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 | N = 21, ≥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 |
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| Spain NCT03978052 | Parc de Salut Mar | NA | Apo E4 carriers with SCD | Randomized, double blind, personalized, placebo controlled, four-arm trial | N = 200, 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 |
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| Spain NCT01699711 [153] | Parc de Salut Mar | 2 | DS neurological disease | Randomized, double blind, placebo controlled | N = 87, 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 |
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| US NCT01504854 [154] | ADCS, National Institute on Aging | 2 | Mild-moderate AD | Randomized, double blind, placebo controlled | N = 119, ≥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. |
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| US NCT00678431 [155] | US Dept. of Veterans Affairs | 3 | Probable AD patients with MMSE 12-26 | Randomized, double blind, placebo controlled | N = 27, 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 |
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| 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 | N = 48, 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 |
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| Turkey NCT04044131 | Istanbul Medipol University Hospital, ScandiBio Therapeutics AB, and others | 2 | Mild to moderate AD (ADASCog ≥ 12 and CDR ≤ 2) | Randomized, double blind, placebo controlled | N = 60, >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 |
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| US NCT01320527 [156, 157] | University of Massachusetts, Worcester | 2 | AD and MCI | Randomized, double blind, placebo controlled | N = 106, ≥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. |
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| US NCT01370954 | Pamlab, Inc. and InfoMedics, Inc. | NA | Early memory loss, MCI, AD, and VD | Prospective observational | N = 204, 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 |
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| US NCT02033941 | Hillel Grossman, NCCIH | 2 | Probable AD with MMSE score of 12-26 | Randomized, double blind, placebo controlled | N = 20, 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 |
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| China NCT03221894 | Dongzhimen Hospital, Beijing | NA | AD (mild-severe on MMSE) | Observational study | N = 90, 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 |
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| South Korea NCT00391833 | Seoul National University Hospital | 1, 2 | AD | Observational randomized, open label | N = 97, 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. |
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| Hong Kong NCT00164749 | Chinese University of Hong Kong, BUPA Foundation, Kwong Wah Hospital | 1, 2 | AD | Randomized, double blind, placebo controlled | N = 34, ≥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. |
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| India NCT01001637 | Jaslok Hospital and Research Center, others | 2 | AD, MMSE score of 5-20 | Randomized, double blind, placebo controlled | N = 26, 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 |
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| 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 | N = 30, ≥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. |
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| US NCT01811381 | Veterans Affairs Office of Research and Development | 2 | MCI, MMSE > 24 | Randomized, double blind | N = 80, 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 |
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| US NCT01716637 | Life Extension Foundation Inc. | 1 | AD (NINCDS-ADRDA criteria) | Open label, crossover | N = 12, 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 |
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| 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 | N = 49, ≥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 |
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| China NCT03090516 | The First Affiliated Hospital with Nanjing Medical University | 2, 3 | Mild-moderate AD | Randomized | N = 240, 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 |
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| US NCT00010803 [159–161] | NCCIH, others | 3 | Normal cognition and MCI patients | Randomized, double blind, placebo controlled | N = 3069, ≥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. |
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| France NCT00276510 [162] | Ipsen | 3b/4 | Patients with memory complaints | Randomized, double blind, placebo controlled | N = 2854, ≥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. |
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| US NCT00042172 | University of Iowa, National Institute of Mental Health | 4 | Patients with MCI and subjective memory complaints | Randomized | N = 40, ≥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 |
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| US NCT01009476 | Janssen-Cilag G.m.b.H | NA | Mild to moderate AD/mixed dementia | Prospective observational, noninterventional | N = 1134, ≥50 years | Galantamine or nootropics (Ginkgo, piracetam, nicergoline, etc.) | Cognitive decline, safety, vital functions, caregiver's burden, etc. | 12 months | Results not posted |
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| US, Israel, UK NCT00940589 | Neurim Pharmaceuticals Ltd. | 2 | Mild-moderate AD (MMSE score > 15) | Randomized, double blind, placebo controlled | N = 73, 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 (P < 0.05) 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%). |
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| US NCT00000171 [163] | National Institute on Aging (NIA) | 3 | AD, MMSE ≤ 26, dyssomnia | Randomized, double blind, placebo controlled | N = 157, ≥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 |
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| US NCT03954899 | NazanAksan, University of Iowa | NA | MCI, MOCA score ≥ 18 | Randomized, double blind, placebo-controlled study assessing disease-modifying role of melatonin | N = 230, 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.