NeuroEPO plus (NeuralCIM®) in mild-to-moderate Alzheimer’s clinical syndrome: the ATHENEA randomized clinical trial
Authors: Sosa Saily , Bringas Giosmany , Urrutia Nelky , Peñalver Ana Ivis , López Danay , González Evelio , Fernández Ana , Hernández Zenaida Milagros , Viña Ariel , Peña Yamile , Batista Juan Felipe , Valenzuela Carmen , León Kalet , Crombet Tania , Rodríguez Teresita , Pérez Leslie ,   on behalf of the ATHENEA Investigators, Álvarez Yolanda , Rodríguez Madelín , Vázquez Nairim , Rodríguez Mirelys , González Yaniuris , Ramos María A. , López Yosvany , Hernández Mara , Madruga Lázaro , Carmona Dianelys , Acosta Julio E. , López Miriam , Amaro Deiry , Baños Olga L. , Álvarez Mariela Ortega , Cordero Anay , Betancourt Melany , Padrón Liana , Chávez Elio , García Isabel , Morgan Yaquelin , Charles Moraima , González Mónica , de la C. Rodríguez Marianela , León Yeniley , López Joe Michel , Acosta Yanelis , de los Ángeles Virués Trinidad , Pérez Laura , León Karen , Periche Rubén , Valero Adonisbel , Pozo Yoelvis César , Horta Greysi , Quesada Rodobaldo , Luz Elvia , Torres Leonel A. , Romero Susana , Rodríguez María E. , Estévez Daymys 
Published: December 2023

Abstract
Background
NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer’s disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus.

Methods
This was a double-blind, randomized, placebo-controlled, phase 2–3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume.

Results
A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was −3.0 (95% CI, −4.3 to −1.7) in the 0.5 mg neuroEPO plus group, −4.0 (95% CI, −5.9 to −2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5–9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2–10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion.

Conclusions
Among participants with mild-moderate Alzheimer’s disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer’s disease.

Trial registration
https://rpcec.sld.cu Identifier: RPCEC00000232.