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Meta-Analysis
. 2016 Jul 13;7(7):CD011272.
doi: 10.1002/14651858.CD011272.pub2.

Rapamycin and rapalogs for tuberous sclerosis complex

Teguh H Sasongko  1 , Nur Farrah Dila Ismail, Zamh Zabidi-Hussin
Affiliations
Meta-Analysis

Rapamycin and rapalogs for tuberous sclerosis complex

Teguh H Sasongko et al. Cochrane Database Syst Rev. .

Update in

  • Rapamycin and rapalogs for tuberous sclerosis complex.
    Sasongko TH, Kademane K, Chai Soon Hou S, Jocelyn TXY, Zabidi-Hussin Z. Sasongko TH, et al. Cochrane Database Syst Rev. 2023 Jul 11;7(7):CD011272. doi: 10.1002/14651858.CD011272.pub3. Cochrane Database Syst Rev. 2023. PMID: 37432030 Free PMC article.

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

Teguh H Sasongko: none known. Nur Farrah Dila Ismail: none known. ZAMH Zabidi‐Hussin: attended as a consultant for Affinitor® at two meetings held by Novartis.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph illustrating percentages of each risk of bias item for all three included studies (Bissler 2013, Koenig 2008 and Franz 2006).
3
3
Risk of bias graph summarizing review authors' judgements about each risk of bias item for each included studies (Bissler 2013, Franz 2013, Koenig 2012).
1.1
1.1. Analysis
Comparison 1 Rapamycin or rapalogs vs placebo (systemic administration), Outcome 1 Response to tumour size.
1.2
1.2. Analysis
Comparison 1 Rapamycin or rapalogs vs placebo (systemic administration), Outcome 2 Response to skin lesions.
1.3
1.3. Analysis
Comparison 1 Rapamycin or rapalogs vs placebo (systemic administration), Outcome 3 Creatinine levels.
1.4
1.4. Analysis
Comparison 1 Rapamycin or rapalogs vs placebo (systemic administration), Outcome 4 Any adverse events.
1.5
1.5. Analysis
Comparison 1 Rapamycin or rapalogs vs placebo (systemic administration), Outcome 5 Adverse events leading to dose reduction, interruption or withdrawal.
2.1
2.1. Analysis
Comparison 2 Rapamycin or rapalogs vs placebo (topical administration), Outcome 1 Response to skin lesions.
See this image and copyright information in PMC

References

References to studies included in this review

Bissler 2013 {published data only}
    1. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST‐2): a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet 2013;381(9869):817‐24. [PUBMED: 23312829] - PubMed
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Franz 2013 {published data only}
    1. Franz D, Lam D, Cauwel H, Jozwiak S. Effect of everolimus on subependymal nodules (SENs) and tubers in patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): Results from the exist‐1 trial [abstract]. Proceedings of the 65th American Academy of Neurology Annual Meeting San Diego, CA United States. Lippincott Williams and Wilkins, 2013.
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    1. Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double‐blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs in R&D 2012;12(3):121‐6. [PUBMED: 22934754] - PMC - PubMed
    1. NCT01031901. Topical rapamycin therapy to alleviate cutaneous manifestations of tuberous sclerosis complex (TSC) and neurofibromatosis I (NF1). https://www.clinicaltrials.gov/ct2/show/NCT01031901?term=NCT01031901&amp... (accessed 14 March 2016).

References to studies excluded from this review

Birca 2010 {published data only}
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Sparagana 2010 {published data only}
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Staehler 2012 {published data only}
    1. Staehler M, Sauter M, Helck A, Linsenmaier U, Weber L, Mayer K, et al. Nephron‐sparing resection of angiomyolipoma after sirolimus pretreatment in patients with tuberous sclerosis. International Urology and Nephrology 2012;44(6):1657‐61. [PUBMED: 23054313] - PubMed
Tanaka 2013 {published data only}
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Wataya‐Kaneda 2011 {published data only}
    1. Wataya‐Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. The British Journal of Dermatology 2011;165(4):912‐6. [PUBMED: 21692771] - PubMed
Wataya‐Kaneda 2015 {published data only}
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Wienecke 2006 {published data only}
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Yalon 2011 {published data only}
    1. Yalon M, Ben‐Sira L, Constantini S, Toren A. Regression of subependymal giant cell astrocytomas with RAD001 (Everolimus) in tuberous sclerosis complex. Child's Nervous System : ChNS : official journal of the International Society for Pediatric Neurosurgery 2011;27(1):179‐81. [PUBMED: 20703486] - PubMed

References to studies awaiting assessment

NCT01289912 {published data only}
    1. NCT01289912. Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC). https://clinicaltrials.gov/ct2/show/NCT01289912?term=NCT01289912&rank=1 (accessed 14 March 2016).
NCT01526356 {published data only}
    1. NCT01526356. Topical Rapamycin to Erase Angiofibromas in TSC (Treatment). https://clinicaltrials.gov/ct2/show/NCT01526356?term=NCT01526356&rank=1 (accessed 14 March 2016).

References to ongoing studies

NCT01713946 {published data only}
    1. NCT01713946. A Placebo‐controlled Study of Efficacy & Safety of 2 Trough‐ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Partial‐onset Seizures (EXIST‐3). https://clinicaltrials.gov/ct2/show/NCT01713946?term=NCT01713946&rank=1 (accessed 14 March 2016).
NCT01730209 {published data only}
    1. NCT01730209. Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With TuberousSclerosis Complex (RAPIT). https://clinicaltrials.gov/ct2/show/NCT01730209?term=NCT01730209&rank=1 (accessed 14 March 2016).
NCT01954693 {published data only}
    1. NCT01954693. A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis (TRON). https://clinicaltrials.gov/ct2/show/NCT01954693?term=NCT01954693&rank=1 (accessed 14 March 2016).
NCT02635789 {published data only}
    1. NCT02635789. Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous SclerosisComplex (TSC). https://clinicaltrials.gov/ct2/show/NCT02635789?term=NCT02635789&rank=1 (accessed 14 March 2016).

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