Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.
To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.
Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.
Date of the last searches: 14 March 2016.
Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.
Data collection and analysis
Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.
Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.
Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 – 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001).
One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants’ perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants’ perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period.
We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.
Plain language summary
Drugs that aim to relieve clinical symptoms of tuberous sclerosis complex
We reviewed the evidence about the effect of rapamycin or rapalogs for reducing the severity of clinical symptoms in people with tuberous sclerosis complex.
Tuberous sclerosis or tuberous sclerosis complex is a genetic disease caused by mutations in tuberous sclerosis complex 1 or tuberous sclerosis complex 2 genes that affects several organs such as the brain, kidneys, heart, lungs and skin. The incidence has been reported to be one in approximately 6000. Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and EMA (European Medicines Agency) for tumours associated with tuberous sclerosis complex (renal angiomyolipoma and subependymal giant cell astrocytoma), the use of these drugs for treating other symptoms of the condition has yet to be established. This review aims to bring together clinical trials in this area to establish the clinical value of rapamycin and rapalogs for various symptoms of tuberous sclerosis complex.
The evidence is current to: 14 March 2016.
The review included three studies with 263 people with tuberous sclerosis complex aged between 0.8 and 61 years of age. However, one study involved five people with sporadic lymphangioleiomyomatosis (without tuberous sclerosis complex) which we could not remove from the analysis. Studies compared rapamycin or rapalogs with placebo and people were selected for one treatment or the other randomly. The duration of the studies was variable. Two of the included studies were funded by Novartis Pharmaceuticals.
There is evidence that oral everolimus (rapalog) increased the number of people who achieved a 50% reduction in the size of subependymal giant cell astrocytoma and renal angiomyolipoma. Oral everolimus also showed benefit in terms of response to skin lesions, although applying rapamycin to the skin only showed a tendency for improvement. Those who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. However, more people receiving the active treatment had severe adverse events causing them to withdraw from the trial, temporarily stop treatment or reduce their dose compared to the control group.
Quality of the evidence
Two of the included studies generally showed a low risk of bias in study design, except for one study where it was unclear whether people knew which group they would be put into. Another included study showed different degrees of risk of bias with regards to study design, for example, due to missing data and lack of clarity about how people where put into the different groups. The results from the studies were generally of high quality, except for response to skin lesions from topical rapamycin due to missing outcome data and seizure frequency due to the way participants were selected.