Table 1.
RCTs based on β-amyloid in recent years.
| Mechanism | RCT | Status | Estimated end | Dementia stage | Enrollment | Duration | Reported outcomes | Details of drugs/RCTs |
|---|---|---|---|---|---|---|---|---|
| ↓Aβ production | ||||||||
| BACE1 inhibitor | Pioglitazone | Phase 2; completed | 2005.1 | Mild-to-moderate | 25 | 18 months | Insulin sensitizer, class of PPARγ agonists | |
| CTS-21166 | Phase 1; completed | 2008.2 | Healthy | 56 | ||||
| MK8931 | Phase 3; ongoing | 2018.3 | Mild-to-moderate | 1960 | ≈6.5 years | With enhanced BBB permeability | ||
| E2609 | Phase 1; completed | 2013.9 | MCI/mild AD | 65 | ||||
| GSI/GSM | NIC5-15 | Phase 2; ongoing | 2013.12 | 40 | Notch-sparing, insulin-sensitizer | |||
| Begacestat | Phase 1; completed | 2009.10 | Elder healthy | 49 | Dose-dependent changes in plasma Aβ levels | Selectively inhibits cleavage of APP over Notch [208] | ||
| CHF 5074 | Phase 2; completed | 2012.4 | MCI | 96 | 12 weeks | NSAID | ||
| EVP-0962 | Phase 2; completed | 2013.10 | MCI/early stage | 52 | 14 days | |||
| α-secretase activator | Atorvastatin | Phase 3; completed∗ | 2007.7 | Mild-to-moderate | 600 | 80 weeks | Tested with AchEI | |
| Simvastatin | Phase 3; completed | 2007.10 | Mild-to-moderate | 400 | 18 months | |||
| Etazolate | Phase 2a; completed | 2009.8 | Mild-to-moderate | 159 | Safe and well tolerated | ↑α-secretase activity, acting as a GABA-A receptor modulator and a PDE-4 inhibitor [209] | ||
| Epigallocatechin-3-gallate (EGCg) | Phase 2/3; ongoing | 2015.6 | Early stage | 50 | 18 months | Prevents the Aβ aggregation via binding to the unfolded peptide | ||
| ↓Aβ aggregation/oligomers | Scyllo-inositol (ELND005/AZD103) | Phase 2; completed | 2010.5 | Mild-to-moderate | 350 | 18 months | Insufficient to support/refute benefits [210] | |
| Tramiprosate (3APS) | Phase 3 | unknown | Mild-to-moderate | 950 | Suggesting disease-modifying effects [211] | |||
| PBT2 | Phase 2; completed | 2007.12 | Mild AD | 80 | 12 weeks | Well-tolerated, ↓CSF Aβ42, and improved executive function [212] | ||
|
| ||||||||
| ↑Aβ clearance | ||||||||
| Active immunotherapy | Affitope AD02 | Phase 2; completed | 2013.12 | Early stage | 335 | >1 year | N-terminal Aβ1-6, a synthetic peptide | |
| Affitope AD03 | Phase 1; completed | 2011.11 | Mild-to-moderate | 28 | i.h. with or without adjuvant aluminum | |||
| UB 311 | Phase 1; completed | 2011.4 | Mild-to-moderate | 19 | N-terminal Aβ1-14 | |||
| V 950 | Phase 1; completed | 2012.1 | 86 | formulated on Aluminum-containing adjuvant | ||||
| CAD 106 | Phase 2; completed | 2012.12 | Mild AD | 177 | A favourable safety profile [213] | N-terminal Aβ1-6; i.m. of adjuvanted CAD106; | ||
| Passive immunotherapy | BAN2401 | Phase 2; ongoing | 2016.12 | MCI/mild AD | 800 | 18 months | mAb against Aβ oligomers | |
| BIIB037 | Phase 1; ongoing | 2014.11 | Prodromal to mild | 160 | Administered via intravenous (IV) infusions in subjects | |||
| Ponezumab | Phase 2; completed | 2011.8 | Mild-to-moderate | 198 | 24 months | |||
| Crenezumab | Phase 2/3; ongoing | 2016.5 | Mild-to-moderate | 361 | 24 months | |||
| Gammagard (IVIg) | Phase 2, completed | 2010.4 | Mild-to-moderate | 24 | 6 months | Improved cognition | ||
| Phase 3; completed | 2012.12 | Mild-to-moderate | 390 | 70 weeks | Showed no significant effect | |||
| Phase 2; ongoing | 2014.10 | MCI | 50 | 24 months | ||||
| AMBAR | Phase 2/3; ongoing | 2016.12 | Mild-to-moderate | 350 | ||||
| Gantenerumab | Phase 3; ongoing | 2019.3 | Mild | 1000 | >5 months | Phase 1 RCT↓brain Aβ; high doses, AE | Mainly targets Aβ plagues | |
| Solanezumab | Phase 3; ongoing | 2016.12 | Mild | 2100 | No benefits in primary outcomes | Mainly targets soluble oligomeric Aβ | ||
| AAB-003 | Phase 1; ongoing | 2014.8 | Mild-to-moderate | 104 | 52 weeks | Previously treated with AAB-003 | ||
| GSK933776 | Phase 1; completed | 2011.5 | 50 | |||||
| SAR228810 | Phase 1; ongoing | 2015.1 | Mild-to-moderate | 48 | 14.5–22 months | |||
|
| ||||||||
| Anti-tau | ||||||||
| ↓tau production | Valproate | Phase 3; complete | 2009.12 | Mild-to-moderate | 313 | 2 years | Did not show cognitive benefits and prevention of behavioral defects; associated with reduced brain volumes | |
| Lithium | Phase 2; ongoing | 2019.4 | 80 | A pilot study was insufficient to support or refute the efficacy [214] | ||||
| ↓tau fibrillization/deposition | Nicotinamide | Phase 1/2; ongoing | 2014.7 | Mild-to-moderate | 50 | 24 weeks | Vitamin B3 | |
| TRx0237 | Phase 3; ongoing | 2015.12 | Mild/mild-to-moderate | 700/833 | 18 months/15 months | |||
| Methylene blue (Rember) | Phase 2; completed | Mild-to-moderate | 321 | 6 months | Showed uncertain results | |||
| Davunetide (AL108) | Phase 2; completed | 2008.1 | MCI | 144 | 12 weeks | Showed benefits on memory | ||
| BMS-241027 | Phase 1; completed | 2013.10 | Mild | 40 | 9 weeks | |||
RCT: randomized controlled trial; PPAR: peroxisome proliferators activated receptor; BBB: blood brain barrier; MCI: mild cognitive impairment; GSI: γ secretase inhibitor; GSM: γ secretase modulator; NSAID: nonsteroidal anti-inflammatory drugs; AChEI: acetylcholinesterase inhibitor; GABA: γ-aminobutyric acid; PDE: phosphodiesterase; CSF: cerebrospinal fluid; i.h.: subcutaneous injection; i.m.: intramuscular injection; mAb: monoclonal antibody; AE: adverse event.
∗RCTs with a combination of another drug.
Data sources: http://www.clinicaltrials.gov/.