Pyridostigmine as Immunomodulator in People Living With HIV

April 8, 2020 updated by: Sergio I. Valdés-Ferrer, MD, PhD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Study of the Role of Peripheral Acetylcholinesterase Inhibitor Pyridostigmine as Immunomodulators in a Population of Patients Living With Human Immunodeficiency Virus Infection.

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.

Study Overview

Status

Suspended

Conditions

Intervention / Treatment

Detailed Description

Human immunodeficiency virus (HIV) infection is a public health problem with enormous personal, and social losses. According to the National Mexican HIV/AIDS survey, more than 235,000 new cases of HIV infection were reported in Mexico between 1983 and 2015.

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 CD4+ and CD8+ T cells, as well as to early immunosenescence. This immunosenescence results in increased susceptibility to opportunistic infections and a profound decrease in circulating and mucosal T cells. In these patients, modulation of the immune response represents a promising mechanism to maintain immunological homeostasis and prevent the development of pathology. From this perspective, it is posible that a reduced immune activation -rather than accelerating the progression of infection- may be an important factor in controlling infection and delaying the progression from chronic infection to acquired immunodeficiency syndrome (AIDS).

The administration of combined antiretroviral therapy (cART) has resulted in a reduction in the mortality of these patients, although the occurrence of late morbidity due to both infection and treatment has increased. Unfortunately, even in countries with complete coverage for HIV-infection, a large group of patients do not start treatment until late stages, in which immunosenescence is profound and the possibilities of immunological recovery (increase in T cell counts CD4+, normalization of the CD4+/CD8+ index, decrease in susceptibility to opportunists, normalization in the cellular response to vaccines) are very low. In this context, finding new immuno-modulatory strategies that are both easily applicable and potentially improving survival and quality of life is crucial.

The therapeutic use of neuroimmune regulators in HIV infection has been poorly explored. The nervous system has evolutionary mechanisms of reflex control of the inflammatory response, such as cholinergic anti-inflammatory pathway. Cholinergic stimulation through the use of nicotinic agonists has shown promising effects in murine and cellular models of systemic inflammation. Since cholinergic agonists are rapidly degraded or cause side effects, we performed a pilot study using pyridostigmine (Mestinon®), an acetylcholinesterase inhibitor (ACh-E), in HIV-infected patients. We observed that administration of pyridostigmine decreases the activation and proliferation of HIV-infected T cells, reduces the production of interferon (IFN)-γ and increases that of interleukin (IL)-10 (Valdés-Ferrer SI et al., AIDS Research And Human Retrovir 2009). In a second open-label pilot study in seven chronically infected patients with full virologic suppression but without concomitant elevation of CD4+ T cell counts, we found that the addition of pyridostigmine to ART led to a sustained and significant increase in the number of CD4 + T cells (PRS record: NCT00518154; Valdés-Ferrer SI, et al., Frontiers in Immunology, 2017). These results suggest that the addition of pyridostigmine to antiretroviral therapy may be beneficial in achieving and maintaining immunological homeostasis in patients with HIV.

The present study will address the potential effectiveness of add-on pyridostigmine (180mg, once per day, P.O.) on CD4+ T cell counts, CD4+/CD8+ ratio, as well as ex-vivo markers of T cell phenotype and activity. The study is designed as a 24-week crossover study where patients will start a 12-week of pyridostigmine or placebo, and then crossing-over for an additional 12 weeks (placebo-to-pyridostigmine, and pyridostigmine-to-placebo).

Since pyridostigmine is a commonly used drug for both myasthenia gravis and as a preventive in biological warfare cases, if our hypotheses are correct, the results can be easily extrapolated to clinical practice, as there is enough long-term evidence of utility and safety of the drug.

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
    • Tlalpan
      • Ciudad de México, Tlalpan, Mexico, 14080
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Placebo
Drug: Placebo
Placebo
Other Names:
  • Starch (pharmaceutical grade)
EXPERIMENTAL: Pyridostigmine
Pyridostigmine 180mg/d slow-release formulation
Drug: Pyridostigmine Bromide
Pyridostigmine 180mg/day p.o.
Other Names:
  • Mestinon Timespan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CD4+ T cell count
Time Frame: Change from baseline, at 12 and 24 weeks
Change in total CD4+ T cel count from baseline
Change from baseline, at 12 and 24 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
soluble CD14 receptor
Time Frame: Change from baseline, at 12 and 24 weeks
Change in circulating (plasma) soluble CD14 receptor from baseline
Change from baseline, at 12 and 24 weeks
CD4+ / CD8+
Time Frame: Change from baseline, at 12 and 24 weeks
Change in index of CD4+ to CD8+ T cells from baseline
Change from baseline, at 12 and 24 weeks
Inteleukin (IL)-6
Time Frame: Change from baseline, at 12 and 24 weeks
Change in circulating (plasmatic) IL-6 from baseline
Change from baseline, at 12 and 24 weeks
TREC levels
Time Frame: Change from baseline, at 12 and 24 weeks
Changes in T cell receptor excision DNA circle (TREC) levels
Change from baseline, at 12 and 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Investigators

  • Study Director: Juan Sierra-Madero, MD, INNSZ

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 1, 2019

Primary Completion (ANTICIPATED)

June 30, 2021

Study Completion (ANTICIPATED)

June 30, 2022

Study Registration Dates

First Submitted

April 1, 2017

First Submitted That Met QC Criteria

October 16, 2017

First Posted (ACTUAL)

October 17, 2017

Study Record Updates

Last Update Posted (ACTUAL)

April 10, 2020

Last Update Submitted That Met QC Criteria

April 8, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Ref. 1873

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All data will be freely available to all research parties involved

IPD Sharing Time Frame

Data will be available after finishing with recruitment.

IPD Sharing Access Criteria

Data will be made available by request.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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