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Pyridostigmine as Immunomodulator in People Living With HIV

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03312244
First Posted: October 17, 2017
Last Update Posted: October 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Sergio I. Valdes-Ferrer, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
  Purpose

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 constant turnover of T cells. This leads to a precipitous fall in the number of CD4 + and CD8 + T cells, as well as to an early immunosenescence phenomenon that conditions 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 feasible that lesser immune activation - rather than accelerating the progression of infection - may be an important actor in controlling infection and delaying the progression from chronic infection to acquired immunodeficiency syndrome (AIDS) .

The administration of highly active antiretroviral therapy (ART) 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 cluntries 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. In brief, the nervous system has evolutionary mechanisms of reflex control of the inflammatory response, such as cholinergic anti-inflammatory reflex (RCA). 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) -gamma 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 virological 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; in preparation for publication). 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 (90mg, once per day, per oris) 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 aditional 12 weeks (placebo-to-pyridostigmine, and pyrodistigmine-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 will be easily extended to clinical practice, as there is enough long-term evidence of utility and safety of the drug.


Condition Intervention Phase
HIV-1-infection CD4+ T Lymphocytopenia Immune Deficiency Immuno-senescence Drug: Pyridostigmine Bromide Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
12x12 weeks of pyridostigmine or placebo followed by crossing-over to the other arm of intervention
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
All participants will be blinded. The steering committee will have the authority to open the blinding in case of adverse effects
Primary Purpose: Treatment
Official Title: Study of the Role of Peripheral Acetylcholinesterase Inhibitor Pyridostigmine as Immunomodulators in a Population of Patients Living With Human Immunodeficiency Virus Infection.

Resource links provided by NLM:


Further study details as provided by Sergio I. Valdes-Ferrer, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran:

Primary Outcome Measures:
  • CD4+ T cell count [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in total CD4+ T cel count from baseline


Secondary Outcome Measures:
  • soluble CD14 receptor [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in circulating (plasma) soluble CD14 receptor from baseline

  • CD4+ / CD8+ [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in index of CD4+ to CD8+ T cells from baseline

  • Inteleukin (IL)-6 [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in circulating (plasmatic) IL-6 from baseline

  • TREC levels [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Changes in T cell receptor excision DNA circle (TREC) levels


Estimated Enrollment: 60
Actual Study Start Date: October 1, 2017
Estimated Study Completion Date: June 30, 2020
Estimated Primary Completion Date: June 30, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pyridostigmine
Pyridostigmine 90mg/d
Drug: Pyridostigmine Bromide
Pyridostigmine 90mg/day p.o.
Placebo Comparator: Placebo
Placebo
Drug: Placebo
Placebo

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 constant turnover of T cells. This leads to a precipitous fall in the number of CD4 + and CD8 + T cells, as well as to an early immunosenescence phenomenon that conditions 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 feasible that lesser immune activation - rather than accelerating the progression of infection - may be an important actor in controlling infection and delaying the progression from chronic infection to acquired immunodeficiency syndrome (AIDS) .

The administration of highly active antiretroviral therapy (ART) 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 cluntries 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. In brief, the nervous system has evolutionary mechanisms of reflex control of the inflammatory response, such as cholinergic anti-inflammatory reflex (RCA). 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) -gamma 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 virological 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; in preparation for publication). 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 (90mg, once per day, per oris) 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 aditional 12 weeks (placebo-to-pyridostigmine, and pyrodistigmine-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 will be easily extended to clinical practice, as there is enough long-term evidence of utility and safety of the drug.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 particiant is female, pregnancy or breast-feeding
  4. Expossure to an investigational agent, chemotherapy or radiotherapy within the previous 28 days
  5. Currently taking or planing to take treatment for Tuberculosis
  6. Being unable to follow or comply with the protocol interventions
  7. Participant is receiving immunosuppressive treatment, including corticosteroids
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03312244


Locations
Mexico
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Tlalpan, Ciudad de México, Mexico, 14080
Sponsors and Collaborators
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
  More Information

Publications:

Responsible Party: Sergio I. Valdes-Ferrer, MD, Investigator, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier: NCT03312244     History of Changes
Other Study ID Numbers: Ref. 1873
First Submitted: April 1, 2017
First Posted: October 17, 2017
Last Update Posted: October 17, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All data will be freely available to all research parties involved

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

Additional relevant MeSH terms:
Infection
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Lymphopenia
T-Lymphocytopenia, Idiopathic CD4-Positive
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Bromides
Immunologic Factors
Adjuvants, Immunologic
Pyridostigmine Bromide
Cholinesterase Inhibitors
Anticonvulsants
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents