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Pyridostigmine as Immunomodulator in People Living With HIV

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.
 
ClinicalTrials.gov Identifier: NCT03312244
Recruitment Status : Suspended (Due to COVID-19, effective 3/19/2020 recruitment is halted until further notice)
First Posted : October 17, 2017
Last Update Posted : April 10, 2020
Sponsor:
Information provided by (Responsible Party):
Sergio I. Valdés-Ferrer, MD, PhD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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.

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

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
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.
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Pyridostigmine
Pyridostigmine 180mg/d slow-release formulation
Drug: Pyridostigmine Bromide
Pyridostigmine 180mg/day p.o.
Other Name: Mestinon Timespan

Placebo Comparator: Placebo
Placebo
Drug: Placebo
Placebo
Other Name: Starch (pharmaceutical grade)




Primary Outcome Measures :
  1. 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 :
  1. soluble CD14 receptor [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in circulating (plasma) soluble CD14 receptor from baseline

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

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

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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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 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

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
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Mexico
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Ciudad de México, Tlalpan, Mexico, 14080
Sponsors and Collaborators
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Investigators
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Study Director: Juan Sierra-Madero, MD INNSZ

Publications of Results:

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Responsible Party: Sergio I. Valdés-Ferrer, MD, PhD, Investigator, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier: NCT03312244    
Other Study ID Numbers: Ref. 1873
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: April 10, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All data will be freely available to all research parties involved
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Data will be available after finishing with recruitment.
Access Criteria: Data will be made available by request.

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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:
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Infection
Lymphopenia
T-Lymphocytopenia, Idiopathic CD4-Positive
Immunologic Deficiency Syndromes
Immune System Diseases
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Bromides
Pyridostigmine Bromide
Anticonvulsants
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs