Summary of findings for the main comparison. Summary of findings for systemic administration.

Oral everolimus (rapalog) compared with placebo for people with TSC
Patient or population: people with TSC Settings: outpatient Intervention: oral everolimus (rapalog) Comparison: placebo
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Placebo	Oral Everolimus (Rapalog)
50% reduction of tumour size1	Renal angiomyolipoma	0 out of 1000 (see comment)	450 out of 1000 (see comment)	RR: 24.7 (95% CI 3.5 ‐ 173.4)	162 (2 studies)	⊕⊕⊕⊕ high3	P = 0.001 0 out of 53 participants in the placebo group and 49 out of 109 participants in the Rapalog group experienced 50% reduction in tumour size. Assumed and corresponding risk are calculated as the event rates in each group.
	SEGA	0 out of 1000 (see comment)	346 out of 1000 (see comment)	RR: 27.9 (95% CI 1.7 ‐ 444.8)	117 (1 study)	⊕⊕⊕⊕ high3	P = 0.02 0 out of 39 participants in the placebo group and 27 out of 78 participants in the Rapalog group experienced 50% reduction in tumour size. Assumed and corresponding risk are calculated as the event rates in each group.
Response to skin lesions2		53 out of 1000	307 out of 1000 (122 to 769 out of 1000)	RR: 5.8 (95% CI 2.3 ‐ 14.5)	224 (2 studies)	⊕⊕⊕⊕ high3	P = 0.0002
Frequency of seizure		Median change = ‐4.1/24 hr (95% CI ‐10.9 to 5.8)	Median change = ‐2.9/24 hr (95% CI ‐4.1 to ‐1.0)	‐	Not reported (1 study)	⊕⊕⊕⊕ moderate4	‐
Creatinine level		Increased in 77 out of 1000 participants	Increased in 12 out of 1000 participants (2 to 118 participants)	RR: 0.16 (95% CI 0.02 ‐ 1.53)	118 (1 study)	⊕⊕⊕⊕ high3	‐
Forced expiratory volume in 1 second (FEV1)		See comments	See comments	See comments	See comments	See comments	For the subset of participants with lymphangioleiomyomatosis and sporadic lymphangioleiomyomatosis the median percentage change of FEV1 in the treatment arm (in 24 out of 79 participants) was ‐1%, while in the placebo arm (10 out of 39 participants) this was ‐4%.
Any adverse events		897 out of 1000	960 out of 1000 (807 to 1000 out of 1000)	RR: 1.07(0.9‐1.2)	117 (1 study)	⊕⊕⊕⊕ high3	P = 0.24
Adverse Events leading to dose reduction, interruption or withdrawal		154 out of 1000	484 out of 1000 (277 to 770 out of 1000)	RR: 3.14(1.8‐5.4)	235 (2 studies)	⊕⊕⊕⊕ high3	P < 0.0001
*The basis for the assumed risk was the event rate in the placebo group unless otherwise stated in the comments. 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; RR: risk ratio; TSC: tuberous sclerosis complex
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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 quality: we are very uncertain about the estimate.

This summary of finding table was generated based on analyses from two of the included studies (Bissler 2013, Franz 2013) which used oral (systemic) administration of everolimus (rapalog). Five of the participants from Bissler study were diagnosed with sporadic lymphangioleiomyomatosis (without TSC) which we could not separate from the current analysis (we will attempt to do this for a future update of the review) (Bissler 2013).

1. Response to tumour size is defined as reduction in at least 50% reduction from baseline in sum of volumes of target tumour in participant.

2. Definition of 'response' to skin lesions was not mentioned in the two study analysed (Bissler 2013; Franz 2013).

3. No downgrading of evidence: High quality of evidences were given even though there are large CIs. The number of participants is relatively large for a rare disease, thus judgement about the quality of evidence (particularly judgements about precision) may be based on the absolute effect. Here the quality rating was considered 'high' because the outcome was appropriately assessed.

4. Downgraded once due to lack of applicability: Most participants had no seizures at baseline or at follow up. Participants were selected for the trial on the basis of their need for intervention for progression of subependymal giant cell astrocytomas rather than presence of seizures (Franz 2013). Further randomised study designed specifically to select people with TSC with seizures may change the outcome.