Effect of IMMUNEPOTENT-CRP on Serum Pro-Inflammatory Cytokines in Mild to Moderate COVID-19

NCT06676709 | Completed Phase 1 DMC

• 2 other identifiers: EN21-00050/LIVFCB-2021-001EN21-00050
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

In this study, the effects of IMMUNEPOTENT-CRP (I-CRP), a dialyzable leukocyte extract (DLE) derived from bovine spleen cells, on the levels of key inflammatory cytokines in outpatients with COVID-19 were examined. I-CRP has been previously studied for its ability to regulate the immune system in other conditions, such as cancer and sepsis. Based on its potential to reduce harmful inflammation, the study aimed to determine if similar benefits could be observed in COVID-19 outpatients.

Conditions

COVID-19; SARS-CoV2 Infection

Keywords

Cytokine storm; Mild to moderate COVID-19; Inflammatory cytokines; Dialyzable Leukocyte Extract (DLE); IMMUNEPOTENT-CRP (I-CRP)

Outcome Measures

Primary Outcomes (1)

• Cytokine and Chemokine Serum Levels Evaluation

  Serum levels of IL-1β, IL-6, IL-10, TNF-α, IFN-α, IFN-γ, and IL-8 were measured using the Human Cytokine/Chemokine Magnetic Bead Panel (Milliplex, Darmstadt, Germany). Cytokine and chemokine concentrations in the serum are expressed in pg/mL.

  Assessments were performed at baseline (Day 0), and during the intervention period at Day 7 and Day 14.

Secondary Outcomes (6)

• Lactate Dehydrogenase (LDH) Levels

  Measurements were taken at baseline (Day 0), Day 7, and Day 14 during the intervention period.

• High-Sensitivity C-Reactive Protein (hs-CRP) Levels

  Measurements were taken at baseline (Day 0), Day 7, and Day 14 during the intervention period.

• Ferritin Levels

  Measurements were taken at baseline (Day 0), Day 7, and Day 14 during the intervention period.

• D-Dimer Levels

  Measurements were taken at baseline (Day 0), Day 7, and Day 14 during the intervention period.

• Lymphocyte Subpopulations

  Lymphocyte subpopulation counts in whole blood were measured at baseline (Day 0), Day 7, and Day 14 during the administration of I-CRP or placebo.

Study Arms (2)

I-CRP group

EXPERIMENTAL

IMMUNEPOTENT-CRP (I-CRP) was supplied in a 5 Unit (U) per vial presentation. One U is defined as the lyophilized product obtained from the dialysis of 1×10\^8 bovine spleen cells. The dosing schedule extended over 14 days. On the first day (Day 0), outpatients ingested seven doses at two-hour intervals each one. From days one through four, four doses were taken one every four hours, and from days five to thirteen, three doses were consumed one every eight hours.

Biological: IMMUNEPOTENT-CRP (I-CRP)

Placebo control

PLACEBO COMPARATOR

The placebo was prepared from a lyophilized corn starch extract and was provided in an identical appearance and presentation to IMMUNEPOTENT-CRP (I-CRP). The dosing schedule extended over 14 days. On the first day (Day 0), outpatients ingested seven doses at two-hour intervals each one. From days one through four, four doses were taken one every four hours, and from days five to thirteen, three doses were consumed one every eight hours.

Biological: Placebo Comparator

Interventions

IMMUNEPOTENT-CRP (I-CRP) BIOLOGICAL

IMMUNEPOTENT-CRP (I-CRP), a bovine dialyzable leukocyte extract (DLE) obtained from disrupted spleen cells, is a mixture of low-molecular-weight peptides (\<12 kDa) that exhibit non-specific immunomodulatory properties.

Also known as: Bovine Dialyzable Leukocyte Extract (DLE)

I-CRP group

Placebo Comparator BIOLOGICAL

The placebo was prepared from a lyophilized corn starch extract and was provided in an identical appearance and presentation to IMMUNEPOTENT-CRP (I-CRP).

Placebo control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Laboratory-confirmed SARS-CoV-2 infection (by antigen or RT-qPCR test).
• With mild to moderate symptoms of COVID-19.
• Aged ≥ 18 years.
• Not participating in any other clinical study.
• Written informed consent duly signed.

You may not qualify if:

• Undergoing any process of primary or secondary immunosuppression.
• Any autoimmune disease.
• Receiving chemotherapy.
• History of lymphoma or any malignancy.
• Pregnancy or breastfeeding women.

Sponsors & Collaborators

• Universidad Autonoma de Nuevo Leon: lead
• Laboratorio de Inmunologia y Virologia - UANL: collaborator
• Hospital Universitario Dr. Jose E. Gonzalez: collaborator

Study Sites (2)

Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon

Monterrey, Nuevo León, 64460, Mexico

Location

Laboratorio de Inmunologia y Virologia

San Nicolás de los Garza, Nuevo León, 66450, Mexico

Location

Related Publications (27)

• Franco-Molina MA, Santana-Krímskaya SE, Zarate-Triviño DG, Zapata-Benavides P, Hernández-Martínez SP, Cervantes-Wong F, et al. Bovine dialyzable leukocyte extract immunepotent CRP: Evaluation of biological activity of the modified product. Appl Sci 2021;11. https://doi.org/10.3390/app11083505.

  BACKGROUND

• Ayala MC, Gonzalez NM, Palacios G, Rivera-Morales LG, Rodriguez-Padilla C. [Dialyzed leukocyte extracts for the treatment of recurrent and severe infections in pediatric patients with cellular immunodeficiency: 15 years of experience]. Rev Alerg Mex. 2019 Jan-Mar;66(1):27-37. doi: 10.29262/ram.v66i1.531. Spanish.

  PMID: 31013404 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Castillo-Leon L, Tamez-Guerra RS, Rodriguez-Padilla C. Bovine dialyzable leukocyte extract protects against LPS-induced, murine endotoxic shock. Int Immunopharmacol. 2004 Dec 15;4(13):1577-86. doi: 10.1016/j.intimp.2004.06.014.

  PMID: 15454111 BACKGROUND

• Armides Franco-Molina M, Mendoza-Gamboa E, Castillo-Tello P, Tamez-Guerra RS, Villarreal-Trevino L, Tijerina-Menchaca R, Castillo-Leon L, Zapata-Benavides P, Rodriguez-Padilla C. In vitro antibacterial activity of bovine dialyzable leukocyte extract. Immunopharmacol Immunotoxicol. 2006;28(3):471-83. doi: 10.1080/08923970600928072.

  PMID: 16997795 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Miranda-Hernandez D, Zapata-Benavides P, Castillo-Leon L, Isaza-Brando C, Tamez-Guerra RS, Rodriguez-Padilla C. In vitro effects of bovine dialyzable leukocyte extract (bDLE) in cancer cells. Cytotherapy. 2006;8(4):408-14. doi: 10.1080/14653240600847266.

  PMID: 16923617 BACKGROUND

• Mendoza-Gamboa E, Franco-Molina MA, Zapata-Benavides P, Castillo-Tello P, Vera-Garcia ME, Tamez-Guerra RS, Rodriguez-Padilla C. Bovine dialyzable leukocyte extract modulates AP-1 DNA-binding activity and nuclear transcription factor expression in MCF-7 breast cancer cells. Cytotherapy. 2008;10(2):212-9. doi: 10.1080/14653240801891659.

  PMID: 18368600 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Zapata-Benavides P, Castillo-Tello P, Isaza-Brando CE, Zamora-Avila D, Rivera-Morales LG, Miranda-Hernandez DF, Sierra-Rivera CA, Vera-Garcia ME, Tamez-Guerra RS, Rodriguez-Padilla C. Antiangiogenic and antitumor effects of IMMUNEPOTENT CRP in murine melanoma. Immunopharmacol Immunotoxicol. 2010 Dec;32(4):637-46. doi: 10.3109/08923971003663253. Epub 2010 Mar 5.

  PMID: 20205507 BACKGROUND

• Lara HH, Ixtepan-Turrent L, Garza-Trevino EN, Badillo-Almaraz JI, Rodriguez-Padilla C. Antiviral mode of action of bovine dialyzable leukocyte extract against human immunodeficiency virus type 1 infection. BMC Res Notes. 2011 Nov 1;4:474. doi: 10.1186/1756-0500-4-474.

  PMID: 22044844 BACKGROUND

• Sierra-Rivera CA, Franco-Molina MA, Mendoza-Gamboa E, Zapata-Benavides P, Santaolalla-Tapia J, Coronado-Cerda EE, Tamez-Guerra RS, Rodriguez-Padilla C. Effect of bovine dialyzable leukocyte extract on induction of cell differentiation and death in K562 human chronic myelogenous leukemia cells. Oncol Lett. 2016 Dec;12(6):4449-4460. doi: 10.3892/ol.2016.5285. Epub 2016 Oct 18.

  PMID: 28101208 BACKGROUND

• Lorenzo-Anota HY, Reyes-Ruiz A, Calvillo-Rodriguez KM, Mendoza-Reveles R, Urdaneta-Peinado AP, Alvarez-Valadez KM, Martinez-Torres AC, Rodriguez-Padilla C. IMMUNEPOTENT CRP increases intracellular calcium through ER-calcium channels, leading to ROS production and cell death in breast cancer and leukemic cell lines. EXCLI J. 2023 Mar 16;22:352-366. doi: 10.17179/excli2022-5568. eCollection 2023.

  PMID: 37223080 BACKGROUND

• Garcia Coronado PL, Franco Molina MA, Zarate Trivino DG, Menchaca Arredondo JL, Zapata Benavides P, Rodriguez Padilla C. Putative Wound Healing Induction Functions of Exosomes Isolated from IMMUNEPOTENT CRP. Int J Mol Sci. 2023 May 18;24(10):8971. doi: 10.3390/ijms24108971.

  PMID: 37240318 BACKGROUND

• Calvillo-Rodriguez KM, Lorenzo-Anota HY, Rodriguez-Padilla C, Martinez-Torres AC, Scott-Algara D. Immunotherapies inducing immunogenic cell death in cancer: insight of the innate immune system. Front Immunol. 2023 Nov 23;14:1294434. doi: 10.3389/fimmu.2023.1294434. eCollection 2023.

  PMID: 38077402 BACKGROUND

• Coronado-Cerda EE, Franco-Molina MA, Mendoza-Gamboa E, Prado-Garcia H, Rivera-Morales LG, Zapata-Benavides P, Rodriguez-Salazar Mdel C, Caballero-Hernandez D, Tamez-Guerra RS, Rodriguez-Padilla C. In Vivo Chemoprotective Activity of Bovine Dialyzable Leukocyte Extract in Mouse Bone Marrow Cells against Damage Induced by 5-Fluorouracil. J Immunol Res. 2016;2016:6942321. doi: 10.1155/2016/6942321. Epub 2016 Apr 17.

  PMID: 27191003 BACKGROUND

• Rodriguez-Salazar MDC, Franco-Molina MA, Mendoza-Gamboa E, Martinez-Torres AC, Zapata-Benavides P, Lopez-Gonzalez JS, Coronado-Cerda EE, Alcocer-Gonzalez JM, Tamez-Guerra RS, Rodriguez-Padilla C. The novel immunomodulator IMMUNEPOTENT CRP combined with chemotherapy agent increased the rate of immunogenic cell death and prevented melanoma growth. Oncol Lett. 2017 Jul;14(1):844-852. doi: 10.3892/ol.2017.6202. Epub 2017 May 18.

  PMID: 28693241 BACKGROUND

• Martinez-Torres AC, Reyes-Ruiz A, Benitez-Londono M, Franco-Molina MA, Rodriguez-Padilla C. IMMUNEPOTENT CRP induces cell cycle arrest and caspase-independent regulated cell death in HeLa cells through reactive oxygen species production. BMC Cancer. 2018 Jan 3;18(1):13. doi: 10.1186/s12885-017-3954-5.

  PMID: 29298674 BACKGROUND

• Martinez-Torres AC, Gomez-Morales L, Martinez-Loria AB, Uscanga-Palomeque AC, Vazquez-Guillen JM, Rodriguez-Padilla C. Cytotoxic activity of IMMUNEPOTENT CRP against non-small cell lung cancer cell lines. PeerJ. 2019 Sep 27;7:e7759. doi: 10.7717/peerj.7759. eCollection 2019.

  PMID: 31579619 BACKGROUND

• Santana-Krimskaya SE, Franco-Molina MA, Zarate-Trivino DG, Prado-Garcia H, Zapata-Benavides P, Torres-Del-Muro F, Rodriguez-Padilla C. IMMUNEPOTENT CRP plus doxorubicin/cyclophosphamide chemotherapy remodel the tumor microenvironment in an air pouch triple-negative breast cancer murine model. Biomed Pharmacother. 2020 Jun;126:110062. doi: 10.1016/j.biopha.2020.110062. Epub 2020 Mar 12.

  PMID: 32172064 BACKGROUND

• Lorenzo-Anota HY, Martinez-Torres AC, Scott-Algara D, Tamez-Guerra RS, Rodriguez-Padilla C. Bovine Dialyzable Leukocyte Extract IMMUNEPOTENT-CRP Induces Selective ROS-Dependent Apoptosis in T-Acute Lymphoblastic Leukemia Cell Lines. J Oncol. 2020 Jun 8;2020:1598503. doi: 10.1155/2020/1598503. eCollection 2020.

  PMID: 32587616 BACKGROUND

• Martinez-Torres AC, Reyes-Ruiz A, Calvillo-Rodriguez KM, Alvarez-Valadez KM, Uscanga-Palomeque AC, Tamez-Guerra RS, Rodriguez-Padilla C. IMMUNEPOTENT CRP induces DAMPS release and ROS-dependent autophagosome formation in HeLa and MCF-7 cells. BMC Cancer. 2020 Jul 13;20(1):647. doi: 10.1186/s12885-020-07124-5.

  PMID: 32660440 BACKGROUND

• Lorenzo-Anota HY, Martinez-Loria AB, Tamez-Guerra RS, Scott-Algara D, Martinez-Torres AC, Rodriguez-Padilla C. Changes in the natural killer cell repertoire and function induced by the cancer immune adjuvant candidate IMMUNEPOTENT-CRP. Cell Immunol. 2022 Apr;374:104511. doi: 10.1016/j.cellimm.2022.104511. Epub 2022 Mar 26.

  PMID: 35381435 BACKGROUND

• Rivera-Lazarin AL, Martinez-Torres AC, de la Hoz-Camacho R, Guzman-Aguillon OL, Franco-Molinaa MA, Rodriguez-Padilla C. The bovine dialyzable leukocyte extract, immunepotent CRP, synergically enhances cyclophosphamide-induced breast cancer cell death, through a caspase-independent mechanism. EXCLI J. 2023 Jan 13;22:131-145. doi: 10.17179/excli2022-5389. eCollection 2023.

  PMID: 36998710 BACKGROUND

• Rivera-Lazarin AL, Calvillo-Rodriguez KM, Izaguirre-Rodriguez M, Vazquez-Guillen JM, Martinez-Torres AC, Rodriguez-Padilla C. Synergistic Enhancement of Chemotherapy-Induced Cell Death and Antitumor Efficacy against Tumoral T-Cell Lymphoblasts by IMMUNEPOTENT CRP. Int J Mol Sci. 2024 Jul 20;25(14):7938. doi: 10.3390/ijms25147938.

  PMID: 39063180 BACKGROUND

• Lara HH, Turrent LI, Garza-Trevino EN, Tamez-Guerra R, Rodriguez-Padilla C. Clinical and immunological assessment in breast cancer patients receiving anticancer therapy and bovine dialyzable leukocyte extract as an adjuvant. Exp Ther Med. 2010 May;1(3):425-431. doi: 10.3892/etm_00000066. Epub 2010 May 1.

  PMID: 22993557 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Castillo-Tello P, Isaza-Brando CE, Garcia ME, Castillo-Leon L, Tamez-Guerra RS, Rodriguez-Padilla C. Bovine dialyzable leukocyte extract modulates cytokines and nitric oxide production in lipopolysaccharide-stimulated human blood cells. Cytotherapy. 2007;9(4):379-85. doi: 10.1080/14653240701320262.

  PMID: 17573613 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Castillo-Leon L, Tamez-Guerra RS, Rodriguez-Padilla C. Bovine dialyzable leukocyte extract modulates the nitric oxide and pro-inflammatory cytokine production in lipopolysaccharide-stimulated murine peritoneal macrophages in vitro. J Med Food. 2005 Spring;8(1):20-6. doi: 10.1089/jmf.2005.8.20.

  PMID: 15857204 BACKGROUND

• Franco-Molina MA, Mendoza-Gamboa E, Zapata-Benavides P, Vera-Garcia ME, Castillo-Tello P, Garcia de la Fuente A, Mendoza RD, Garza RG, Tamez-Guerra RS, Rodriguez-Padilla C. IMMUNEPOTENT CRP (bovine dialyzable leukocyte extract) adjuvant immunotherapy: a phase I study in non-small cell lung cancer patients. Cytotherapy. 2008;10(5):490-6. doi: 10.1080/14653240802165681.

  PMID: 18821359 BACKGROUND

• Reyes-Ruiz A, Calvillo-Rodriguez KM, Martinez-Torres AC, Rodriguez-Padilla C. The bovine dialysable leukocyte extract IMMUNEPOTENT CRP induces immunogenic cell death in breast cancer cells leading to long-term antitumour memory. Br J Cancer. 2021 Apr;124(8):1398-1410. doi: 10.1038/s41416-020-01256-y. Epub 2021 Feb 3.

  PMID: 33531687 BACKGROUND

MeSH Terms

Conditions

COVID-19; Cytokine Release Syndrome

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Study Officials

• Cristina Rodriguez-Padilla, Ph.D.

  Universidad Autonoma de Nuevo Leon

  STUDY DIRECTOR

• Rene Rodriguez-Gutierrez, Ph.D.

  Universidad Autonoma de Nuevo Leon

  STUDY CHAIR

• Jose Manuel Vazquez-Guillen, Ph.D.

  Universidad Autonoma de Nuevo Leon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full-Time Research Professor

Study Record Dates

• First Submitted: October 29, 2024
• First Posted: November 6, 2024
• Study Start: April 20, 2021
• Primary Completion: February 3, 2022
• Study Completion: March 5, 2022
• Last Updated: November 8, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: The data will be available for a period of 3 years following the publication of the study.
• Access Criteria: The IPD will be made available to other researchers after the publication of the study results in a peer-reviewed scientific journal. Data will be available upon reasonable request and subject to approval by the study's Ethics Committee. Interested researchers may request access to the IPD by contacting the principal investigator of the study. Requests must include a clear description of the research purpose, and researchers must agree to use the data only for the specified purposes and comply with applicable ethical and data protection regulations.

Locations

ME (2)