drugset / Trial / NCT03359538
Rapamycin Treatment for ALS
Phase 2
Completed
63 enrolled
University Hospital of Modena
Azienda Ospedaliera Niguarda Cà Granda · collabAzienda Ospedaliero Universitaria Maggiore della Carita · collabFondazione I.R.C.C.S. Istituto Neurologico Carlo Besta · collabFondazione Salvatore Maugeri · collabIRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy · collabUniversity of Modena and Reggio Emilia · collabUniversity of Padova · collabUniversity of Turin, Italy · collab
RandomizedParallel-groupDouble-blindTreatment
Summary
In the last years research has pointed out potential mechanisms of pathogenesis in ALS including lack of degradation of abnormally accumulated proteins inside motor neurons, and an unbalanced function of the immune system leading to the prevalence of a neurotoxic function over neuroprotection. These two mechanisms contribute to ALS progression hence representing important therapeutic targets to modify disease expression. With a phase II clinical trial the investigators aim to study the biological response in ALS treated with Rapamycin, to obtain predictive information for a larger study. Eight Italian Centres will enroll 63 patients; treatment will be double blinded to patients and physicians, and will last 18 weeks.Follow up will be carried out for 36 months (total duration: 54 weeks).
Timeline
- Start
- 2017-09-19
- Primary completion
- 2020-12-15
- Completion
- 2022-02-15
Publications
- Background Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, Shaw C, Chandran S, Finkbeiner S. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014 Aug;10(8):677-85. doi: 10.1038/nchembio.1563. Epub 2014 Jun 29.
- Background Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.
- Background Buchan JR, Kolaitis RM, Taylor JP, Parker R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell. 2013 Jun 20;153(7):1461-74. doi: 10.1016/j.cell.2013.05.037.
- Background Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem. 2009 Oct 2;284(40):27416-24. doi: 10.1074/jbc.M109.031278. Epub 2009 Aug 3.
- Background Chio A, Hammond ER, Mora G, Bonito V, Filippini G. Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):38-44. doi: 10.1136/jnnp-2013-306589. Epub 2013 Dec 13.
- Background Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A; FALS Sequencing Consortium; Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.
- Background Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008.
- Background Deivasigamani S, Verma HK, Ueda R, Ratnaparkhi A, Ratnaparkhi GS. A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis. Biol Open. 2014 Oct 31;3(11):1127-38. doi: 10.1242/bio.201410066.
- Background Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8.
- Background Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K, Sugino M, Hanafusa T. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24;66(2):265-7. doi: 10.1212/01.wnl.0000194316.91908.8a.
- Background Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006 Jun 15;441(7095):880-4. doi: 10.1038/nature04723. Epub 2006 Apr 19.
- Background Lattante S, de Calbiac H, Le Ber I, Brice A, Ciura S, Kabashi E. Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD. Hum Mol Genet. 2015 Mar 15;24(6):1682-90. doi: 10.1093/hmg/ddu580. Epub 2014 Nov 19.
- Background Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014 Oct 22;84(2):275-91. doi: 10.1016/j.neuron.2014.09.034. Epub 2014 Oct 22.
- Background Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol. 2009 May 29;210(1-2):73-9. doi: 10.1016/j.jneuroim.2009.02.012.
- Background Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004 Jun;36(6):585-95. doi: 10.1038/ng1362. Epub 2004 May 16.
- Background Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012 Jan 29;13(3):255-63. doi: 10.1038/ni.2215.
- Background Staats KA, Hernandez S, Schonefeldt S, Bento-Abreu A, Dooley J, Van Damme P, Liston A, Robberecht W, Van Den Bosch L. Rapamycin increases survival in ALS mice lacking mature lymphocytes. Mol Neurodegener. 2013 Sep 11;8:31. doi: 10.1186/1750-1326-8-31.
- Background Thomas M, Alegre-Abarrategui J, Wade-Martins R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain. 2013 May;136(Pt 5):1345-60. doi: 10.1093/brain/awt030. Epub 2013 Mar 9.
- Background Wang IF, Guo BS, Liu YC, Wu CC, Yang CH, Tsai KJ, Shen CK. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15024-9. doi: 10.1073/pnas.1206362109. Epub 2012 Aug 29.
- Background Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X, Wang Z, Le W. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy. 2011 Apr;7(4):412-25. doi: 10.4161/auto.7.4.14541. Epub 2011 Apr 1.
- Trist BG, Fifita JA, Hogan A, Grima N, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Blair IP, Double KL. Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration. Acta Neuropathol Commun. 2022 Aug 25;10(1):122. doi: 10.1186/s40478-022-01421-9.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Sirolimus | Small molecule | 1 mg/m2 | Oral |
| Comparator | Sirolimus | Small molecule | 2 mg/m2 | Oral |