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. 2023 Jul 11;7(7):CD011272.
doi: 10.1002/14651858.CD011272.pub3.

Rapamycin and rapalogs for tuberous sclerosis complex

Teguh Haryo Sasongko  1   2 , Kumaraswamy Kademane  3 , Stanley Chai Soon Hou  4 , Tan Xin Yi Jocelyn  4 , Zamh Zabidi-Hussin  5
Affiliations

Rapamycin and rapalogs for tuberous sclerosis complex

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

Abstract

Background: Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.

Objectives: To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.

Search methods: We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences. Date of the last searches: 15 July 2022.

Selection criteria: Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.

Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.

Main results: The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies. Systemic administration Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence). Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence). Topical (skin) administration Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in the placebo arm reported a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; 1 study; 164 participants; high-certainty evidence). More participants in the intervention arm responded to facial angiofibroma at one to three months (RR 28.74, 95% CI 1.78 to 463.19; P = 0.02) and three to six months (RR 39.39, 95% CI 2.48 to 626.00; P = 0.009; low-certainty evidence). Similar results were noted for cephalic plaques at one to three months (RR 10.93, 95% CI 0.64 to 186.08; P = 0.10) and three to six months (RR 7.38, 95% CI 1.01 to 53.83; P = 0.05; low-certainty evidence). More participants on placebo showed a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; P < 0.0001; 1 study; 164 participants; moderate-certainty evidence). The intervention arm reported a higher general improvement score (MD -1.01, 95% CI -1.68 to -0.34; P < 0.0001), but no difference specifically in the adult subgroup (MD -0.75, 95% CI -1.58 to 0.08; P = 0.08; 1 study; 36 participants; moderate-certainty evidence). Participants in the intervention arm reported higher satisfaction than with placebo (MD -0.92, 95% CI -1.79 to -0.05; P = 0.04; 1 study; 36 participants; low-certainty evidence), although again with no difference among adults (MD -0.25, 95% CI -1.52 to 1.02; P = 0.70; 1 study; 18 participants; low-certainty evidence). Groups did not differ in change in quality of life at six months (MD 0.30, 95% CI -1.01 to 1.61; P = 0.65; 1 study; 62 participants; low-certainty evidence). Treatment led to a higher risk of any AE compared to placebo (RR 1.72, 95% CI 1.10, 2.67; P = 0.02; 3 studies; 277 participants; moderate-certainty evidence); but no difference between groups in severe AEs (RR 0.78, 95% CI 0.19 to 3.15; P = 0.73; 1 study; 179 participants; moderate-certainty evidence).

Authors' conclusions: Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo. Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events. With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.

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Conflict of interest statement

Teguh Haryo Sasongko: none known. ZAMH Zabidi‐Hussin: attended as a consultant for Affinitor® at two meetings held by Novartis. Kumaraswamy Kademane: none known. Stanley Chai Soon Hou: none known. Tan Xin Yi Jocelyn: none known.

Figures

1
1
2
2
Risk of bias graph illustrating percentages of each risk of bias item for all ten included studies (Bissler 2013 (EXIST 2), Franz 2013 (EXIST 1), French 2016 (EXIST 3); Koenig 2012; Koenig 2018; Krueger 2017; Overwater 2016; Overwater 2019; Wataya‐Kaneda 2017; Wataya‐Kaneda 2018).
3
3
Risk of bias graph summarizing review authors' judgements about each risk of bias item for each included studies (Bissler 2013 (EXIST 2); Franz 2013 (EXIST 1); French 2016 (EXIST 3); Koenig 2012; Koenig 2018; Krueger 2017; Overwater 2016; Overwater 2019; Wataya‐Kaneda 2017; Wataya‐Kaneda 2018).
1.1
1.1. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 1: Response to tumour size (50% reduction from baseline)
1.2
1.2. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 2: Response to skin lesions
1.3
1.3. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 3: Increased creatinine levels
1.4
1.4. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 4: Reduction in seizure frequency
1.5
1.5. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 5: Change in attention and executive function ‐ Stockings of Cambridge (CANTAB)
1.6
1.6. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 6: Socialization and behaviour (Social Cognition ‐ SRS)
1.7
1.7. Analysis
Comparison 1: Systemic administration of rapamycin or rapalogs versus placebo, Outcome 7: Adverse events
2.1
2.1. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 1: Improvement in skin lesions
2.2
2.2. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 2: Deterioration in skin lesions
2.3
2.3. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 3: Mean general improvement in facial angiofibroma at 12 weeks
2.4
2.4. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 4: Change in quality of life (combined DLQI and CDLQI)
2.5
2.5. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 5: Mean participant satisfaction at 12 weeks
2.6
2.6. Analysis
Comparison 2: Topical administration of rapamycin or rapalogs versus placebo, Outcome 6: Adverse events
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bissler 2013 (EXIST 2) {published data only}
    1. Bissler J, Kingswood C, Zonnenberg BA, Frost M, Belousova E, Radzikowska E, et al. Updated safety results from EXIST-2: everolimus therapy for angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM). Journal of Clinical Oncology 2012;30(15 Suppl 1):4632. [CN-01028275]
    1. Bissler J, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Sauter M, et al. Everolimus for renal angiomyolipoma associated with tuberous sclerosis complex: exist-2 long-term efficacy and safety. Journal of Urology 2014;191(4 Suppl 1):e540. [DOI: 10.1016/j.juro.2014.02.1508] [CN-01058878] - DOI
    1. Bissler J, Kingswood JC, Zonnenberg B, Frost M, Belousova E, Radzikowska E, et al. Exist-2: effect of everolimus on angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangiomyomatosis. Journal of Urology 2012;187(4 Suppl 1):e528. [DOI: 10.1016/j.juro.2012.02.1636] [CN-01033818] - DOI
    1. Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, et al. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrology, Dialysis, Transplantation 2019;34(6):1000-8. [DOI: ] [PMID: ] - PMC - PubMed
    1. Bissler JJ, Kingswood C, Zonnenberg B, Frost M, Belousova E, Radzikowska E, et al. Examining everolimus in a study of tuberous sclerosis complex (TSC) trial (EXIST-2): updated safety results. BJU International 2012;110:7. [CN-01030577]
Franz 2013 (EXIST 1) {published data only}
    1. Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, et al. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.. Nephrology, Dialysis, Transplantation 2019;34(6):1000-8. [DOI: ] [PMID: ] - PMC - PubMed
    1. Bissler JJ, Franz DN, Frost MD, Belousova E, Bebin EM, Sparagana S, et al. The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma. Pediatric Nephrology 2018;33(1):101-9. [DOI: 10.1007/s00467-017-3806-1] [PMID: ] - DOI - PMC - PubMed
    1. Franz D, Belousova E, Frost M, Kuperman R, Bebin M, Korf B, et al. Everolimus for the treatment of renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma. Neurology 2012;78(1 Meeting Abstracts):P04.188. [DOI: 10.1212/WNL.78.1] [CN-01033658] - DOI
    1. Franz D, Belousova E, Sparagana S, Bebin E, Frost M, Kuperman R, et al. Long-term efficacy and safety of everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in exist-1: approximately 3.5 years of exposure. Neurology 2015;84:P2.235. [CN-01102987]
    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. In: 65th American Academy of Neurology Annual Meeting San Diego, CA United States. Lippincott Williams and Wilkins, 2013.
French 2016 (EXIST 3) {published data only}
    1. Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, et al. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet. Child & Adolescent Health 2018;2(7):495-504. [PMID: ] - PubMed
    1. De Vries PJ, Franz DN, Lawson JA, Yapici Z, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for the treatment of refractory seizures in people with tuberous sclerosis complex. Journal of Intellectual Disability Research 2016;60(9):839. [DOI: 10.1111/jir.12324] - DOI
    1. Franz D, De Vries P, Curatolo P, Nabbout R, Fan J, Neary M, et al. Psychometric evaluation of quality of life in a three-arm, randomized, double-blind, placebo-controlled phase 3 study of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures (EXIST-3). Annals of Neurology 2017;82:S282. [DOI: 10.1002/ana.25022] [CN-01612522] - DOI
    1. Franz D, Lawson J, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Efficacy and safety of everolimus based on prior and concomitant antiepileptic drugs in patients with tuberous sclerosis complex (TSC)-associated treatment-refractory seizures: a subanalysis of the phase 3 EXIST-3 study. Neurology 2018;90(15 Suppl):S9.007. [CN-01608776]
    1. French J, Lawson J, Yapici Z, Polster T, Nabbout R, Curatolo P, et al. Exposure-response analysis of adjunctive everolimus therapy in patients with refractory partial-onset seizures associated with tuberous sclerosis complex (TSC). European Journal of Neurology 2016;23:54. [DOI: 10.1111/ene.13091] [CN-01267457] - DOI
Koenig 2012 {published data only}
    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. [DOI: 10.2165/11634580-000000000-00000] [PMID: ] - DOI - PMC - PubMed
    1. NCT01031901. Topical rapamycin therapy to alleviate cutaneous manifestations of tuberous sclerosis complex (TSC) and neurofibromatosis I (NF1). clinicaltrials.gov/ct2/show/NCT01031901 (first posted 15 December 2009).
Koenig 2018 {published data only}
    1. Koenig MK, Bell CS, Hebert AA, Roberson J, Samuels JA, Slopis JM, et al. Efficacy and safety of topical rapamycin in patients with facial angiofibromas secondary to tuberous sclerosis complex: the TREATMENT randomized clinical trial. JAMA Dermatology 2018;154(7):773-80. [DOI: 10.1001/jamadermatol.2018.0464] [PMID: ] - DOI - PMC - PubMed
    1. NCT01526356. Topical rapamycin to erase angiofibromas in TSC [Phase II study of topical rapamycin to erase angiofibromas in TSC-multicenter evaluation of a novel therapy]. clinicaltrials.gov/ct2/show/record/NCT01526356 (first posted 3 February 2012). [DEPARTMENT OF DEFENSE USAMRMC ( OTHER GRANT/FUNDING NUMBER: W81XWH-11-1-0240] [HSC-MS-11-0501]
Krueger 2017 {published data only}
    1. Krueger DA, Sadhwani A, Byars AW, Vries PJ, Franz DN, Whittemore VH, et al. Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders. Annals of Clinical and Translational Neurology 2017;4(12):877-87. [DOI: 10.1002/acn3.494] [PMID: ] - DOI - PMC - PubMed
    1. NCT01289912. Trial of RAD001 and neurocognition in tuberous sclerosis complex (TSC) [Randomized double-blind phase 2 trial of RAD001 for neurocognition in individuals with tuberous sclerosis complex]. clinicaltrials.gov/ct2/show/record/NCT01289912 (first posted 4 February 2011). [10-06-0247]
Overwater 2016 {published data only}
    1. EUCTR2010‐022655‐29‐NL. Randomised open label cross-over study into the efficacy of RApamycin in children with Tuberous sclerosis complex with intractable Epilepsy (RATE-trial). trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2010-022655-29-NL (date of registration 22 October 2010).
    1. NTR3178. Study into treatment of children with difficult to treat epilepsy due to Tuberous sclerosis complex with rapamycin [Randomised open label cross-over study into the efficacy of rapamycin in children with tuberous sclerosis complex with intractable epilepsy]. trialsearch.who.int/Trial2.aspx?TrialID=NTR3178 (date of registration 2 December 2011). [MEC-2010-362]
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Overwater 2019 {published data only}
    1. NCT01730209. Efficacy of RAD001/everolimus in autism and neuropsychological deficits in children with tuberous sclerosis complex. clinicaltrials.gov/ct2/show/NCT01730209 (first posted 21 November 2012). [NL38619.078.11]
    1. Overwater IE, Rietman AB, Mous SE, Bindels-de Heus K, Rizopoulos D, ten Hoopen LW, et al. A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology 2019;93(2):e200-9. [DOI: 10.1212/WNL.0000000000007749] [PMID: ] - DOI - PubMed
Wataya‐Kaneda 2017 {published data only}
    1. JPRN‐UMIN000012420. Randomized, double-blind, placebo-controlled, clinical trial with OSD-001 for skin lesions due to tuberous sclerosis complex. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014541 (date of disclosure 27 November 2013).
    1. Wataya-Kaneda M, Nakamura A, Tanaka M, Hayashi M, Matsumoto S, Yamamoto K, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: a randomized clinical trial. JAMA dermatology 2017;153(1):39-48. [DOI: 10.1001/jamadermatol.2016.3545] [PMID: ] - DOI - PubMed
Wataya‐Kaneda 2018 {published data only}
    1. NCT02635789. Phase III trial of topical formulation of sirolimus to skin lesions in patients with tuberous sclerosis complex (TSC) [A double-blind, randomized, placebo-controlled phase III trial to investigate the efficacy and safety of NPC-12G gel (topical formulation of sirolimus) to angiofibroma and other skin lesions in patients with tuberous sclerosis complex (TSC)]. https://clinicaltrials.gov/ct2/show/NCT02635789 (first posted 21 December 2015). [NPC-12G-1]
    1. Wataya-Kaneda M, Ohno Y, Fujita Y, Yokozeki H, Niizeki H, Ogai M, et al. Sirolimus gel treatment for tuberous sclerosis complex involving facial angiofibromas and cephalic plaques: a multicenter randomized controlled trial. Journal of Investigative Dermatology 2018;138(5):S179. [DOI: 10.1016/j.jid.2018.03.1067] - DOI
    1. Wataya-Kaneda M, Ohno Y, Fujita Y, Yokozeki H, Niizeki H, Ogai M, et al. Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatology 2018;154(7):781-8. [DOI: 10.1001/jamadermatol.2018.1408] [PMID: ] - DOI - PMC - PubMed

References to studies excluded from this review

Birca 2010 {published data only}
    1. Birca A, Mercier C, Major P. Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex. Journal of Neurosurgery. Pediatrics 2010;6(4):381-4. [PMID: ] - PubMed
Bissler 2019 {published data only}
    1. Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, et al. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2 [Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019 Jun 1;34(6):1000-1008. doi: 10.1093/ndt/gfy132. PMID: 30053159;]. Nephrology, Dialysis Transplantation 1 June 2019;34(6):1000-8. [PUBMED CENTRAL: PMC6545468] [PMID: (PMID) 30053159] - PMC - PubMed
Cabrera 2011 {published data only}
    1. Cabrera Lopez C, Marti T, Catala V, Torres F, Mateu S, Ballarin Castan J, et al. Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis. Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia 2011;31(3):292-8. [PMID: ] - PubMed
ChiCTR‐OPC‐14005488 {published data only}
    1. Li Han-zhong, Zhang Yu-shi, Li Shu-qiang. Efficacy of everolimus for TSC-associated renal angiomyolipoma. www.chictr.org.cn/showprojen.aspx?proj=9856 (first registered 7 November 2014).
ChiCTR‐OPN‐16008236 {published data only}
    1. ChiCTR‐OPN‐16008236. TSC1/2 gene detection and everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. www.chictr.org.cn/showprojen.aspx?proj=13935 (first posted 7 April 2016).
Cuevas 2012 {published data only}
    1. Cuevas Asencio I, Albornoz Lapez R, Salido Vallejo R, Reyes Malia M. Topical sirolimus 0.4% formulation for treatment of facial angiofibromas [Formulación de sirolimus tópico al 0,4% para el tratamiento de angiofibromas faciales]. Farmacia Hospitalaria 2012;36(5):433-4. [DOI: 10.1016/j.farma.2011.09.006] [PMID: ] - DOI - PubMed
Dabora 2011 {published data only}
    1. Dabora SL, Franz DN, Ashwal S, Sagalowsky A, DiMario FJ Jr, Miles D, et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One 2011;6(9):e23379. [PMID: ] - PMC - PubMed
Davies 2008 {published data only}
    1. Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox JA, McCartney DL, et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. New England Journal of Medicine 2008;358(2):200-3. [DOI: 10.1056/NEJMc072500] [PMID: ] - DOI - PubMed
Davies 2011 {published data only}
    1. Davies DM, Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clinical Cancer Research 2011;17(12):4071-81. [PMID: ] - PubMed
DRKS00005584 {published data only}
    1. DRKS00005584. EMINENTS (Everolimus MaINtEnNance Therapy in SEGA) [Maintenance therapy with everolimus in patients with tuberous sclerosis successfully treated for subependymal giant cell astrocytoma]. www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DR... (first registered 3 March 2015). [DRKS-ID: DRKS00005584] [EUDRACT-NO: EudraCT-No. (for studies acc. to Drug Law): 2015-000941-22] [UNIVERSAL TRIAL NUMBER (UTN): U1111-1152-1134]
EUCTR2007‐005978‐30‐ES {published data only}
    1. EUCTR2007‐005978‐30‐ES. Clinical trial to determine the efficacy and safety of rapamycin in angiomyolipomas in patients with tuberous sclerosis [Ensayo clínico para evaluar la eficacia y seguridad de la rapamicina en los angiomiolipomas en pacientes con esclerosis tuberosa]. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2007-005978-30-ES (first registered 3 December 2007).
EUCTR2010‐022583‐13‐DE {published data only}
    1. EUCTR2010-022583-13-DE. The EFFECTS STUDY: Everolimus For Fast Expanded aCcess in TSC SEGA [An open‐label, multi‐center, expanded access study of RAD001 in patients with subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC). The EFFECTS STUDY: everolimus For Fast Expanded aCcess in TSC SEGA ‐ EFFECTS STUDY]. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2010-022583-13-DE (first posted 23 December 2010). [ID NUMBER: CN-01814546]
Foster 2012 {published data only}
    1. Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australasian Journal of Dermatology 2012;53(1):52-6. [PMID: ] - PubMed
Franz 2006 {published data only}
    1. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of Neurology 2006;59(3):490-8. [PMID: ] - PubMed
Franz 2018 {published data only}
    1. Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial. Neurology. Clinical Practice 2018;8(5):412-20. [DOI: 10.1212/CPJ.0000000000000514] [PMID: ] - DOI - PMC - PubMed
Gupta 2019 {published data only}
    1. Gupta N, Lee HS, Young LR, Strange C, Moss J, Singer LG, et al. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. European Respiratory Journal 2019;53(4):1802066. [PMID: ] - PMC - PubMed
Herry 2007 {published data only}
    1. Herry I, Neukirch C, Debray MP, Mignon F, Crestani B. Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex. European Journal of Internal Medicine 2007;18(1):76-7. [PMID: ] - PubMed
Hofbauer 2008 {published data only}
    1. Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, Wuthrich RP, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. British Journal of Dermatology 2008;159(2):473-5. [PMID: ] - PubMed
JPRN‐UMIN000002844 {published data only}
    1. JPRN-UMIN000002844. Development of topical treatment with rapamycin for skin lesions of tuberous sclerosis complex. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003457 (first registered 3 December 2009).
JPRN‐UMIN000006108 {published data only}
    1. JPRN-UMIN000006108. Clinical trial for development of topical rapamycin treatment for white macules due to tuberous sclerosis complex, vitiligo vulgaris, and other congenital diseases. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007206 (first registered 3 August 2011). [ID NO.: CN-01836103]
JPRN‐UMIN000011559 {published data only}
    1. JPRN‐UMIN000011559. Therapeutic drug monitoring of Everolimus in patients with renal cell carcinoma and tuberous sclerosis. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013524 (first registered 01 September 2013).
JPRN‐UMIN000015114 {published data only}
    1. JPRN-UMIN000015114. Clinical study of safety and efficacy of rapamycin topical medication for skin lesions due to tuberous sclerosis complex. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017546 (first registered 10 September 2014).
JPRN‐UMIN000024270 {published data only}
    1. JPRN‐UMIN000024270. Study of everolimus for autistic spectrum disorder in tuberous sclerosis. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027932 (first registered 03 October 2016).
Kenerson 2002 {published data only}
    1. Kenerson HL, Aicher LD, True LD, Yeung RS. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Research 2002;62(20):5645-50. [PMID: ] [WEB ADDRESS: https://cancerres.aacrjournals.org/content/62/20/5645.long] - PubMed
Koenig 2008 {published data only}
    1. Koenig MK, Butler IJ, Northrup H. Regression of subependymal giant cell astrocytoma with rapamycin in tuberous sclerosis complex. Journal of Child Neurology 2008;23(10):1238-9. [PMID: ] - PMC - PubMed
Krueger 2010 {published data only}
    1. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine 2010;363(19):1801-11. [DOI: 10.1056/NEJMoa1001671] [PMID: ] - DOI - PubMed
Krueger 2013a {published data only}
    1. Ess KC, Roach ES. New therapies for tuber-less sclerosis: White matter matters? American Academy of Neurology 2012;78(8):520-1. [DOI: 10.1212/WNL.0b013e318248a232] - DOI - PubMed
    1. Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 2013;80(6):574-80. [DOI: 10.1212/WNL.0b013e3182815428] [PMID: ] - DOI - PMC - PubMed
    1. NCT00411619. Everolimus (RAD001 therapy of giant cell astrocytomas in patients with tuberous sclerosis complex. www.clinicaltrials.gov/ct2/show/NCT00411619 (first registered 14 December 2006). [CCHMC IRB# 06-07-50]
    1. Tillema JM, Leach JL, Krueger DA, Franz DN. Everolimus alters white matter diffusion in tuberous sclerosis complex. Neurology 2012;78(8):526-31. [PMID: ] - PubMed
Krueger 2013b {published data only}
    1. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Annals of Neurology 2013;74(5):679-87. [DOI: 10.1002/ana.23960] [PMID: ] - DOI - PubMed
    1. NCT01070316. Everolimus (RAD001) therapy for epilepsy in patients with tuberous sclerosis complex (TSC). clinicaltrials.gov/ct2/show/record/NCT01070316 (first posted 18 February 2010);NA:NA. [2009-0998]
Lam 2010 {published data only}
    1. Lam C, Bouffet E, Tabori U, Mabbott D, Taylor M, Bartels U. Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors. Pediatric Blood & Cancer 2010;54(3):476-9. [DOI: 10.1002/pbc.22298] [PMID: ] - DOI - PubMed
NCT00001465 {published data only}
    1. NCT00001465. Study of the disease process of lymphangioleiomyomatosis [Characterization of the Pathogenesis of Lymphangioleiomyomatosis (LAM)]. clinicaltrials.gov/ct2/show/NCT00001465 (first posted 03 November 1999).
NCT00001532 {published data only}
    1. NCT00001532. Role of genetic factors in the development of lung disease. clinicaltrials.gov/ct2/show/NCT00001532 (first posted 04 November 1999).
NCT00001975 {published data only}
    1. NCT00001975. Study of skin tumors in tuberous sclerosis [Cutaneous tumorigenesis in patients with tuberous sclerosis]. clinicaltrials.gov/ct2/show/NCT00001975 (first posted 21 January 2000).
NCT00457808 {published data only}
    1. NCT00457808. Rapamycin therapy for patients with tuberous sclerosis complex and sporadic LAM [Rapamycin therapy of angiomyolipomas in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis]. clinicaltrials.gov/ct2/show/NCT00457808 (first posted 09 April 2007). [CCHMC IRB # 02-10-16] [R21CA103486 ( U.S. NIH Grant/Contract )]
NCT00457964 {published data only}
    1. NCT00457964. RAD001 therapy of angiomyolipomata in patients with TS complex and sporadic LAM [RAD001 therapy of angiomyolipomata in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis]. clinicaltrials.gov/ct2/show/NCT00457964 (first posted 09 April 2007). [CCHMC IRB #2008-0812(04-07-22)]
NCT00490789 {published data only}
    1. NCT00490789. Trial of efficacy and safety of sirolimus in tuberous sclerosis and LAM [A trial of the efficacy and safety of sirolimus (rapamycin) therapy for renal angiomyolipmoas in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis]. clinicaltrials.gov/ct2/show/NCT00490789 (first posted 25 June 2007). [TESSTAL]
NCT00552955 {published data only}
    1. NCT00552955. Effect of fasting on the size of abdominal lymphatic tumors in women [Effect of fasting on the size of lymphangioleiomyomas in patients with lymphangioleiomyomatosis]. clinicaltrials.gov/ct2/show/NCT00552955 (first posted 02 November 2007). [08-H-0016] [080016]
NCT00792766 {published data only}
    1. NCT00792766. Long term follow up for RAD001 therapy of angiomyolipomata in patients with tuberous sclerosis (TSC) and sporadic lymphangioleiomyomatosis (LAM) [Long term follow up for RAD001 therapy of angiomyolipomata in patients with tuberous sclerosis (TSC) and sporadic lymphangioleiomyomatosis]. clinicaltrials.gov/ct2/show/NCT00792766 (first posted 18 November 2008). [CCHMC IRB# 2008-0333]
NCT01092208 {published data only}
    1. NCT01092208. Studies of autistic patients: gene networks and clinical subtypes. clinicaltrials.gov/ct2/show/NCT01092208 (first posted 24 March 2010). [10-CH-0084] [100084]
NCT01217125 {published data only}
    1. NCT01217125. Rapamycin in angiomyolipomas in patients with tuberous sclerosis [Clinical trial to determine the efficacy and safety of rapamycin in angiomyolipomas in patients with tuberous sclerosis]. clinicaltrials.gov/ct2/show/NCT01217125 (first posted 08 October 2010). [EudraCT 2007-005978-30]
NCT01266291 {published data only}
    1. NCT01266291. Sabril for complex partial seizures in adult tolerability study (TS) patients [Sabril for treatment of adult refractory partial seizures symptomatic of tuberous sclerosis: an open label, phase IV prospective safety and tolerability study]. clinicaltrials.gov/ct2/show/NCT01266291 (first posted 24 December 2010). [811542]
NCT01767779 {published data only}
    1. NCT01767779. Potential EEG biomarkers and antiepileptogenic strategies for epilepsy in TSC [Potential EEG biomarkers and antiepileptogenic strategies for epilepsy in TSC]. clinicaltrials.gov/ct2/show/NCT01767779 (first posted 14 January 2013). [1P20NS080199-01( U.S. NIH Grant/Contract )]
NCT01780441 {published data only}
    1. NCT01780441. Early biomarkers of autism in infants with tuberous sclerosis complex (TSC) [Longitudinal study to identify early biomarkers of autism spectrum disorder (ASD) in infants with tuberous sclerosis complex (TSC)]. clinicaltrials.gov/ct2/show/NCT01780441 (first posted 31 January 2013). [1U01NS082320-01 ( U.S. NIH Grant/Contract )] [IRB-P00005074]
NCT01929642 {published data only}
    1. NCT01929642. Rapalogues for autism phenotype in TSC: a feasibility study. clinicaltrials.gov/ct2/show/NCT01929642 (first posted 28 August 2013). [AM00037881]
NCT02104011 {published data only}
    1. NCT02104011. Treatment of renal angiomyolipomas in tuberous sclerosis by beta-blockers [Treatment of renal angiomyolipomas in tuberous sclerosis by beta-blockers: pilot trial]. clinicaltrials.gov/ct2/show/NCT02104011 (first posted 04 April 4 2014). [CHUBX 2011/35]
NCT02201212 {published data only}
    1. NCT02201212. Everolimus for cancer with TSC1 or TSC2 mutation [A phase II trial of everolimus for cancer patients with inactivating mutations in TSC1 or TSC2 or activating MTOR mutations]. clinicaltrials.gov/ct2/show/NCT02201212 (first posted 28 July 2014). [14-229] [CRAD001MUS217T]
NCT02325505 {published data only}
    1. NCT02325505. Characterization of patients with tuberous sclerosis complex, lymphangioleiomyomatosis and angiomyolipoma [Clinical Profile Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma Followed at Hospital Das Clínicas, University of Sao Paulo Medical School]. clinicaltrials.gov/ct2/show/NCT02325505 (first posted 25 December 2014). [4147/14/127]
NCT02451696 {published data only}
    1. NCT02451696. A pilot study to evaluate the effects of everolimus on brain mTOR activity and cortical hyperexcitability in TSC and FCD. clinicaltrials.gov/ct2/show/NCT02451696 (first posted 22 May 2015). [14-00245]
NCT02461459 {published data only}
    1. NCT02461459. Autism spectrum disorder (ASD) and intellectual disability (ID) determinants in tuberous sclerosis complex (TSC). clinicaltrials.gov/ct2/show/NCT02461459 (first posted 03 June 2015). [1U54NS092090 ( U.S. NIH Grant/Contract )] [IRB-P00013585]
NCT02634931 {published data only}
    1. NCT02634931. Long-term trial of topical sirolimus to angiofibroma in patient with tuberous sclerosis complex [A long-term, single-arm, open-label trial of NPC-12G (topical formulation of sirolimus) to angiofibroma and other skin lesions in patients with tuberous sclerosis complex]. clinicaltrials.gov/ct2/show/NCT02634931 (first posted 18 December 2015). [NPC-12G-2]
NCT02654340 {published data only}
    1. NCT02654340. Biomarkers for tuberous sclerosis complex (BioTuScCom) [Biomarkers for tuberous sclerosis complex: an international multicenter observational longitudinal protocol]. clinicaltrials.gov/ct2/show/NCT02654340 (first posted 13 January 2016). [TSC 08-2018]
NCT03047213 {published data only}
    1. NCT03047213. Sapanisertib in treating patients with locally advanced or metastatic bladder cancer with TSC1 and/or TSC2 mutations [An open label, multicenter, single arm phase II study to evaluate the activity and tolerability of the novel mTOR inhibitor, MLN0128 (TAK-228), in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract whose tumors harbor a TSC1 and/or a TSC2 mutation]. clinicaltrials.gov/ct2/show/NCT03047213 (first posted 08 February 2017). [1505015958] [2000021268] [9767 ( Other Identifier: CTEP )] [9767 ( Other Identifier: Yale University Cancer Center LAO )] [NCI-2015-00121 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )] [UM1CA186689 ( U.S. NIH Grant/Contract )]
NCT03213678 {published data only}
    1. NCT03213678. PI3K/mTOR inhibitor LY3023414 in treating patients with relapsed or refractory advanced solid tumors, non-hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutations (a pediatric MATCH treatment trial) [NCI-COG pediatric MATCH (Molecular Analysis For Therapy Choice)- phase 2 subprotocol of LY3023414 in patients with solid tumors]. clinicaltrials.gov/ct2/show/NCT03213678 (first posted 11 July 11 2017). [APEC1621D ( Other Identifier: CTEP )] [APEC1621D ( Other Identifier: Children's Oncology Group )] [NCI-2017-01249 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )] [U10CA180886 ( U.S. NIH Grant/Contract )]
NCT03525834 {published data only}
    1. NCT03525834. Safety and efficacy of everolimus (Afinitor®) in Chinese adult patients with angiomyolipoma associated with tuberous sclerosis complex [Phase IV, single arm study of safety and efficacy of everolimus in Chinese adults with tuberous sclerosis complex who have renal angiomyolipoma not requiring immediate surgery]. clinicaltrials.gov/ct2/show/NCT03525834 (first posted 16 May 2018). [CRAD001M2401]
NCT03649919 {published data only}
    1. NCT03649919. Multi-center clinical study on the diagnosis and treatment management of rare neurological disease in children [Multi-center clinical study on the diagnosis and treatment management of rare neurological disease in children]. clinicaltrials.gov/ct2/show/NCT03649919 (first posted 28 August 2018). [EKYY-MCSDTMRNDC]
Pressey 2010 {published data only}
    1. Pressey JG, Wright JM, Geller JI, Joseph DB, Pressey CS, Kelly DR. Sirolimus therapy for fibromatosis and multifocal renal cell carcinoma in a child with tuberous sclerosis complex. Pediatric Blood & Cancer 2010;54(7):1035-7. [DOI: 10.1002/pbc.22401] [PMID: ] - DOI - PubMed
Salido 2012 {published data only}
    1. Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galan-Gutierrez M, Velez A, et al. Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma. Journal of the European Academy of Dermatology and Venereology 2012;26(10):1315-8. [PMID: ] - PubMed
Sallas 2015 {published data only}
    1. Sallas W, Chiparus O, Cheung W, Urva S, Wang J, Cauwel H, et al. Population PK-PD modeling of everolimusin the treatment of patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytomas (SEGA). Journal of Pharmacokinetics and Pharmacodynamics 2013;40(1):S40. [ABSTRACT NO.: M-035] [DOI: 10.1007/s10928-013-9308-2] - DOI
Sparagana 2010 {published data only}
    1. Sparagana SP, Wilkes DC, Thompson CE, Bowers DC. Optic nerve tumor in tuberous sclerosis complex is not responsive to sirolimus. Pediatric Neurology 2010;42(6):443-6. [PMID: ] - PubMed
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. [PMID: ] - PubMed
Tanaka 2013 {published data only}
    1. Tanaka M, Wataya-Kaneda M, Nakamura A, Matsumoto S, Katayama I. First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex. British Journal of Dermatology 2013;169(6):1314-8. [PMID: ] - PubMed
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. British Journal of Dermatology 2011;165(4):912-6. [PMID: ] - PubMed
Wataya‐Kaneda 2012 {published data only}
    1. Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. A novel application of topical rapamycin formulation, an inhibitor of mTOR, for patients with hypomelanotic macules in tuberous sclerosis complex. Archives of Dermatology 2012;148(1):138-9. [DOI: 10.1001/archderm.148.1.138] [PMID: ] - DOI - PubMed
Wataya‐Kaneda 2015 {published data only}
    1. Wataya-Kaneda M, Tanaka M, Yang L, Yang F, Tsuruta D, Nakamura A, et al. Clinical and histologic analysis of the efficacy of topical rapamycin therapy against hypomelanotic macules in tuberous sclerosis complex. JAMA Dermatology 2015;151(7):722-30. [DOI: 10.1001/jamadermatol.2014.4298] [PMID: ] - DOI - PubMed
Wheless 2013 {published data only}
    1. Wheless JW, Almoazen H. A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex. Journal of Child Neurology 2013;28(7):933-6. [DOI: 10.1177/0883073813488664] [PMID: ] - DOI - PubMed
Wienecke 2006 {published data only}
    1. Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T, Kretzler M. Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex. American Journal of Kidney Diseases 2006;48(3):e27-9. [PMID: ] - PubMed
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 2011;27(1):179-81. [PMID: ] - PubMed
Young 2013 {published data only}
    1. Kwiatkowski D. A biomarker for lymphangioleiomyomatosis. Lancet Respiratory Medicine 2013;1(6):424-5. [DOI: 10.1016/S2213-2600(13)70098-5] - DOI - PubMed
    1. Wu H, Nikolaidis NM, Young LR, McCormack FX. Serum levels of vegf-c are elevated in sporadic but not tuberous sclerosis associated-lam, correlate with the need for supplemental oxygen, and impact lung function response to sirolimus. American Journal of Respiratory and Critical Care Medicine 2018;197:A1100. [DOI: 10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A1100] - DOI
    1. Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, et al. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet. Respiratory Medicine 2013;1(6):445-52. [PMID: ] - PMC - PubMed
    1. Young LR, Inoue Y, Moss J, Singer L, Strange C, Nakata K, et al. Baseline serum VEGF-D levels are associated with disease severity and treatment response in lymphangioleiomyomatosis. American Journal of Respiratory and Critical Care Medicine 2011;183:A6351. [DOI: 10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A6351] - DOI
Zhang 2018 {published data only}
    1. Fonseca dos Santos-Junior E, Ricardo Mendes de Oliveira J. The importance of the study of brain calcifications in patients with tuberous sclerosis complex. Seizure - European Journal of Epilepsy 2018;61:199. [DOI: 10.1016/j.seizure.2018.08.023] - DOI - PubMed
    1. Zhang MN, Zou LP, Wang YY, Pang LY, Ma SF, Huang LL, et al. Calcification in cerebral parenchyma affects pharmacoresistant epilepsy in tuberous sclerosis. Seizure 2018;60:86-90. [PMID: ] - PubMed

References to studies awaiting assessment

NCT03140449 {published data only}
    1. NCT03140449. Topical Rapamycin and calcitriol for angiofibroma of tuberous sclerosis [Study of combination therapy with topical rapamycin and calcitriol for cutaneous lesions of tuberous sclerosis: a double-blind randomized controlled trial]. clinicaltrials.gov/ct2/show/NCT03140449 (first posted 04 May 2017). [201306009MINB]
Randell 2016 {published data only}
    1. NCT01954693. A study of everolimus in the treatment of neurocognitive problems in tuberous sclerosis [TRON: a randomised, double blind, placebo-controlled study of RAD001 (everolimus) in the treatment of neurocognitive problems in tuberous sclerosis]. clinicaltrials.gov/ct2/show/NCT01954693 (first posted 07 October 2013). [DOI: 10.1186/ISRCTN09739757] [EUDRACT NUMBER: 2011-004854-25] [SPON803-10] - DOI
    1. Randell E, McNamara R, Davies DM, Owen-Jones E, Kirby N, Angel L, et al. The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial. Trials 2016;17:398. [PMID: ] - PMC - PubMed

References to ongoing studies

EUCTR2011‐006308‐12‐ES {published data only}
    1. EUCTR2011‐006308‐12-ES. Clinical trial in patients with tuberous sclerosis for the study of the effects of topical rapamycin in reducing facial tumors associated with the disease [Phase II clinical trial, to study the efficacy and safety of topical rapamycin in reducing facial angiofibromas.]. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2011-006308-12-ES (date of registration 29 March 2012).
NCT02860494 {published data only}
    1. NCT02860494. Topical everolimus in patients with tuberous sclerosis complex [Topical everolimus versus placebo for the treatment of facial angiofibromas in patients with tuberous sclerosis complex. A phase II/III, multicentre, randomized, double-blind, placebo-controlled study of 3 doses of topical everolimus]. clinicaltrials.gov/ct2/show/NCT02860494 (first posted 09 August 2016). [EUDRACT NUMBER: 2018-002531-18] [69HCL16_0062]
NCT03363763 {published data only}
    1. NCT03363763. Topical sirolimus ointment for cutaneous angiofibromas in subjects with tuberous sclerosis complex [Phase 2 multi center prospective rand. double blind placebo cont. parallel design study to evaluate safety & efficacy of topical sirolimus for cutaneous angiofibromas in subjects w/ tuberous sclerosis complex followed by opt. open label]. clinicaltrials.gov/ct2/show/NCT03363763 (first posted 06 December 2017). [AUCTA-UAP006-PH2]
NCT03826628 {published data only}
    1. NCT03826628. Dose-ranging efficacy and safety study of topical rapamycin cream for facial angiofibroma associated with tuberous sclerosis complex [A phase 2/3, multi-center, double-blind, placebo-controlled, randomized, parallel-group, dose-response comparison of the efficacy and safety study of topical rapamycin cream for the treatment of facial angiofibromas (FA) associated with tuberous sclerosis complex (TSC) in patients 6 years of age and over]. clinicaltrials.gov/ct2/show/NCT03826628 (first posted 01 February 2019);NA:NA. [DOI: ] [DSLP-01]

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References to other published versions of this review

Sasongko 2014
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