The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

Alzheimer's and Dementia

Volumn 13, Issue 1, 2017, Pages 8-19

  Bateman, Randall J ^a   Benzinger, Tammie L ^b   Berry, Scott ^c   Clifford, David B ^a   Duggan, Cynthia ^a   Fagan, Anne M ^a   Fanning, Kathleen ^a   Farlow, Martin R ^d   Hassenstab, Jason ^a   McDade, Eric M ^a   Mills, Susan ^a   Paumier, Katrina ^a   Quintana, Melanie ^c   Salloway, Stephen P ^e   Santacruz, Anna ^a   Schneider, Lon S ^f   Wang, Guoqiao ^g   Xiong, Chengjie ^g  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c BERRY CONSULTANTS   (United States)

^d INDIANA UNIVERSITY   (United States)

^e BUTLER HOSPITAL   (United States)

^f UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^g WASHINGTON UNIVERSITY   (United States)

Author keywords

Adaptive clinical trial; Alzheimer's disease; Alzheimer's prevention trial; Amyloid; Autosomal dominant Alzheimer's disease; Biomarkers; Cognitive composite; DIAN TU; Disease progression model; Dose adjustment; Tau

Indexed keywords

BIOLOGICAL MARKER; NEW DRUG; NOOTROPIC AGENT; NEUROLEPTIC AGENT;

ALZHEIMER DISEASE; ARTICLE; AUTOSOMAL DOMINANT INHERITANCE; COGNITION ASSESSMENT; DAILY LIFE ACTIVITY; DISEASE COURSE; HUMAN; LATE ONSET DISORDER; LONGITUDINAL STUDY; MENTAL PERFORMANCE; NEUROPROTECTION; OBSERVATIONAL METHOD; OBSERVATIONAL STUDY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PREVENTION STUDY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SECONDARY ANALYSIS; STUDY DESIGN; TREATMENT DURATION; ALGORITHM; CLINICAL TRIAL (TOPIC); COGNITION DISORDERS; COMPLICATION; FEMALE; MALE; MEDICAL RESEARCH; METHODOLOGY; NEUROPSYCHOLOGICAL TEST; PROCEDURES; PUBLIC-PRIVATE PARTNERSHIP; THEORETICAL MODEL;

ALGORITHMS; ALZHEIMER DISEASE; ANTIPSYCHOTIC AGENTS; BIOMEDICAL RESEARCH; CLINICAL TRIALS AS TOPIC; COGNITION DISORDERS; DISEASE PROGRESSION; FEMALE; HUMANS; MALE; MODELS, THEORETICAL; NEUROPSYCHOLOGICAL TESTS; PUBLIC-PRIVATE SECTOR PARTNERSHIPS; RESEARCH DESIGN;

EID: 85002578779     PISSN: 15525260     EISSN: 15525279     Source Type: Journal    
DOI: 10.1016/j.jalz.2016.07.005     Document Type: Article

References (73)

1. [1] Brookmeyer, R., Evans, D.A., Hebert, L., Langa, K.M., Heeringa, S.G., Plassman, B.L., et al. National estimates of the prevalence of Alzheimer's disease in the United States. Alzheimers Dement 7 (2011), 61–73.
2. [2] Bateman, R.J., Aisen, P.S., De Strooper, B., Fox, N.C., Lemere, C.A., Ringman, J.M., et al. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther, 3, 2011, 1.
3. [3] Ryman, D.C., Acosta-Baena, N., Aisen, P.S., Bird, T., Danek, A., Fox, N.C., et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83 (2014), 253–260.
4. [4] Bateman, R.J., Xiong, C., Benzinger, T.L., Fagan, A.M., Goate, A., Fox, N.C., et al., Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367 (2012), 795–804.
5. [5] Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400 (1999), 173–177.
6. [6] Lemere, C.A., Maron, R., Spooner, E.T., Grenfell, T.J., Mori, C., Desai, R., et al. Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci 920 (2000), 328–331.
7. [7] Chang, W.P., Huang, X., Downs, D., Cirrito, J.R., Koelsch, G., Holtzman, D.M., et al. Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J 25 (2011), 775–784.
8. [8] Qu, B.X., Xiang, Q., Li, L., Johnston, S.A., Hynan, L.S., Rosenberg, R.N., Abeta42 gene vaccine prevents Abeta42 deposition in brain of double transgenic mice. J Neurol Sci 260 (2007), 204–213.
9. [9] Sperling R, Salloway S, Raskind M, Ferris S, Liu E, Yuen E, et al. A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease who are apolipoprotien E ε4 carriers. Top-line clinical and biomarker results for carriers. Presented at the 16th Congress of the European Federation of Neurological Societies. Eur J Neurol 2012;19:70.
10. [10] Sperling R, Salloway S, Raskind M, Ferris S, Honig L, Porsteinsson A, et al., eds. Bapineuzumab Phase 3 trials in mild to moderate Alzheimer's disease dementia in apolipoprotein ε4 carriers (Study 302) and non-carriers (Study 301). Top-line clinical and biomarker results for carriers, non-carriers, pooled studies, and mild and moderate groups. Oral presentation. 137th American Neurological Association Annual Meeting October 7-9, 2012; Boston, MA: ANA.
11. [11] Dodel, R.C., Hampel, H., Du, Y., Immunotherapy for Alzheimer's disease. Lancet Neurol 2 (2003), 215–220.
12. [12] Rinne, J.O., Brooks, D.J., Rossor, M.N., Fox, N.C., Bullock, R., Klunk, W.E., et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9 (2010), 363–372.
13. [13] Siemers, E.R., Dean, R.A., Friedrich, S., Ferguson-Sells, L., Gonzales, C., Farlow, M.R., et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 30 (2007), 317–325.
14. [14] Doody, R.S., Thomas, R.G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 370 (2014), 311–321.
15. [15] Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 370 (2014), 322–333.
16. [16] Orgogozo, J.M., Gilman, S., Dartigues, J.F., Laurent, B., Puel, M., Kirby, L.C., et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61 (2003), 46–54.
17. [17] Panza, F., Frisardi, V., Imbimbo, B.P., Seripa, D., Solfrizzi, V., Pilotto, A., Monoclonal antibodies against beta-amyloid (Abeta) for the treatment of Alzheimer's disease: the Abeta target at a crossroads. Expert Opin Biol Ther 11 (2011), 679–686.
18. [18] Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 369 (2013), 341–350.
19. [19] Vellas, B., Tarenflurbil for Alzheimer's disease: a “shot on goal” that missed. Lancet Neurol 9 (2010), 235–237.
20. [20] Salloway S, Sperling R, Honig L, Porsteinsson A, Sabbagh M, Liu E, et al. A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease who are apolipoprotien E ε4 non-carriers. Top-line clinical and biomarker results for non-carriers. Presented at the 16th Congress of the European Federation of Neurological Societies. Eur J Neurol 2012;19.
21. [21] Strobel G. Biogen Antibody Buoyed by Phase 1 Data and Hungry Investors. International Conference on Alzheimer's and Parkinson's 2015 [Internet]. 2015 Part 1 of 10: B. Available at: http://www.alzforum.org/news/conference-coverage/biogen-antibody-buoyed-phase-1-data-and-hungry-investors. Accessed January 11, 2016.
22. [22] Liu-Siefert, H., ER, Aisen, P.S., Andersen, S.W., Holdridge, K.D., Siemers, E.R., Delayed-start analyses of up to 3.5 years in phase 3 solanezumab expedition program in mild Alzheimer's disease. Alzheimer's and Dementia 11 (2015), 262–263.
23. [23] Strobel, G., Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well. Alzheimer's Association International Conference, 2015 Available at: http://www.alzforum.org/news/conference-coverage/aducanumab-solanezumab-gantenerumab-data-lift-crenezumab-well. Accessed January 11, 2016.
24. [24] Jack, C.R. Jr., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9 (2010), 119–128.
25. [25] Petersen, R.C., Aisen, P.S., Beckett, L.A., Donohue, M.C., Gamst, A.C., Harvey, D.J., et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology 74 (2010), 201–209.
26. [26] Yamamoto, A., Sudo, H., Endo, A., Therapeutic effects of ML-236B in primary hypercholesterolemia. Atherosclerosis 35 (1980), 259–266.
27. [27] Marks, D., Thorogood, M., Neil, H.A., Humphries, S.E., A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168 (2003), 1–14.
28. [28] Hardy, J., Selkoe, D.J., The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 (2002), 353–356.
29. [29] Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 (1991), 704–706.
30. [30] Vos, S.J., Xiong, C., Visser, P.J., Jasielec, M.S., Hassenstab, J., Grant, E.A., et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol 12 (2013), 957–965.
31. [31] Lim, Y.Y., Maruff, P., Pietrzak, R.H., Ellis, K.A., Darby, D., Ames, D., et al. Abeta and cognitive change: examining the preclinical and prodromal stages of Alzheimer's disease. Alzheimers Dement, 10, 2014 743–751.e1.
32. [32] Wang, F., Gordon, B.A., Ryman, D.C., Ma, S., Xiong, C., Hassenstab, J., et al. Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease. Neurology 85 (2015), 790–798.
33. [33] Hassenstab J, Lim Y, Fagan A, Ma S, Xiong C, Bateman R, et al., eds. CSF Biomarkers and Cognitive Decline in Autosomal Dominant Alzheimer Disease. Alzheimer's Association International Conference; 2015 Washington, DC.
34. [34] Maloney, J.A., Bainbridge, T., Gustafson, A., Zhang, S., Kyauk, R., Steiner, P., et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem 289 (2014), 30990–31000.
35. [35] Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P.V., Snaedal, J., et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368 (2013), 107–116.
36. [36] Zempel, H., Thies, E., Mandelkow, E., Mandelkow, E.M., Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30 (2010), 11938–11950.
37. [37] Gomez-Isla, T., Price, J.L., McKeel, D.W. Jr., Morris, J.C., Growdon, J.H., Hyman, B.T., Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 16 (1996), 4491–4500.
38. [38] Price, J.L., Morris, J.C., Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 45 (1999), 358–368.
39. [39] Braak, H., Braak, E., Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 16 (1995), 271–278 discussion 278–84.
40. [40] Crary, J.F., Trojanowski, J.Q., Schneider, J.A., Abisambra, J.F., Abner, E.L., Alafuzoff, I., et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128 (2014), 755–766.
41. [41] Thal, D.R., Papassotiropoulos, A., Saido, T.C., Griffin, W.S., Mrak, R.E., Kolsch, H., et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease. Acta Neuropathol 120 (2010), 169–183.
42. [42] Shepherd, C., McCann, H., Halliday, G.M., Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol 118 (2009), 37–52.
43. [43] Schwarz, A.J., Yu, P., Miller, B.B., Shcherbinin, S., Dickson, J., Navitsky, M., et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139:Pt 5 (2016), 1539–1550.
44. [44] Benzinger, L., Su, Y., Gordon, B., Christensen, J., Hornbeck, R., Mishra, S., et al. Patterns of tau deposition using [18F]-AV-1451 in autosomal dominant Alzheimer's disease: results from the DIAN. Hum Amyloid Imaging, S7, 2016, 125.
45. [45] Jack, C.R. Jr., Holtzman, D.M., Biomarker modeling of Alzheimer's disease. Neuron 80 (2013), 1347–1358.
46. [46] Benzinger, T.L., Blazey, T., Jack, C.R., Koeppe, R.A., Su, Y., Xiong, C., et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A 110 (2013), E4502–E4509.
47. [47] Fleisher, A.S., Chen, K., Quiroz, Y.T., Jakimovich, L.J., Gutierrez Gomez, M., Langois, C.M., et al. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol 72 (2015), 316–324.
48. [48] Mills, S.M., Mallmann, J., Santacruz, A.M., Fuqua, A., Carril, M., Aisen, P.S., et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris) 169 (2013), 737–743.
49. [49] Moulder, K.L., Snider, B.J., Mills, S.L., Buckles, V.D., Santacruz, A.M., Bateman, R.J., et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res Ther, 5, 2013, 48.
50. [50] Reiman, E.M., Langbaum, J.B., Tariot, P.N., Lopera, F., Bateman, R.J., Morris, J.C., et al. CAP-advancing the evaluation of preclinical Alzheimer disease treatments. Nat Rev Neurol 12 (2016), 56–61.
51. [51] Lim, Y., Pietrzak, R., Snyder, P., Darby, D., Maruff, P., Preliminary data on the effect of culture on the assessment of Alzheimer's disease-related verbal memory impairment with the International Shopping List Test. Arch Clin Neuropsychol 27 (2012), 136–147.
52. [52] Acevedo, A., Krueger, K.R., Navarro, E., Ortiz, F., Manly, J.J., Padilla-Velez, M.M., et al. The Spanish translation and adaptation of the Uniform Data Set of the National Institute on Aging Alzheimer's Disease Centers. Alzheimer Dis Assoc Disord 23 (2009), 102–109.
53. [53] Reiman, E.M., Langbaum, J.B., Fleisher, A.S., Caselli, R.J., Chen, K., Ayutyanont, N., et al. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 26 Suppl 3 (2011), 321–329.
54. [54] Reiman, E.M., Quiroz, Y.T., Fleisher, A.S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol 11 (2012), 1048–1056.
55. [55] Tarawneh, R., D'Angelo, G., Macy, E., Xiong, C., Carter, D., Cairns, N.J., et al. Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann Neurol 70 (2011), 274–285.
56. [56] Tarawneh, R., D'Angelo, G., Crimmins, D., Herries, E., Griest, T., Fagan, A.M., et al. Diagnostic and prognostic utility of the synaptic marker neurogranin in Alzheimer disease. JAMA Neurol 73 (2016), 561–571.
57. [57] Kester, M.I., Teunissen, C.E., Crimmins, D.L., Herries, E.M., Ladenson, J.H., Scheltens, P., et al. Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol 72 (2015), 1275–1280.
58. [58] Kvartsberg, H., Duits, F.H., Ingelsson, M., Andreasen, N., Öhrfelt, A., Andersson, K., et al. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement 11 (2015), 1180–1190.
59. [59] Brinkmalm, A., Brinkmalm, G., Honer, W.G., Frolich, L., Hausner, L., Minthon, L., et al. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol Neurodegener, 9, 2014, 53.
60. [60] Skillback, T., Farahmand, B., Bartlett, J.W., Rosen, C., Mattsson, N., Nagga, K., et al. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology 83 (2014), 1945–1953.
61. [61] Zetterberg, H., Wilson, D., Andreasson, U., Minthon, L., Blennow, K., Randall, J., et al. Plasma tau levels in Alzheimer's disease. Alzheimers Res Ther, 5, 2013, 9.
62. [62] Blazey T, Jack C, Kantarci K, Preboske G, Ringman J, Brickman A, et al., eds. Prevalence and growth of cerebral microhemorrhages in autosomal dominant Alzheimer's disease. Alzheimer's Association International Conference and Alzheimer's Imaging Consortium, July 13–18, 2013; Boston, MA.
63. [63] Wang, X., Cusick, M.F., Wang, Y., Sun, P., Libbey, J.E., Trinkaus, K., et al. Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. NMR Biomed 27 (2014), 843–852.
64. [64] Wang, Y., Wang, Q., Haldar, J.P., Yeh, F.C., Xie, M., Sun, P., et al. Quantification of increased cellularity during inflammatory demyelination. Brain 134:Pt 12 (2011), 3590–3601.
65. [65] Salloway, S., Sperling, R., Gilman, S., Fox, N.C., Blennow, K., Raskind, M., et al. Bapineuzumab 201 Clinical Trial I. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73 (2009), 2061–2070.
66. [66] Jacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., et al. Combined treatment with a BACE inhibitor and anti-Abeta antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci 34 (2014), 11621–11630.
67. [67] DeMattos, R., May, P., Racke, M., Hole, J., Tzaferis, J., Liu, F., et al. Combination therapy with a plaque-specific abeta antibody and BACE inhibitor results in dramatic plaque lowering in aged PDAPP transgenic mice. Alzheimers Dement, 10, 2014, 149.
68. [68] Strobel G. Combination drug trials: time to open a new front in AD? Availalbe at: http://www.alzforum.org/news/conference-coverage/combination-drug-trials-time-open-new-front-ad. Accessed January 11, 2016.
69. [69] Strobel, G., Combination trial debate energizes keystone symposium. Keystone Symposium: Alzheimer's Disease—From fundamentals to light at the end of the translational tunnel 2014 [Internet], 2014 Part 1 of 4. Retrieved January 11, 2016 from http://www.alzforum.org/news/conference-coverage/combination-trial-debate-energizes-keystone-symposium.
70. [70] Stephenson, D., Perry, D., Bens, C., Bain, L.J., Berry, D., Krams, M., et al. Charting a path toward combination therapy for Alzheimer's disease. Expert Rev Neurother 15 (2015), 107–113.
71. [71] Perry, D., Sperling, R., Katz, R., Berry, D., Dilts, D., Hanna, D., et al. Building a roadmap for developing combination therapies for Alzheimer's disease. Expert Rev Neurother 15 (2015), 327–333.
72. [72] Grill, J.D., Bateman, R.J., Buckles, V., Oliver, A., Morris, J.C., Masters, C.L., et al. A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease. Alzheimers Res Ther, 7, 2015, 50.
73. [73] Alzheimer's Association. Changing the trajectory of Alzheimer's disease: how a treatment by 2025 saves lives and dollars. Available at: https://www.alz.org/documents_custom/trajectory.pdf. Accessed January 11, 2016.