Pyridostigmine as Immunomodulator in People Living With HIV

NCT03312244 | Suspended Phase 2 DMC

• 1 other identifier: Ref. 1873
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Human immunodeficiency virus (HIV) infection is characterized by persistent immune activation and a constant turnover of T cells. This leads to a precipitous fall in the number of T cells, as well as to an early immunosenescence. This results in increased susceptibility to opportunistic infections. In these patients, modulation of the immune response represents a promising mechanism to maintain immunological homeostasis and prevent the development of pathology. We hypothesize that the addition of pyridostigmine to the regular combined antiretroviral therapy will result in a decrease in T cell overactivation and a reduction in circulating inflammatory markers.

Conditions

HIV-1-infection; CD4+ T Lymphocytopenia; Immune Deficiency; Immuno-senescence

Outcome Measures

Primary Outcomes (1)

• CD4+ T cell count

  Change in total CD4+ T cel count from baseline

  Change from baseline, at 12 and 24 weeks

Secondary Outcomes (4)

• soluble CD14 receptor

  Change from baseline, at 12 and 24 weeks

• CD4+ / CD8+

  Change from baseline, at 12 and 24 weeks

• Inteleukin (IL)-6

  Change from baseline, at 12 and 24 weeks

• TREC levels

  Change from baseline, at 12 and 24 weeks

Study Arms (2)

Pyridostigmine

EXPERIMENTAL

Pyridostigmine 180mg/d slow-release formulation

Drug: Pyridostigmine Bromide

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Pyridostigmine Bromide DRUG

Pyridostigmine 180mg/day p.o.

Also known as: Mestinon Timespan

Pyridostigmine

Placebo DRUG

Placebo

Also known as: Starch (pharmaceutical grade)

Placebo

Eligibility Criteria

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

You may qualify if:

• HIV-1 infected subjects 18 years of age or older
• Receiving stable ART for at least six months
• At least two undetectable viral load determinations in the previous six months
• Patient agrees to participate and signs informed consent

You may not qualify if:

• Concomitant active infectious or neoplastic disease
• History of new AIDS-defining events in the previous six months
• If a participant is female, pregnancy or breast-feeding
• Exposure to an investigational agent, chemotherapy or radiotherapy within the previous 28 days
• Currently taking or planning to take treatment for Tuberculosis
• Being unable to follow or comply with the protocol interventions
• The participant is receiving immunosuppressive treatment, including corticosteroids

Sponsors & Collaborators

• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran: lead

Study Sites (1)

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Mexico City, Tlalpan, 14080, Mexico

Location

Related Publications (12)

• Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997 Jul 4;277(5322):112-6. doi: 10.1126/science.277.5322.112.

  PMID: 9204894 RESULT

• Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens PT. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med. 1998 Feb;4(2):208-14. doi: 10.1038/nm0298-208.

  PMID: 9461195 RESULT

• Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A, Hirschel B, Ledergerber B, Vernazza P, Bernasconi E, Rickenbach M, Egger M, Battegay M; Swiss HIV Cohort Study Group. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med. 2003 Oct 13;163(18):2187-95. doi: 10.1001/archinte.163.18.2187.

  PMID: 14557216 RESULT

• Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. Blood. 2011 May 26;117(21):5582-90. doi: 10.1182/blood-2010-12-322453. Epub 2011 Mar 14.

  PMID: 21403129 RESULT

• Moore DM, Hogg RS, Yip B, Wood E, Tyndall M, Braitstein P, Montaner JS. Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr. 2005 Nov 1;40(3):288-93. doi: 10.1097/01.qai.0000182847.38098.d1.

  PMID: 16249702 RESULT

• Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, Bandera A, Capetti A, Rizzardini G, Clerici M. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS. 2010 Aug 24;24(13):1991-2000. doi: 10.1097/QAD.0b013e32833c93ce.

  PMID: 20651586 RESULT

• Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96. doi: 10.1172/JCI30555.

  PMID: 17273548 RESULT

• Valdes-Ferrer SI, Crispin JC, Belaunzaran PF, Cantu-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses. 2009 Aug;25(8):749-55. doi: 10.1089/aid.2008.0257.

  PMID: 19645607 RESULT

• Ku NS, Song YG, Han SH, Kim SB, Kim HW, Jeong SJ, Kim CO, Kim JM, Choi JY. Short communication: factors influencing time to CD4(+) T cell counts >200 cells/mm(3) in HIV-infected individuals with CD4(+) T cell <50 cells/mm(3) at the time of starting combination antiretroviral therapy. AIDS Res Hum Retroviruses. 2012 Dec;28(12):1594-7. doi: 10.1089/AID.2011.0282. Epub 2012 Jun 25.

  PMID: 22632127 RESULT

• Kawashima K, Fujii T. The lymphocytic cholinergic system and its biological function. Life Sci. 2003 Mar 28;72(18-19):2101-9. doi: 10.1016/s0024-3205(03)00068-7.

  PMID: 12628464 RESULT

• Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052):98-101. doi: 10.1126/science.1209985. Epub 2011 Sep 15.

  PMID: 21921156 RESULT

• Valdes-Ferrer SI, Crispin JC, Belaunzaran-Zamudio PF, Rodriguez-Osorio CA, Cacho-Diaz B, Alcocer-Varela J, Cantu-Brito C, Sierra-Madero J. Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study. Front Immunol. 2017 Oct 18;8:1301. doi: 10.3389/fimmu.2017.01301. eCollection 2017.

  PMID: 29093707 RESULT

MeSH Terms

Conditions

T-Lymphocytopenia, Idiopathic CD4-Positive; Immunologic Deficiency Syndromes

Interventions

Pyridostigmine Bromide; Starch

Condition Hierarchy (Ancestors)

Lymphopenia; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Glucans; Biopolymers; Polymers; Macromolecular Substances; Dietary Carbohydrates; Carbohydrates; Polysaccharides

Study Officials

• Juan Sierra-Madero, MD

  INNSZ

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All participants will be blinded. The steering committee will have the authority to open the blinding in case of adverse effects
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Investigator

Model Details: 12x12 weeks of pyridostigmine or placebo followed by crossing-over to the other arm of intervention

Study Record Dates

• First Submitted: April 1, 2017
• First Posted: October 17, 2017
• Study Start: July 1, 2019
• Primary Completion: June 30, 2021
• Study Completion: June 30, 2022
• Last Updated: April 10, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Data will be available after finishing with recruitment.
• Access Criteria: Data will be made available by request.

Locations

ME (1)