Enrichment factors for clinical trials in mild-to-moderate Alzheimer's disease

Clive Ballard, Alireza Atri, Neli Boneva, Jeffrey L Cummings, Lutz Frölich, José Luis Molinuevo, Pierre N Tariot, Lars Lau Raket, Clive Ballard, Alireza Atri, Neli Boneva, Jeffrey L Cummings, Lutz Frölich, José Luis Molinuevo, Pierre N Tariot, Lars Lau Raket

Abstract

Introduction: Heterogeneity of outcomes in Alzheimer's disease (AD) clinical trials necessitates large sample sizes and contributes to study failures. This analysis determined whether mild-to-moderate AD populations could be enriched for cognitive decline based on apolipoprotein (APOE) ε4 genotype, family history of AD, and amyloid abnormalities.

Methods: Modeling estimated the number of randomized patients needed to detect a 2-point treatment difference on the AD Assessment Scale-Cognitive subscale using placebo data from three randomized, double-blind trials (ClinicalTrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654).

Results: An 80% power to detect a 2-point treatment effect required the randomization of 148 amyloid-positive patients; 178 ε4 homozygous or amyloid-positive patients; and 231 ε4 homozygous, family history-positive, or amyloid-positive patients, compared with 1619 unenriched patients (per arm).

Discussion: Enrichment in mild-to-moderate AD clinical trials can be achieved using combinations of biomarkers/risk factors to increase the likelihood of observing potential treatment effects.

Keywords: Alzheimer's disease; Biomarkers; Clinical trial; Enrichment; Power.

Figures

Fig. 1
Fig. 1
Distribution of biomarkers/risk factors, (A) individually and (B) in combination, among patients receiving placebo. Abbreviations: A+, Amyloid positive (n = 98 tested); APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; FH+, first-degree relative with Alzheimer's disease.
Fig. 2
Fig. 2
Mean score change from baseline among patients receiving placebo, split by individual biomarker/risk factor status. *P < .05, **P < .01, ***P < .001 versus corresponding group without the biomarker/risk factor. Error bars are 95% confidence intervals. Abbreviations: A+, Amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; ADCS-ADL23, AD Cooperative Study–Activities of Daily Living, 23-item version; ADCS-CGIC, AD Cooperative Study–Clinical Global Impression of Change; APOE, apolipoprotein E; ε4++, APOE ε4 homozygous; ε4+−, APOE ε4 heterozygous; ε4−, APOE ε4 noncarrier; FH+, first-degree relative with AD; MMSE, Mini–Mental State Examination; NPI, Neuropsychiatric Inventory.
Fig. 3
Fig. 3
Mean score change from baseline among patients receiving placebo, split by combined enrichment group status. *P < .05, **P < .01, ***P < .001 versus corresponding nonenriched group. Error bars are 95% confidence intervals. Abbreviations: A+, Amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; ADCS-ADL23, AD Cooperative Study–Activities of Daily Living, 23-item version; ADCS-CGIC, AD Cooperative Study–Clinical Global Impression of Change; APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; FH+, first-degree relative with AD; MMSE, Mini–Mental State Examination; NPI, Neuropsychiatric Inventory.
Fig. 4
Fig. 4
Estimated study powers to detect a treatment effect based on (A) randomized and (B) screened patients. Abbreviations: A+, amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; ε4+−, APOE ε4 heterozygous; FH+, first-degree relative with AD; Optimal, optimal power curve (full 2-point treatment effect on the ADAS-Cog. no withdrawal); Phase 3, total phase 3 population.

References

    1. Cummings J.L., Morstorf T., Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37.
    1. Au R., Piers R.J., Lancashire L. Back to the future: Alzheimer's disease heterogeneity revisited. Alzheimers Dement (Amst) 2015;1:368–370.
    1. Yashin A.I., Fang F., Kovtun M., Wu D., Duan M., Arbeev K. Hidden heterogeneity in Alzheimer's disease: insights from genetic association studies and other analyses. Exp Gerontol. 2018;107:148–160.
    1. Komarova N.L., Thalhauser C.J. High degree of heterogeneity in Alzheimer's disease progression patterns. PLoS Comput Biol. 2011;7:e1002251.
    1. Cummings J., Lee G., Ritter A., Zhong K. Alzheimer's disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018;4:195–214.
    1. Pharmaceutical Research and Manufacturers of America Medicines in development for cancer 2018 report. Available at.
    1. Yu P., Sun J., Wolz R., Stephenson D., Brewer J., Fox N.C., Coalition Against Major Diseases and the Alzheimer's Disease Neuroimaging Initiative Operationalizing hippocampal volume as an enrichment biomarker for amnestic MCI trials: effect of algorithm, test–retest variability, and cut point on trial cost, duration, and sample size. Neurobiol Aging. 2014;35:808–818.
    1. Sevigny J., Suhy J., Chiao P., Chen T., Klein G., Purcell D. Amyloid PET screening for enrichment of early-stage Alzheimer disease clinical trials: experience in a Phase 1b clinical trial. Alzheimer Dis Assoc Disord. 2016;30:1–7.
    1. Wolz R., Schwarz A.J., Gray K.R., Yu P., Hill D.L.G., Alzheimer's Disease Neuroimaging Initiative Enrichment of clinical trials in MCI due to AD using markers of amyloid and neurodegeneration. Neurology. 2016;87:1235–1241.
    1. Chang T.S., Teng E., Elashoff D., Grill J.D., Alzheimer's Disease Neuroimaging Initiative Optimizing effect sizes with imaging enrichment and outcome choices for mild Alzheimer disease clinical trials. Alzheimer Dis Assoc Disord. 2017;31:19–26.
    1. Weiner M.W., Veitch D.P., Aisen P.S., Beckett L.A., Cairns N.J., Green R.C., Alzheimer's Disease Neuroimaging Initiative The Alzheimer's Disease Neuroimaging Initiative 3: continued innovation for clinical trial improvement. Alzheimers Dement. 2017;13:561–571.
    1. Herrmann N., Gauthier S., Boneva N., Lemming O.M., 10158 Investigators A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer's disease. Int Psychogeriatr. 2013;25:919–927.
    1. Sando S.B., Melquist S., Cannon A., Hutton M.L., Sletvold O., Saltvedt I. APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; a case control study from central Norway. BMC Neurol. 2008;8:9.
    1. Mayeux R., Sano M., Chen J., Tatemichi T., Stern Y. Risk of dementia in first-degree relatives of patients with Alzheimer's disease and related disorders. Arch Neurol. 1991;48:269–273.
    1. Ossenkoppele R., Jansen W.J., Rabinovici G.D., Knol D.L., van der Flier W.M., van Berckel B.N.M., the Amyloid PET Study Group Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015;313:1939–1949.
    1. Jansen W.J., Ossenkoppele R., Knol D.L., Tijms B.M., Scheltens P., Verhey F.R.J., the Amyloid Biomarker Study Group Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924–1938.
    1. Atri A., Frölich L., Ballard C., Tariot P.N., Molinuevo J.L., Boneva N. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319:130–142.
    1. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E.M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939–944.
    1. Folstein M.F., Folstein S.E., McHugh P.R. “Mini–mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198.
    1. Rosen W.G., Mohs R.C., Davis K.L. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356–1364.
    1. Galasko D., Bennett D., Sano M., Ernesto C., Thomas R., Grundman M., The Alzheimer's Disease Cooperative Study An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord. 1997;11:S33–S39.
    1. Robert P., Ferris S., Gauthier S., Ihl R., Winblad B., Tennigkeit F. Review of Alzheimer's disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? Alzheimers Res Ther. 2010;2:24.
    1. Schneider L.S., Olin J.T., Doody R.S., Clark C.M., Morris J.C., Reisberg B., The Alzheimer's Disease Cooperative Study Validity and reliability of the Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change. Alzheimer Dis Assoc Disord. 1997;11:S22–S32.
    1. Guy W. National Institute of Mental Health; Rockville, MD: 1976. ECDEU Assessment Manual for Psychopharmacology, Revised.
    1. Cummings J.L. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48:S10–S16.
    1. Li Q.X., Villemagne V.L., Doecke J.D., Rembach A., Sarros S., Varghese S., AIBL Research Group Alzheimer's disease normative cerebrospinal fluid biomarkers validated in PET amyloid-β characterized subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. J Alzheimers Dis. 2015;48:175–187.
    1. Palmqvist S., Zetterberg H., Mattsson N., Johansson P., Minthon L., Blennow K., Alzheimer's Disease Neuroimaging Initiative; Swedish BioFINDER Study Group Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. 2015;85:1240–1249.
    1. Winblad B., Amouyel P., Andrieu S., Ballard C., Brayne C., Brodaty H. Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol. 2016;15:455–532.
    1. Desikan R.S., Fan C.C., Wang Y., Schork A.J., Cabral H.J., Cupples L.A. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 2017;14:e1002258.
    1. van der Lee S.J., Wolters F.J., Ikram M.K., Hofman A., Ikram M.A., Amin A. The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol. 2018;17:434–444.
    1. Seltzer B., Zolnouni P., Nunez M., Goldman R., Kumar D., Ieni J., Donepezil “402” Study Group Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852–1856.
    1. Jiang Q., Lee C.Y.D., Mandrekar S., Wilkinson B., Cramer P., Zelcer N. ApoE promotes the proteolytic degradation of Aß. Neuron. 2008;58:681–693.
    1. Ito K., Corrigan B., Zhao Q., French J., Miller R., Soares H., Alzheimer's Disease Neuroimaging Initiative Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database. Alzheimers Dement. 2011;7:151–160.
    1. McCarney R., Warner J., Iliffe S., van Haselen R., Griffin M., Fisher P. The Hawthorne Effect: a randomised, controlled trial. BMC Med Res Methodol. 2007;7:30.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다