Oxidative Stress, Neuroinflammation, and NADPH Oxidase: Implications in the Pathogenesis and Treatment of Alzheimer’s Disease

Table 1

Drug trials of NOX inhibitors in Alzheimer’s disease and its precursor conditions.

Country, trial code, reference if published	Sponsor	Phase	Diagnosis	Study design	Sample size and age	Treatment	Outcome	Duration	Results and status
Germany NCT00951834	Charité University, Berlin	2, 3	Early stage AD	Randomized, placebo controlled	, ≥60 years	EGCG (200-800 mg) as an add-on to donepezil	(1) ADASCog score; (2) Safety, MMSE, brain atrophy, time to hospitalization, time to death, and others	18 months	Results not posted
Spain NCT03978052	Parc de Salut Mar	NA	Apo E4 carriers with SCD	Randomized, double blind, personalized, placebo controlled, four-arm trial	, 60-80 years	Multimodal intervention (diet, physical activity and cognitive activity) and EGCG (5-6 mg/kg up to 520 mg/day)	(1) ADCS-PACC-like score; (2) Changes in functional neuronal connectivity tested by fMRI, changes in structural connectivity networks	12 months of treatment; 24 months total study duration	Ongoing
Spain NCT01699711 [153]	Parc de Salut Mar	2	DS neurological disease	Randomized, double blind, placebo controlled	, 14-29 years	EGCG (9 mg/kg) and cognitive training	(1) Change in cognitive evaluation and amyloidosis biomarkers; (2) Change in DYRK1A activity biomarkers, lipid oxidation biomarkers, neurophysiology, neuroimaging, and others	12 months	EGCG better than placebo in improving visual recognition memory, inhibitory control and adaptive behaviour
US NCT01504854 [154]	ADCS, National Institute on Aging	2	Mild-moderate AD	Randomized, double blind, placebo controlled	, ≥50 years	Oral resveratrol (500 mg/day; increased up to maximum 2 g/day)	(1) Number of adverse events, volumetric MRI brain changes from baseline; (2) Change in ADCS-ADL, CSF-Aβ40 levels	52 weeks	Nausea, diarrhoea, weight loss common with resveratrol. CSF and plasma Aβ declined more in placebo group. Brain volume loss and ventricular volume increase more in resveratrol group.
US NCT00678431 [155]	US Dept. of Veterans Affairs	3	Probable AD patients with MMSE 12-26	Randomized, double blind, placebo controlled	, 50-90 years	Oral liquid resveratrol, glucose and malate	(1) ADASCog; (2) ADCS-CGIC	12 months	All outcome scores showed less deterioration in treatment group; however, statistically insignificant
US NCT02502253	Johns Hopkins University, Icahn School of Medicine at Mount Sinai	1	Amnestic MCI; impaired fasting glucose or clinically stable type 2 diabetes	Randomized	, 50-90 years	BDPP, low-, moderate-, high-dose study	Adverse events and serious adverse events, CSF penetration of BDPP, effect on mood, and effect on cognition	4 months	Recruiting
Turkey NCT04044131	Istanbul Medipol University Hospital, ScandiBio Therapeutics AB, and others	2	Mild to moderate AD ( and )	Randomized, double blind, placebo controlled	, >50 years	Mixture of NAC, carnitine, nicotinamide riboside, and serine (metabolic cofactors)	(1) MMSE, ADASCog, ADCS-ADL; (2) Volumetric brain MRI, resting state fMRI, NPI, MOCA, serum omics, microbiota, adverse events, and biochemical monitoring	3 months	Recruiting
US NCT01320527 [156, 157]	University of Massachusetts, Worcester	2	AD and MCI	Randomized, double blind, placebo controlled	, ≥40 years	NF having folic acid 400 μg, vitamin B12 6 μg, vitamin E 30 IU, SAM 400 mg, NAC 600 mg, acetyl-L-carnitine 500 mg	(1) Cognitive improvement by CLOX-1 and DRS; (2) Improvement in NPI and ADL	12 months; first assessment at 3 months	Statistically significant improvement in the NF group versus placebo in cognitive assessment by CLOX-1 and DRS. Nonsignificant improvement in NPI and ADL. Continuation as open-label in 24 patients and evaluated at 12 months; participants maintained baseline cognitive performance and BPSD.
US NCT01370954	Pamlab, Inc. and InfoMedics, Inc.	NA	Early memory loss, MCI, AD, and VD	Prospective observational	, 50-80 years	Medical food CerefolinNAC® having NAC 600 mg, methyl cobalamin 2 mg, L-methyl folate calcium 6 mg	(1) QOL-AD measure of quality of life; (2) Overall patient satisfaction	3 months	Results not posted
US NCT02033941	Hillel Grossman, NCCIH	2	Probable AD with MMSE score of 12-26	Randomized, double blind, placebo controlled	, all ages	Grape seed polyphenolic extract	(1) Pharmacokinetic analysis, CSF tau and phosphorylated tau protein, adverse events; (2) Aβ in plasma and CSF, scores on ADASCog, ADCS-CGIC, MMSE, ADL	22 months	Recruiting
China NCT03221894	Dongzhimen Hospital, Beijing	NA	AD (mild-severe on MMSE)	Observational study	, 50-85 years	GRAPE granules (having herbal medicines such as ginseng, Curcuma, Acorus, Polygala, and berberine)	(1) MMSE; (2) ADL, NPI, and CDR	12 months	Results not posted, status as of 2017 was recruiting
South Korea NCT00391833	Seoul National University Hospital	1, 2	AD	Observational randomized, open label	, 40-83 years	Panax ginseng powder 4.5 g/day	MMSE and ADASCog scores	12 weeks therapy; assessment at 12 weeks and after 12 weeks of discontinuation of therapy	Statistically significant improvement in MMSE and ADASCog scores between the groups at 12 weeks. Improvement dissipated at 24 weeks (after 12 weeks of ginseng discontinuation) and adverse events were seen in 12% of patients treated with ginseng and 15% of the control group. Dizziness, headache, diarrhoea, and anorexia were the common adverse events seen in both groups.
Hong Kong NCT00164749	Chinese University of Hong Kong, BUPA Foundation, Kwong Wah Hospital	1, 2	AD	Randomized, double blind, placebo controlled	, ≥50 years	Curcumin powder or capsule (4 g or 1 g) along with standard treatment of ginkgo leaf extract 120 mg/d in all groups (including placebo)	(1) Plasmaisoprostanes, serum Aβ40; (2) Change in cognitive function (MMSE score), curcumin and metabolites in plasma	6 months (some variables at 1 month)	Cognitive scores did not improve with curcumin. Vitamin E increased over 1 month with curcumin. Serum Aβ40 did not change.
India NCT01001637	Jaslok Hospital and Research Center, others	2	AD, MMSE score of 5-20	Randomized, double blind, placebo controlled	, 50-80 years	Solid lipid curcumin particle (SLCP) formulation	(1) Mental capacity (based on tests); (2) Blood concentration of Aβ	2 months	Results not posted
US NCT00099710 [158]	John Douglas French Foundation	Phase 2	Mild-moderate AD	Randomized, double blind, placebo controlled for 6 months followed by open label for next 6 months	, ≥50 years	Curcumin C3 complex (2 g or 4 g daily)	(1)Adverse events, ADASCog, changes in clinical laboratory tests; (2) NPI, ADCS-ADL, plasma Aβ, CSF isoprostanes, t-tau, p-tau, and Aβ	6 months	No difference in clinical efficacy or biomarkers. Clinically insignificant increase in blood glucose and decrease in hematocrit in curcumin group. GI symptoms occurred in 12.5% patients of curcumin group leading to withdrawal from study.
US NCT01811381	Veterans Affairs Office of Research and Development	2	MCI,	Randomized, double blind	, 50-90 years	Curcumin; aerobic and anaerobic yoga/exercises	(1) Blood biomarkers: TNFα, N-terminal BNP, IL-6, IL-1β, VCAM-1, ApoE, etc.; (2) NPI, adverse events, 18-FDG-PET, FAQ	12 months	Active, not recruiting
US NCT01716637	Life Extension Foundation Inc.	1	AD (NINCDS-ADRDA criteria)	Open label, crossover	, 60-85 years	Perispinal etanercept injection subcutaneously and dietary supplements having curcumin, quercetin, resveratrol, ω-3 fatty acids	(1) MMSE score (2) ADASCog score, MOCA score	16 weeks	Results not posted
France NCT00814346	Ipsen	2	Three groups: mild AD; cognitively normal elderly; cognitively impaired elderly (MMSE-20-28 for AD)	Randomized double blind, placebo controlled followed by open label	, ≥65 years	EGb761® Ginkgo (120 mg twice daily)	(1) Change in brain glucose metabolism (18-FDG-PET) at 1 month; (2) CDR, MMSE, GDS, MMSE, adverse events in memory complaint/normal group	18 months	(1) Not reported; (2) Falls occurred in 12%; constipation, insomnia, and depression occurred in 7.3% each; gastrooesophageal reflux, vertigo, and dyspnoea occurred in 4.8% each, in the open phase
China NCT03090516	The First Affiliated Hospital with Nanjing Medical University	2, 3	Mild-moderate AD	Randomized	, 50-85 years	Donepezil versus donepezil plus ginkgo versus ginkgo	MMSE score, EEG, MRI, ADASCog score, LFT, RFT, NPI, and ADL	3 months	Recruiting as of August 2019
US NCT00010803 [159–161]	NCCIH, others	3	Normal cognition and MCI patients	Randomized, double blind, placebo controlled	, ≥75 years	Ginkgo (EGb761®) 120 mg twice daily	(1) All cause dementia including AD; (2) CVD events or mortality, progression of cognitive decline	8 years	Ginkgo had no effect on decreasing dementia, cognitive decline, and cardiovascular events. More PVD events were seen in placebo group.
France NCT00276510 [162]	Ipsen	3b/4	Patients with memory complaints	Randomized, double blind, placebo controlled	, ≥70 years	Ginkgo (EGb761®) 120 mg BD	(1) Conversion to AD; (2) Concomitant diseases, safety, rate of cognitive abilities decline	5 years	Ginkgo had no effect on decreasing AD, overall deaths and stroke. No difference in safety profile.
US NCT00042172	University of Iowa, National Institute of Mental Health	4	Patients with MCI and subjective memory complaints	Randomized	, ≥65 years	Donepezil versus placebo for 6 months then donepezil plus ginkgo versus donepezil alone for next 6 months	Brain blood flow using PET	12 months	Results not posted
US NCT01009476	Janssen-Cilag G.m.b.H	NA	Mild to moderate AD/mixed dementia	Prospective observational, noninterventional	, ≥50 years	Galantamine or nootropics (Ginkgo, piracetam, nicergoline, etc.)	Cognitive decline, safety, vital functions, caregiver’s burden, etc.	12 months	Results not posted
US, Israel, UK NCT00940589	Neurim Pharmaceuticals Ltd.	2	Mild-moderate AD ()	Randomized, double blind, placebo controlled	, 50-85 years	AChase inhibitor and melatonin (prolonged release) 2 mg versus AChase inhibitor and placebo	(1) ADASCog change; (2) iADL change, MMSE change	6 months	Nonsignificant change in ADASCog between the groups.; iADL improved significantly () in placebo compared to melatonin (1.62 versus 0.77). MMSE declined less in the melatonin group (-0.3 versus -1.9).; Adverse events: gastrointestinal seen in 28.2% of the melatonin group versus 14.7% of the control group; respiratory disorders seen in 20.5% of the melatonin group versus 11.7% of the control group. Angina, falls seen only in the melatonin group (7.7% each); increased blood sugar in the melatonin group (5%) versus the control group (2.9%).; Neuropsychiatric disorders common in the melatonin group (17.9%) versus the control group (14.7%).
US NCT00000171 [163]	National Institute on Aging (NIA)	3	AD, , dyssomnia	Randomized, double blind, placebo controlled	, ≥55 years	Melatonin 2.5 mg SR, melatonin 10 mg IR	(1) Change in nocturnal sleep time; (2) Awake period, daytime agitation, change in ADASCog, MMSE, HAM-D	8 weeks	No significant change in objective sleep outcomes.; Caregiver rating of sleep quality better in 2.5 mg SR melatonin versus placebo. Adverse events similar between the groups
US NCT03954899	NazanAksan, University of Iowa	NA	MCI,	Randomized, double blind, placebo-controlled study assessing disease-modifying role of melatonin	, 60-80 years	Melatonin 5 mg	(1) Episodic memory; (2) Overall cognitive function, CSF-p-tau, t-tau, Aβ42, sleep efficiency, and others	44 weeks	Recruiting

Abbreviations: AChase = acetylcholine esterase; AD = Alzheimer’s disease; ADASCog = Alzheimer’s Disease Assessment Scale—cognitive subscale; ADCS = Alzheimer’s Disease Cooperative Study; ADCS-CGIC = Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change; ADCS-PACC = Alzheimer’s Disease Cooperative Study—Preclinical Alzheimer Cognitive Composite; ADL = activities of daily living; Apo E = apolipoprotein E; Aβ40 = amyloid beta 40; BDPP = bioactive dietary polyphenol preparation (has grape seed polyphenolic extract and resveratrol); BNP = brain-type natriuretic peptide; BPSD = behavioural and psychological symptoms in dementia; CDR = clinical dementia rating; CSF = cerebrospinal fluid; CVD = cardiovascular disease; DRS = Dementia Rating Scale; DS = Down’s syndrome; DYRK1A = dual-specificity tyrosine phosphorylation-regulated kinase-1A; EEG = electroencephalogram; EGCG = epigallocatechin gallate; FAQ = Functional Activities Questionnaire; FDG = fluorodeoxyglucose; fMRI = functional magnetic resonance imaging; GDS = Geriatric Depression Scale; HAM-D = Hamilton Depression Rating Scale; iADL = instrumental activities of daily living; IL = interleukin; LFT = liver function test; MCI = mild cognitive impairment; MMSE = Mini Mental State Examination; MOCA = Montreal Cognitive Assessment; NA = not applicable; NAC = N-acetyl cysteine; NCCIH = National Center for Complementary and Integrative Health; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; NPI = neuropsychiatric inventory; NF = nutraceutical formulation; PET = positron emission tomography; p-tau = phosphorylated tau protein; PVD = peripheral vascular disease; QOL = quality of life; RFT = renal function test; SCD = subjective cognitive decline; TNFα = tumor necrosis factor α; t-tau = total tau protein; VCAM-1 = vascular cell adhesion molecule-1; VD = vascular dementia.