Table 3 Main features of published clinical studies: study design, intervention, safety profile, and outcomes
From: Anticancer drugs repurposed for Alzheimer’s disease: a systematic review
Reference | Study design | Study population | Randomization | Objective(s) | Treatment duration | Intervention | AEs/SAEs | Number of dropouts | Achievement of endpoints |
|---|---|---|---|---|---|---|---|---|---|
Cummings et al. [52] | Phase II, proof-of-concept randomized double-blinded, parallel-group, placebo-controlled single-site study | Treatment group: male 6/female 10 Age 74.9 ±6.6 Placebo group: male 1/female 3 Age 78.1 ±8.0 NINCDS-ADRDA criteria for AD Positive amyloid PET Average MMSE B, 13.7 P, 17.0 | 4:1 (n=20) 16 bexarotene 4 placebo | Drug-placebo change from baseline to week 4 of composite Aβ burden of the brain Change in cognitive scores from baseline to week 4 (MMSE, ADAS-Cog, ADCS-ADL, NPI, CDR-SOB) Change in Aβ40 and Aβ42 serum levels | 4 weeks | Bexarotene (150mg/d) for 7d followed by 300mg/d from day 8 to 28 | 15/20 had increases in triglyceride levels (>200mg/dl) and cholesterol levels (>300mg/dl) | 1 discontinued due to elevated triglyceride levels All controls completed the study | 1. Significant reduction in composite amyloid burden in ApoE-ε4 noncarriers 2. No cognitive improvements |
Piette et al. [51] | Phase II, multicenter, randomized double-blinded, placebo-controlled study | Treatment group: male 11/female 15 Age 72 ±12 Placebo group: male 2/female 6 Age 78 ±11 Mild to moderate AD (NINCD-ADRDA) Median MMSE score M, 19.1 P, 18 | 5:5:3 (n=34) 12 masitinib 3mg/kg/d 14 masitinib 6mg/kg/d 8 placebo | Improvement defined as a decrease ≥ 4 in ADAS-Cog Improvement defined as an increase in ADCS-ADL ≥ 3, CIBIC-Plus, CDR, and MMSE Safety | 24 weeks | Masitinib (3 to 6mg/kg/d) | AEs (M), 65% (n=17) AEs (P), 38% (n=3) SAEs (M), 15% (n=4) SAEs (P), 13% (n=1) | 21 prematurely ended: 9 adverse events (M) 2 protocol violation (1M; 1 P) 2 withdrawal of consent (M) 8 investigator death (7M; 1 P) | 1. ADAS-Cog worsening at 12 and 24 weeks (6% in masitinib, 50% in placebo, p=0.04; p=0.046) 2. ADCS-ADL improvement at 12 weeks (50% in masitinib, 0% in placebo, p=0.05) Improvements not statistically significant at 24 weeks 3. MMSE significant difference between groups after 12 (p=0.047) and 24 weeks (p=0.031) |
Turner et al. [53] | Phase II randomized, double-blinded, placebo-controlled single-site study | Subjects with mild to moderate AD (NIA-AA) Treatment group: male 3/female 14 Age 72.2 ±6.9 Placebo group: male 2/female 6 Age 69.2 ±6.06 Average MMSE N, 19.2 P, 19.8 CSF Aβ <1100pg/ml or positive amyloid PET | 1:1 (n=37) 17 nilotinib 20 placebo Block randomization | Safety, tolerability Pharmacokinetics Effects on amyloid biomarkers on CSF Aβ42 and Aβ40, CNS amyloid burden [PET], CSF p-tau, total tau, and hippocampal volume (MRI) Clinical assessments (MMSE, ADAS-Cog, ADCS-ADL, NPI, CDR-SOB) | 12 months | Nilotinib (150mg/d followed by 300mg/d) | SAEs 0% in the nilotinib group Mood swings (70.6%) mainly with 300mg/d dosage SAEs 25% in the placebo group | 3 discontinued in placebo due to SAEs 3 voluntary discontinuation in nilotinib | 1. Well-tolerated 2. Reduction in CNS amyloid burden and levels of CSF Aβ1-42, Aβ1-40, and p-tau with both dosages 3. Attenuation of hippocampal volume loss (−27%) 3. No significant efficacy in cognitive tests |
Ghosal et al. [54] | Phase I Randomized Double-blinded Placebo-controlled proof-of-mechanism study | Healthy subjects (median age 30–32 y) all carrying ApoE ε3/ε3 Treatment group: female 6/male 0 Age 30.2±6.6 Placebo group: male 3/female 3 Age 32±9.6 | 1:1 (n=12) 6 bexarotene 6 placebo Atmospheric method for randomization | CNS penetration Increment of ApoE Alteration of Aβ Clearance | 5 days | Bexarotene (450mg/d) | No SAEs were reported 3: increase triglyceride levels (>200 mg/ml) 1: increase cholesterol levels (>200mg/dl) 2: abnormal thyroid levels | No dropouts | 1. Poor CNS penetration Bexarotene plasma to CSF ratio 85:1 2. No effect on clearance of Aβ |
Decourt et al. [48] | Phase II, randomized double-blinded, placebo-controlled, single-site study | Male 16 (64%) Treatment group: male n.a./female n.a. Age 73.6 ±8.22 Placebo group: male n.a./female n.a. Age 73.6 ±4.84 Probable AD for at least 1 year (NINCD-ADRDA) Average MMSE T, 21.8 P, 22.0 | 2:1 (n=25) 17 thalidomide 8 placebo | Safety, tolerability ADAS-Cog ADCS-ADL, CDR-SOB, MMSE | 24 weeks | Thalidomide (escalating dose regimens from 50 to 400 mg/d) | 15/17 (88%) had AEs All AEs were reported for both arms | 10/17 (67%) in the thalidomide arm terminated early 2/4 (50%) in the placebo group terminated early | 1. Not well-tolerated, poor safety 2. Results on clinical outcomes were negative |