study inhaler but approx 25% of each group did not, so there is some potential for bias. |
High risk of bias |
Number of events similar to the number that withdrew, and no reasons for withdrawal specified. No evidence that the analysis corrected for bias. Withdrawal from the study could be related to participants’ health status so it is possible that missingness in the outcome was influenced by its true value. The circumstances of the trial make it likely that missingness in the outcome depends on its true value, e.g. participants might drop out if their asthma symptioms get worse or they had an adverse reaction. |
Low risk of bias |
No information about the method of measuring the outcome. Measurment of the outcome likely to be the same between the groups. No information on whether the assessors were aware of the intervention. The outcome assessment is not subjective. |
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. |
| 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. Number adverse events measured in the whole population. |
Low risk of bias |
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). Raw numbers are available for the review's analyses. 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. No analyses on this outcome. Authors kept good accounts of reasons for missing data and reported the SAEs. |
Some concerns |
Study report mentions a data and safety monitoring board which implies adverse event measuring procedures were followed. Measurement of the outcome would not have differed between groups. The outcome assessor was the study participant (who was blinded) and AEs were overseen by a safety monitoring board, though unsure if they were blinded. Assessment of the outcome may have been influenced by knowledge of intervention received. It was unlikely that assessment of the outcome was influenced by knowledge of intervention received given the small events numbers and oversight from the safety monitoring board. |
Some concerns |
Trial registered before participant enrolment began (https://clinicaltrials.gov/ct2/show/study/NCT00394329). However, registry record contains no prospective information about analyses and no SAP or protocol available. The numerical result is not likely to have been selected on the basis of the results from multiple outcome measurements or analyses. |
Some concerns |
Used tool algorithm. |
| Subgroup 1.5.2 Non‐serious adverse events |
| Foresi 2000 |
Low risk of bias |
Described as randomized but no details to assess sequence generation or allocation concealment.
Some imbalances across groups (statistical tests not presented) but may be expected for sample size and do not systematically favour one group over another. |
High risk of bias |
Not described fully but described as double‐blind ‐ placebo used to blind intervention in the event of an exacerbation. |
High risk of bias |
Per‐protocol analysis was performed on 175 out of 213 randomized patients (191 who completed minus 38 with protocol violations), and adverse events were only reported for those who had an exacerbation (minority of population). Those included in the analysis were those who had an exacerbation, for which rates differed across groups and relate to asthma severity and effectiveness of the intervention. Withdrawal rates fromthe study also likely to be related to participants’ health status, as these include adverse events and other reasons. |
Low risk of bias |
No information about how adverse events were measured or managed. However, all participants visited the clinic once a month to discuss progress, symtpoms and adherence, and all kept daily symptom/management diaries.
Symptoms were recorded in daily dairies by the participant, who was blinded. |
High risk of bias |
No trial registration, study protocol or SAP.
No clear definitions for non‐serious adverse events.
Outcome was not analysed. |
High risk of bias |
Used algorithm |
| 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. |
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. |
Some concerns |
"double‐blind, placebo‐controlled trial" "Drug groups were labelled as A, B, C, and D to mask statisticians to treatment group during the first complete run‐through of data analyses." "Active and placebo inhalers were…identical apart from the presence or absence of inhaled corticosteroid, to achieve allocation concealment and blinding of investigators and pariticipants". |
High risk of bias |
Only 94 out of 403 participants (23%) started the study inhaler, so most of the population were not included in the analysis of adverse events
No evidence that the analysis was not biased by focusing on those who had an exacerbation.
Those included in the analysis were those who had an exacerbation, for which rates differed across groups and relate to asthma severity and effectiveness of the intervention. |
High risk of bias |
No information about how adverse events were measures or monitored. The participant's management plan only requested the daily diary of symptoms was completed if they felt their asmtha was deterioating. As there were more exacerbations in the active group we can assume more patients deteriotaed. Therefore, more participants in the active group would have been capturing other non‐series adverse events in their diaries (and possibly why the active group had 9 events and the placebo 3). |
High risk of bias |
The trial was registered (http://www.isrctn.com/ISRCTN46018181) 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.
No clear definitions for non‐serious adverse events. |
