Pyridostigmine as Immunomodulator in People Living With HIV
Primary Purpose
HIV-1-infection, CD4+ T Lymphocytopenia, Immune Deficiency
Status
Suspended
Phase
Phase 2
Locations
Mexico
Study Type
Interventional
Intervention
Pyridostigmine Bromide
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for HIV-1-infection
Eligibility Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Sites / Locations
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Pyridostigmine
Placebo
Arm Description
Pyridostigmine 180mg/d slow-release formulation
Placebo
Outcomes
Primary Outcome Measures
CD4+ T cell count
Change in total CD4+ T cel count from baseline
Secondary Outcome Measures
soluble CD14 receptor
Change in circulating (plasma) soluble CD14 receptor from baseline
CD4+ / CD8+
Change in index of CD4+ to CD8+ T cells from baseline
Inteleukin (IL)-6
Change in circulating (plasmatic) IL-6 from baseline
TREC levels
Changes in T cell receptor excision DNA circle (TREC) levels
Full Information
NCT ID
NCT03312244
First Posted
April 1, 2017
Last Updated
April 8, 2020
Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
1. Study Identification
Unique Protocol Identification Number
NCT03312244
Brief Title
Pyridostigmine as Immunomodulator in People Living With HIV
Official Title
Study of the Role of Peripheral Acetylcholinesterase Inhibitor Pyridostigmine as Immunomodulators in a Population of Patients Living With Human Immunodeficiency Virus Infection.
Study Type
Interventional
2. Study Status
Record Verification Date
April 2020
Overall Recruitment Status
Suspended
Why Stopped
Due to COVID-19, effective 3/19/2020 recruitment is halted until further notice
Study Start Date
July 1, 2019 (Actual)
Primary Completion Date
June 30, 2021 (Anticipated)
Study Completion Date
June 30, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-1-infection, CD4+ T Lymphocytopenia, Immune Deficiency, Immuno-senescence
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
12x12 weeks of pyridostigmine or placebo followed by crossing-over to the other arm of intervention
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
All participants will be blinded. The steering committee will have the authority to open the blinding in case of adverse effects
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pyridostigmine
Arm Type
Experimental
Arm Description
Pyridostigmine 180mg/d slow-release formulation
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Pyridostigmine Bromide
Other Intervention Name(s)
Mestinon Timespan
Intervention Description
Pyridostigmine 180mg/day p.o.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Starch (pharmaceutical grade)
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
CD4+ T cell count
Description
Change in total CD4+ T cel count from baseline
Time Frame
Change from baseline, at 12 and 24 weeks
Secondary Outcome Measure Information:
Title
soluble CD14 receptor
Description
Change in circulating (plasma) soluble CD14 receptor from baseline
Time Frame
Change from baseline, at 12 and 24 weeks
Title
CD4+ / CD8+
Description
Change in index of CD4+ to CD8+ T cells from baseline
Time Frame
Change from baseline, at 12 and 24 weeks
Title
Inteleukin (IL)-6
Description
Change in circulating (plasmatic) IL-6 from baseline
Time Frame
Change from baseline, at 12 and 24 weeks
Title
TREC levels
Description
Changes in T cell receptor excision DNA circle (TREC) levels
Time Frame
Change from baseline, at 12 and 24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
Exclusion Criteria:
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan Sierra-Madero, MD
Organizational Affiliation
INNSZ
Official's Role
Study Director
Facility Information:
Facility Name
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
City
Ciudad de México
State/Province
Tlalpan
ZIP/Postal Code
14080
Country
Mexico
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
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9204894
Citation
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Pyridostigmine as Immunomodulator in People Living With HIV
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