Summary of findings 2. Intratympanic plus systemic corticosteroids (combined therapy) versus systemic corticosteroids alone as primary therapy.

Intratympanic plus systemic corticosteroids (combined therapy) versus systemic corticosteroids alone as primary therapy
Patient or population: sudden sensorineural hearing loss Settings: initial therapy Intervention: combination of intratympanic and systemic steroid therapy Comparison: systemic steroid therapy
Outcomes	Anticipated absolute effects* (95% CI)		No of participants (studies)	Relative effect (95% CI)	Certainty of the evidence (GRADE)	Comments
	Systemic therapy (assumed risk)	Combined therapy (corresponding risk)
Change in hearing threshold determined by PTA Range 0 dB to 140 dB Negative values represent lowering and positive values represent raising of the hearing threshold. A lower hearing threshold represents hearing improvement.	The mean change in PTA ranged across control groups from ‐33.0 dB to ‐13.0 dB	The mean change in PTA in the intervention groups was on average ‐8.55 dB greater (‐4.61 greater to ‐12.48 greater)	435 (6 studies)	MD ‐8.55 dB (95% CI ‐12.48 to ‐4.61)	⊕⊕⊝⊝ low1	The change in hearing threshold may be slightly increased in participants who receive combined therapy. However, it is unclear whether this increase would be noticeable to patients.
Proportion of patients whose hearing is improved	579 per 1000a	735 per 1000 (666 to 816)	788 (10 studies)	RR 1.27 (95% CI 1.15 to 1.41)	⊕⊝⊝⊝ very low2	The evidence is very uncertain as to whether combined therapy changes the proportion of participants whose hearing is improved.
Final hearing threshold determined by PTA A lower value represents better hearing	The mean final PTA ranged across control groups from 39.1 dB to 59 dB	The mean final PTA in the intervention groups was on average 9.11 dB lower (1.67 lower to 16.56 lower)	194 (3 studies)	MD ‐9.11 dB (95% CI ‐16.56 to ‐1.67)	⊕⊝⊝⊝ very low3	Combined therapy may result in slightly lower (more favourable) final hearing thresholds compared to systemic corticosteroids alone (as primary therapy) but the evidence is very uncertain, and it is not clear whether the change would be of importance to patients.
Adverse eventsb	Events in control group	Events in intervention group	No of Participants (studies)	Relative effect (95% CI)	Certainty of the evidence (GRADE)	Comments
Persistent tympanic membrane perforation	Comparison not applicablec	5 studies reported a rate between 0% (0/85) and 5.5% (2/36) for those who received an intratympanic injection	474 (5 studies)	Not calculable	⊕⊝⊝⊝ very low4	The evidence is very uncertain regarding the risk of tympanic membrane perforation for those who received intratympanic steroids.
Vertigo/dizziness: timing not reported	No study reported on this outcome for both the intervention and comparator groups.
Vertigo/dizziness: at the time of injection	Comparison not applicablec	4 studies reported a rate between 0% (0/60) and 8.1% (3/37) for those who received an intratympanic injectiond	341 (4 studies)	Not calculable	⊕⊝⊝⊝ very low5	The evidence is very uncertain regarding the risk of vertigo/dizziness at the time of intratympanic injection for those who received intratympanic corticosteroid as primary treatment.
Ear pain: timing not reported	No study reported on this outcome for both the intervention and comparator groups.
Ear pain: at the time of injection	Comparison not applicablec	One study reported a rate of 5/37 (13.5%)	73 (1 study)	Not calculable	⊕⊝⊝⊝ very low6	The evidence is very uncertain regarding the risk of ear pain at the time of intratympanic injection for those who received combined treatment as primary treatment.
*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; PTA: pure tone audiometry; RR: risk ratio
aTen studies recruited participants suffering from sudden sensorineural hearing loss. The incidence of improvement for the 10 studies was 57.86%. We have used 579 per 1000 to express the assumed risk. bOnly the most widely reported adverse events are described here. For adverse events that could feasibly occur in either group, we have only included the studies that provided a rate for both groups. For adverse events that could only occur in one group, we have only included the studies that reported the rate in that group, and presented these as a range. A full description of adverse event data is available for reference in Table 4. cComparisons between patients receiving intratympanic therapy and those receiving only systemic therapy were regarded as invalid for the following adverse events: persistent tympanic membrane perforation, vertigo observed at the time of intratympanic injection and ear pain observed at the time of intratympanic injection. This is explained in Data extraction and management.  dIn one study, two groups received intratympanic injection: one group received intratympanic corticosteroid and the other received intratympanic and systemic corticosteroid (Tsounis 2018).    GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

¹Downgraded one level due to risk of bias: we rated a study contributing moderate weight to the overall effect estimate as high risk of bias due to concern about random sequence generation and allocation concealment. Five studies were at high risk of other bias, and one study was at risk of attrition bias. Downgraded one level due to imprecision: the 95% CI overlaps the threshold for clinical relevance, taken to be 10 dB.

²Downgraded one level due to risk of bias: we judged 8 of 10 studies to be at high or unclear risk of selection bias and at high risk of other bias. Downgraded one level due to imprecision: the 95% CI overlaps the threshold for clinical relevance. Downgraded one level due to inconsistency: the I² value was moderate (47%).

³Downgraded two levels due to risk of bias: we judged all three studies to be at high or unclear risk of selection bias and high risk of other bias. We also judged one of three studies to be at high risk of bias for incomplete outcome data and selective reporting. Downgraded one level due to imprecision: the 95% CI overlaps the threshold for clinical relevance and the sample size is smaller than the optimal information size (taken as 400 participants).

⁴Downgraded two levels due to risk of bias: we judged two studies to be at high risk of bias because of concern about random sequence generation, two studies because of selective reporting, one study because of concern about blinding and one study because of concern about allocation concealment.

⁵Downgraded two levels due to risk of bias: we judged one study to be at high risk of bias because of concern about random sequence generation and blinding, one study because of selective reporting and one study because of incomplete outcome data. Downgraded two levels due to imprecision: the number of events is smaller than the optimal information size (taken as 300 events) and an effect estimate could not be calculated.

⁶Downgraded two levels due to imprecision: the number of events is smaller than the optimal information size (taken as 300 events) and an effect estimate could not be calculated. Downgraded one level because of indirectness: provision of data by only a single study from a single setting, which may not adequately represent all patients with ISSNHL.