Evaluation of Baricitinib on HIV-1 Reservoir and Safety in Virologically Suppressed Patients with HIV-1

Trial ID: 2024-520159-26-00
Protocol: BCN05-Bari
Sponsor: Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia

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Diseases & Conditions

HIV infection

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of baricitinib, administered at a dose of 2 mg once daily for 12 weeks, in individuals with **human immunodeficiency virus** (HIV) who are on suppressive antiretroviral therapy (ART). Additionally, the study aims to assess changes in levels of phosphorylated STAT (pSTAT) in CD4+ T cells, serving as a pharmacodynamic biomarker of baricitinib activity after the 12-week treatment period. These objectives are clinically relevant as they address the potential of baricitinib to be safely integrated into the treatment regimen of virologically suppressed people with HIV, while also providing insights into its pharmacodynamic effects.

Secondary objectives include:

Evaluating the effect of baricitinib on proapoptotic pathways mediated by BCL-2 after 12 weeks of treatment.
Assessing the impact on the JAK/STAT signaling pathway following the same treatment duration.
Investigating the effect on the HIV-1 reservoir.
Examining the impact on homeostatic cytokines, inflammatory biomarkers, and cell death markers.
Evaluating the effects on immune cell subsets.
Characterizing the pharmacokinetics of baricitinib in plasma when administered at 2 mg once daily in people with HIV on suppressive ART.

These secondary objectives aim to provide a comprehensive understanding of baricitinib's effects on various biological pathways and its pharmacokinetic profile, which are crucial for optimizing therapeutic strategies in this patient population.

Participants

The clinical trial involves participants diagnosed with **Human immunodeficiency virus** (HIV), specifically those who are on suppressive antiretroviral therapy (ART). The study population includes both males and females aged between 18 and 65 years. Participants are required to have a confirmed HIV-1 infection and must have been receiving suppressive combination antiretroviral therapy (cART) for at least two years, with a maintained plasma viral load of less than 50 copies/mL. The trial population was selected based on their willingness to comply with the study protocol, including adherence to their cART regimen and availability for follow-up. Participants must also be willing to undergo blood draws and, if applicable, use effective contraception. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed as an **exploratory Phase 2 randomized, double-blind, placebo-controlled study** to evaluate the safety and impact of **baricitinib** on the HIV-1 reservoir in virologically suppressed individuals with HIV-1. The trial will involve the administration of baricitinib at a dose of 2 mg once daily for a duration of 12 weeks. The study aims to assess the safety and tolerability of baricitinib, as well as changes in levels of phosphorylated STAT (pSTAT) in CD4+ T cells, serving as a pharmacodynamic biomarker of baricitinib activity. The trial is expected to commence recruitment on June 2, 2025, and conclude by June 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed HIV-1 infection, and adherence to suppressive cART. The study will include follow-up visits at weeks 0, 4, 12, and 24, during which safety laboratory tests will be conducted, and levels of pSTAT 1, 3, and 5 in CD4+ T cells will be measured using flow cytometry. Secondary endpoints will evaluate changes in various biomarkers and baricitinib concentrations in plasma at specified intervals. The end-of-study visit will mark the completion of the participant's involvement in the trial.

Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including the development of Grade 3 or 4 treatment-related adverse events or laboratory abnormalities, as defined by the Division of AIDS (DAIDS) Table for grading the Severity of Adult and Pediatric Adverse Events. The trial will ensure that participants comply with the protocol requirements and are available for follow-up throughout the study duration. The study will utilize a placebo, maltodextrine powder, to maintain the double-blind design, ensuring that neither participants nor investigators are aware of the treatment assignments.

Treatment

The clinical trial involves the administration of **baricitinib**, marketed under the name Olumiant, as the experimental medication. Olumiant is provided in the form of **film-coated tablets**, each containing 2 mg of baricitinib. The tablets are administered orally, with a dosage of 2 mg once daily. The treatment period for baricitinib is set for a maximum of 12 weeks, with a total maximum dose of 168 mg. Baricitinib is a chemical substance, and its activity is monitored through changes in levels of phosphorylated STAT (pSTAT) in CD4+ T cells, serving as a pharmacodynamic biomarker. The tablets have been reencapsulated to ensure that the investigational medicinal product (IMP) and placebo are indistinguishable.

The study also includes the use of a placebo, which is composed of **maltodextrine powder**. The placebo is utilized to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is designed to be indistinguishable from the active treatment in appearance and administration. The role of the placebo in the trial is to serve as a comparator to evaluate the safety and efficacy of baricitinib in virologically suppressed individuals with HIV-1.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the proportion of participants developing Grade 3 or 4 treatment-related adverse events or laboratory abnormalities, as defined by the Division of AIDS (DAIDS) Table for grading the Severity of Adult and Pediatric Adverse Events. Safety laboratory tests will be conducted at weeks 0, 4, 12, and 24. Additionally, levels of phosphorylated STAT (pSTAT) 1, 3, and 5 in CD4+ T cells will be measured at weeks 0 and 12 using flow cytometry.

Secondary endpoints will evaluate changes in various biomarkers and immune cell characteristics. These include changes in levels of BCL-2 in CD4+ T cells, measured by flow cytometry at weeks 0 and 12, and changes in levels of IFITM2, pJAK1/2, cleaved-caspase 3, and other pro-apoptotic markers in CD4+ T cells, assessed by Western blot at the same time points. The study will also measure changes in total and intact proviral HIV-1 DNA (IPDA) in CD4 T cells, as well as changes in soluble plasma levels of proinflammatory and anti-inflammatory biomarkers, at weeks 0 and 12. Furthermore, changes in T cell immune subsets and frequencies of T cells expressing activation, exhaustion, and senescence markers will be evaluated using multiparametric flow cytometry. Baricitinib concentrations in plasma will be measured at weeks 4 and 12.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Males and females aged between 18 and 65 years on the day of the screening visit.
Confirmed HIV-1 infection.
Receiving suppressive cART for at least 2 years (defined as maintained plasma viral load <50 copies/mL, allowing for isolated blips [<200 cop/ml, non-consecutive, representing <20% total determinations]).
Being on the same cART regimen within at least 4 weeks prior to baseline visit (week 0).
Willing and able to be adherent to their cART regimen for the duration of the study.
Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
In the opinion of the clinical investigator, the candidate has understood the information provided and can give written Informed Consent.
If heterosexually active female of childbearing potential1, using an effective method of contraception different from hormonal contraception (intra-uterine device (IUD), anatomical sterility in self or partner or sexual abstinence) from 14 days prior to the first IMP administration and commit to use it until 3 months after the last IMP administration. All female candidates of childbearing potential who are not sexually active with men at screening, must agree to utilize an effective method of contraception if they become sexually active during the study.
If female of childbearing potential, willing to undergo urine pregnancy tests at the designated time points.
If positive IgG for varicella zoster, adequate herpes zoster vaccination at least 4 weeks prior to week 0 visit.
Willing to accept blood draws at time points specified in the Schedule of Events.

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Exclusion Criteria

If female of childbearing potential, pregnant or planning a pregnancy during the entire study or lactating.
Prior history or clinical manifestations of any physical or psychiatric disorder that could impair the subject’s ability to complete the study.
Any active AIDS-defining disease or progression of HIV-related disease, except cutaneous Kaposi’s sarcoma not requiring systemic therapy.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal, or penile intraepithelial neoplasia.
Systemic treatment for cancer within 1 year of study entry.
Known hypersensitivity to any component of the IMP formulation, or severe or multiple allergies to drugs or pharmaceutical agents.
Potential participant received or plans to receive: i. Licensed live attenuated vaccines within 28 days before or after inflammation and immune biomarkers visit (weeks 0 and 12). ii. Other vaccines (eg, tetanus, hepatitis A, hepatitis B, rabies, pneumococcal, recombinant Herpes Zoster, Influenza, COVID-19 vaccines) within 14 days before or after inflammation and immune biomarkers visits (weeks 0 and 12).
Receipt of blood products within 3 months of study entry.
Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents (use on inhaled steroids for asthma or topic steroids for localized skin conditions are permitted).
Any other current or prior therapy which, in the opinion of the investigator, would make the individual unsuitable for the study or influence the results of the study.
Prior history of thrombotic events (deep venous thrombosis, pulmonary embolism, or arterial thrombosis) or known inherited prothrombotic disorders (Factor V Leiden, prothrombin G2021A mutation, antithrombin deficiency, protein S deficiency, protein C deficiency, etc.)
Current use of combined hormonal contraceptives or substitutive hormonal treatment.
History of any of the following cardiovascular diseases: myocardial infarction, unstable angina, congestive heart failure, uncontrolled arrhythmias, cardiac revascularization, stroke, uncontrolled hypertension, or uncontrolled diabetes within 6 months.
Current smokers over 10 cigarettes per day or former smokers with a history of smoking more than 10 pack-years, unless they quit smoking more than 15 years ago.
Positive hepatitis C IgG, unless confirmed clearance of HCV infection (undetectable plasma viral load, spontaneous or following treatment).
Chronic hepatitis B, defined as positive hepatitis B surface antigen (HBsAg); or past hepatitis B, defined as positive hepatitis B core antibody (HBcAb), unless ART regimen contains FTC/TFV during the study.
Symptomatic herpes zoster or recurrent genital herpes within 24 weeks from screening, or any history of disseminated herpes simplex, disseminated herpes zoster, ophthalmic zoster, or CNS zoster.
History of active, past, or latent tuberculosis, confirmed through medical history, clinical records, or positive TB IGRAs by QuantiFERON test, unless documented preventive TB treatment with 6 or 9 months of daily isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or a 3-month regimen of daily isoniazid plus rifampicin.
Any laboratory abnormalities including: Hematology: - Hemoglobin <10.0 g/dl, - Absolute neutrophil count ≤1,000 /mm3, -Absolute lymphocyte count ≤500 /mm3, - Platelets >450,000/mm3, Biochemistry: - eGFR <30 ml/min, - AST > 2.5 x ULN, - ALT > 2.5 x ULN