A phase III trial of ALZT-OP1 (cromolyn + ibuprofen) in early Alzheimer's disease: Primary results and exploratory analyses by APOE4 genotype

Background This study tested ALZT-OP1 (inhaled cromolyn 17.1 mg and oral ibuprofen 10 mg) in early Alzheimer's disease (AD). Objective To evaluate the efficacy and safety of ALZT-OP1 in early AD. Methods Cognite was a Phase III, double-blind, placebo-controlled, four-arm factorial trial in 619 participants with early AD (cerebrospinal fluid [CSF] amyloid-β 42 (Aβ 42 ) 180–690 pg/mL; Clinical Dementia Rating–Global 0.5). Randomization was 1:1:1:1 to cromolyn, ibuprofen, combination therapy, or placebo for 72 weeks. The primary endpoint was change from baseline to Week 72 in Clinical Dementia Rating–Sum of Boxes (CDR-SB), comparing combination versus each monotherapy. Secondary and exploratory endpoints included comparisons with placebo, subgroup analyses by apolipoprotein E4 ( APOE4 ) status, Mini-Mental State Examination scores, CSF biomarkers, and safety. Results In the modified intent-to-treat population (n = 594), the primary endpoint was not met. No statistically significant difference was found between combination and cromolyn (difference 0.16, 95% CI −0.58 to 0.90; p = 0.675) or ibuprofen (0.40, 95% CI −0.32 to 1.13; p = 0.276). APOE4 non-carriers receiving combination therapy showed a numerical benefit versus placebo (least-squares mean difference −0.96; 95% CI −2.00 to 0.08; p = 0.069), although this was not statistically significant. ALZT-OP1 was safe and well tolerated. Conclusions ALZT-OP1 did not demonstrate efficacy in an unselected early AD population. The numerical benefit observed in APOE4 non-carriers warrants prospective evaluation in a genotype-stratified trial. ALZT-OP1 was safe and well tolerated over 72 weeks, and the study provides insights for future AD trial design. The study is registered at ClinicalTrials.gov ( https://clinicaltrials.gov/study/NCT02547818 ; NCT02547818).