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中华脑科疾病与康复杂志(电子版) ›› 2022, Vol. 12 ›› Issue (01) : 9 -20. doi: 10.3877/cma.j.issn.2095-123X.2022.01.002

所属专题: 指南共识

专家共识

阿尔茨海默病药物临床试验中国专家共识
中国医师协会神经内科医师分会, 阿尔茨海默病药物临床试验写作组   
  • 收稿日期:2022-02-14 出版日期:2022-02-15
  • 基金资助:
    国家重点研发计划专项(2017YFC1310103); 北京市医院管理局临床医学发展专项(ZYLX201837、ZYLX201834); 国家科技创新2030-重大项目(2021ZD0201802、2021ZD0201808); 国家自然科学基金区域创新发展联合基金重点项目(U20A20354); 北京市科学技术委员会资助课题(Z201100005520016、Z201100005520017)

Guideline on the clinical trial of medicines for the treatment of Alzheimer’s disease in China

Chinese Medical Doctor Association on Neurology, Alzheimer’s Disease Drug Clinical Trial Writing Group   

  • Received:2022-02-14 Published:2022-02-15
引用本文:

中国医师协会神经内科医师分会, 阿尔茨海默病药物临床试验写作组. 阿尔茨海默病药物临床试验中国专家共识[J]. 中华脑科疾病与康复杂志(电子版), 2022, 12(01): 9-20.

Chinese Medical Doctor Association on Neurology, Alzheimer’s Disease Drug Clinical Trial Writing Group. Guideline on the clinical trial of medicines for the treatment of Alzheimer’s disease in China[J]. Chinese Journal of Brain Diseases and Rehabilitation(Electronic Edition), 2022, 12(01): 9-20.

阿尔茨海默病(AD)是最常见的痴呆类型,严重危害老年人群健康。临床试验是AD药物研发的重要环节。近年国际AD诊断标准的更新和生物标志物在AD临床试验中的应用,为提升AD临床试验的科学性和合理性提供了新助力。专家组在检索国内外AD临床试验文献和指南基础上,结合国际AD药物和干预研究设计新进展,撰写AD药物临床试验中国专家共识,旨在进一步规范我国AD药物临床试验,推动AD药物研发进展,同时也为临床药物应用提供有效性和安全性支持。

Alzheimer’s disease (AD) is the most common type of dementia and a major disease seriously endangering the health of the elderly. Clinical trials are the important parts of AD drug researches and development. In recent years, the update of international AD diagnostic criteria and the application of biomarkers provide new help to improve the scientificity and rationality of AD clinical trials. Based on the review of previous AD clinical trials and guidelines, and the advances of drug and intervention research designs for AD, the experts group wrote the guideline on AD drug clinical trials, which aims to further standardize AD drug clinical trials, promote the development of drug research, and provide support for the effectiveness and safety of clinical drugs in China.

[1]
Gauthier S, Rosa-Neto P, Morais JA, et al. World Alzheimer report 2021-Journey through the diagnosis of dementia[EB/OL]. London: Alzheimer’s Disease International, 2021.

URL    
[2]
Wu YT, Ali GC, Guerchet M, et al. Prevalence of dementia in mainland China, Hong Kong and Taiwan: an updated systematic review and meta-analysis[J]. Int J Epidemiol, 2018, 47(3): 709-719.
[3]
Jia J, Wei C, Chen S, et al. The cost of Alzheimer’s disease in China and re-estimation of costs worldwide[J]. Alzheimers Dement, 2018, 14(4): 483-491.
[4]
Vaz M, Silvestre S. Alzheimer’s disease: recent treatment strategies[J]. Eur J Pharmacol, 2020, 887: 173554.
[5]
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Center for biologics evaluation guidance for industry Alzheimer’s disease: developing drugs for the treatment of early stage disease[EB/OL]. 2013.

URL    
[6]
European Medicines Agency, Committee For Medicinal Products For Human Use (CHMP). Guideline on medicinal products for the treatment of Alzheimer’s Disease and other dementias[EB/OL]. 2008.

URL    
[7]
European Medicines Agency, Committee For Medicinal Products For Human Use (CHMP). Clinical investigation of medicines for the treatment of Alzheimer’s disease[EB/OL]. 2018.

URL    
[8]
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), et al. Early Alzheimer’s disease: developing drugs for treatment, guidance for industry[EB/OL]. 2018.

URL    
[9]
关亮.治疗阿尔茨海默病药物临床试验技术指导原则[J].中国现代医生, 2007, 45(20): 72-75.
[10]
阿尔茨海默病创新药物临床试验中国专家小组.阿尔茨海默病创新药物临床试验中国专家共识[J].中华老年病研究电子杂志, 2016, 3(1): 1-11.
[11]
Mangialasche F, Solomon A, Winblad B, et al. Alzheimer’s disease: clinical trials and drug development[J]. Lancet Neurol, 2010, 9(7): 702-716.
[12]
Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials[J]. JAMA, 2018, 319(2): 130-142.
[13]
Fujino T, Yamada T, Asada T, et al. Efficacy and blood plasmalogen changes by oral administration of plasmalogen in patients with mild Alzheimer’s disease and mild cognitive impairment: a multicenter, randomized, double-blind, placebo-controlled trial[J]. EBioMedicine, 2017, 17: 199-205.
[14]
Decourt B, Drumm-Gurnee D, Wilson J, et al. Poor safety and tolerability hamper reaching a potentially therapeutic dose in the use of thalidomide for Alzheimer’s disease: results from a double-blind, placebo-controlled trial[J]. Curr Alzheimer Res, 2017, 14(4): 403-411.
[15]
Wang T, Kuang W, Chen W, et al. A phase II randomized trial of sodium oligomannate in Alzheimer’s dementia[J]. Alzheimers ResTher, 2020, 12(1): 110.
[16]
Hager K, Baseman AS, Nye JS, et al. Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer’s disease: post-hoc analysis of a randomized placebo-controlled study[J]. Alzheimers Res Ther, 2016, 8(1): 47.
[17]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: a phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease[J]. Neurology, 2018, 90(21): e1889-e1897.
[18]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease[J]. Alzheimers Res Ther, 2017, 9(1): 95.
[19]
Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria[J]. Lancet Neurol, 2007, 6(8): 734-746.
[20]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease[J]. Alzheimers Dement, 2011, 7(3): 263-269.
[21]
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria[J]. Lancet Neurol, 2014, 13(6): 614-629.
[22]
Nakamura Y, Kitamura S, Homma A, et al. Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer’s disease: results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan[J]. Expert Opin Pharmacother, 2014, 15(7): 913-925.
[23]
Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease[J]. N Engl J Med, 2018, 378(4): 321-330.
[24]
Hannestad J, Duclos T, Chao W, et al. Safety and tolerability of GRF6019 infusions in severe Alzheimer’s disease: a phase II double-blind placebo-controlled trial[J]. J Alzheimers Dis, 2021, 81(4): 1649-1662.
[25]
Rafii MS, Aisen PS. Alzheimer’s disease clinical trials: moving toward successful prevention[J]. CNS Drugs, 2019, 33(2): 99-106.
[26]
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease[J]. Alzheimers Dement, 2018, 14(4): 535-562.
[27]
Morris JC. The clinical dementia rating (CDR): current version and scoring rules[J]. Neurology, 1993, 43(11): 2412-2414.
[28]
Reisberg B, Ferris SH, de Leon MJ, et al. Global Deterioration Scale (GDS)[J]. Psychopharmacol Bull, 1988, 24(4): 661-663.
[29]
Rikkert MG, Tona KD, Janssen L, et al. Validity, reliability, and feasibility of clinical staging scales in dementia: a systematic review[J]. Am J Alzheimers Dis Other Demen, 2011, 26(5): 357-365.
[30]
Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease[J]. Alzheimers Dement (N Y), 2016, 2(3): 169-176.
[31]
Gault LM, Lenz RA, Ritchie CW, et al. ABT-126 monotherapy in mild-to-moderate Alzheimer’s dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension[J]. Alzheimers Res Ther, 2016, 8(1): 44.
[32]
Lozupone M, Solfrizzi V, D’Urso F, et al. Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs[J]. Expert Opin Emerg Drugs, 2020, 25(3): 319-335.
[33]
Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial[J]. JAMA Neurol, 2015, 72(11): 1324-1333.
[34]
Craft S, Raman R, Chow TW, et al. Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: a randomized clinical trial[J]. JAMA Neurol, 2020, 77(9): 1099-1109.
[35]
Lowe SL, Duggan Evans C, Shcherbinin S, et al. Donanemab (LY3002813) phase 1b study in Alzheimer’s disease: rapid and sustained reduction of brain amyloid measured by florbetapir F18 imaging[J]. J Prev Alzheimers Dis, 2021, 8(4): 414-424.
[36]
Maher-Edwards G, Watson C, Ascher J, et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer’s disease[J]. Alzheimers Dement (N Y), 2015, 1(1): 23-36.
[37]
Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease[J]. J Alzheimers Dis, 2015, 44(2): 705-720.
[38]
Jia J, Ji Y, Feng T, et al. Sixteen-week interventional study to evaluate the clinical effects and safety of rivastigmine capsules in Chinese patients with Alzheimer’s disease[J]. J Alzheimers Dis, 2019, 72(4): 1313-1322.
[39]
Maier F, Spottke A, Bach JP, et al. Bupropion for the treatment of apathy in Alzheimer disease: a randomized clinical trial[J]. JAMA Netw Open, 2020, 3(5): e206027.
[40]
Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody[J]. Alzheimers Res Ther, 2021, 13(1): 80.
[41]
Wang HY, Pei Z, Lee KC, et al. PTI-125 reduces biomarkers of Alzheimer’s disease in patients[J]. J Prev Alzheimers Dis, 2020, 7(4): 256-264.
[42]
Scheltens P, Hallikainen M, Grimmer T, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study[J]. Alzheimers Res Ther, 2018, 10(1): 107.
[43]
Vijverberg EGB, Axelsen TM, Bihlet AR, et al. Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD[J]. Alzheimers Res Ther, 2021, 13(1): 142.
[44]
Farlow MR, Thompson RE, Wei LJ, et al. A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer’s disease[J]. J Alzheimers Dis, 2019, 67(2): 555-570.
[45]
Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline[J]. JAMA Neurol, 2014, 71(8): 961-970.
[46]
Xiao S, Chan P, Wang T, et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia[J]. Alzheimers Res Ther, 2021, 13(1): 62.
[47]
Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients[J]. Alzheimers Dement, 2016, 12(2): 110-120.
[48]
Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial[J]. Lancet, 2016, 388(10062): 2873-2884.
[49]
Sabbagh MN, Hendrix S, Harrison JE. FDA position statement "Early Alzheimer’s disease: developing drugs for treatment, guidance for industry" [J]. Alzheimers Dement (N Y), 2019, 5: 13-19.
[50]
Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)[J]. Alzheimers Res Ther, 2018, 10(1): 96.
[51]
Farlow MR, Andreasen N, Riviere ME, et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease[J]. Alzheimers Res Ther, 2015, 7(1): 23.
[52]
Howard R, Zubko O, Bradley R, et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial[J]. JAMA Neurol, 2020, 77(2): 164-174.
[53]
Padala PR, Boozer EM, Lensing SY, et al. Neuromodulation for apathy in Alzheimer’s disease: a double-blind, randomized, sham-controlled pilot study[J]. J Alzheimers Dis, 2020, 77(4): 1483-1493.
[54]
Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease[J]. Neurology, 2015, 85(16): 1383-1391.
[55]
Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial[J]. Front Aging Neurosci, 2016, 8: 108.
[56]
Zhao L, Zhao Q, Zhou Y, et al. Atorvastatin may correct dyslipidemia in adult patients at risk for Alzheimer’s disease through an anti-inflammatory pathway[J]. CNS Neurol Disord Drug Targets, 2016, 15(1): 80-85.
[57]
Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer’s disease[J]. N Engl J Med, 2021, 384(18): 1691-1704.
[58]
Yoshida K, Moein A, Bittner T, et al. Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer’s disease[J]. Alzheimers Res Ther, 2020, 12(1): 16.
[59]
Malpas CB, Vivash L, Genc S, et al. A phase IIa randomized control trial of VEL015 (sodium selenate) in mild-moderate Alzheimer’s disease[J]. J Alzheimers Dis, 2016, 54(1): 223-232.
[60]
Henderson ST, Morimoto BH, Cummings JL, et al. A placebo-controlled, parallel-group, randomized clinical trial of AC-1204 in mild-to-moderate Alzheimer’s disease[J]. J Alzheimers Dis, 2020, 75(2): 547-557.
[61]
Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial[J]. Lancet Neurol, 2017, 16(2): 123-134.
[62]
Prins ND, Harrison JE, Chu HM, et al. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease[J]. Alzheimers Res Ther, 2021, 13(1): 106.
[63]
Heritier SR, Gebski VJ, Keech AC. Inclusion of patients in clinical trial analysis: the intention-to-treat principle[J]. Med J Aust, 2003, 179(8): 438-440.
[64]
Moreno-Betancur M, Chavance M. Sensitivity analysis of incomplete longitudinal data departing from the missing at random assumption: methodology and application in a clinical trial with drop-outs[J]. Stat Methods Med Res, 2016, 25(4): 1471-1489.
[65]
Malek-Ahmadi M, Chen K, Perez SE, et al. Cognitive composite score association with Alzheimer’s disease plaque and tangle pathology[J]. Alzheimers Res Ther, 2018, 10(1): 90.
[66]
Donohue MC, Aisen PS. Mixed model of repeated measures versus slope models in Alzheimer’s disease clinical trials[J]. J Nutr Health Aging, 2012, 16(4): 360-364.
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