LM11A-31 Safety and Tolerability in Aging People Living With HIV and Neurocognitive Impairment

• Women and men of any race or ethnicity, aged 50-75 years, inclusive.
• Have capacity to provide informed consent, as demonstrated with a capacity screening tool.
• Sign informed consent form (ICF).
• Evidence of HIV infection. If unavailable in the participant's medical record, HIV infection will be confirmed using a point-of-care antibody test (MedMira Rapid Test, Canada). If the result differs from the participant's self-report, a clinical HIV antigen-antibody assay will be performed.
• Stable antiretroviral therapy (ART) regimen for at least 1 year with plasma HIV RNA ≤ 40 copies/mL at screening and for at least 6 months.
• CD4+ T-cell count > 350/μL.
• Mild to moderate neurocognitive impairment (NCI), defined as a Brain Baseline Assessment of Cognition and Everyday Functioning (BRACE) and global T score from a full 7 domain neurocognitive test battery that is at least 1 standard deviation below age- and sex-standardized norms.

• For women of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to treatment initiation. Women of childbearing potential as well as male study participants with partners of childbearing potential must use a suitable barrier method (e.g., male condom) in conjunction with a highly effective form of contraception, while receiving the protocol-specified treatment and for 90 days after stopping.

  • Women of childbearing potential (WOCBP) are defined as women who have experienced menarche and are neither postmenopausal nor permanently sterile. Permanent sterility includes prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. Postmenopausal status is defined as at least 12 consecutive months without menstruation, with no alternative medical explanation for the amenorrhea.
  • No sperm donations should be made from a participant while on study drug and for 90 days after stopping study drug.

Exclusion Criteria:

• Neurological conditions other than HIV disease that may affect study outcomes. Exclusionary neurological conditions include: head injury with loss of consciousness for more than 30 minutes or resulting in neurologic complications; poorly controlled or untreated seizure disorder; Alzheimer's Disease (AD) and related dementias, demyelinating diseases, a history of stroke, an intracranial mass lesion and other non-HIV neurological disorders that in the opinion of the study clinician would lead to impaired cognition.

  o Note: The comprehensive medical evaluations, which includes a careful history and standardized neurologic examination, will collect symptoms and signs of any prior clinically significant cerebrovascular events, such as unilateral upper motor neuron pattern weakness, visual field defect, or hyperreflexia.

• Current or past severe central nervous system (CNS) infection (e.g., cryptococcal meningitis, toxoplasmic encephalitis).

• Clinically significant psychiatric disorder that could make study participation problematic or unsafe. Exclusionary psychiatric disorders include:

  • Untreated major depressive disorder, schizophrenia or bipolar disorders and lifetime history of schizophrenia or other psychotic disorders
  • Severe depression or suicidal intent on the Patient Health Questionaire-9 (PHQ-9) or Columbia-Suicide Severity Rating Scale (C-SSRS).
• Current substance use disorder (dependence of abuse) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. Exclusionary substance use includes: DSM-V-diagnosed alcohol use disorder (moderate or severe) within the past 12 months and, for other substances (except nicotine), moderate or severe substance use disorder within the past 5 years, or a mild substance use disorder within the past 6 months.
• Any illicit drug use as demonstrated on drug screening, except cannabis
• Pregnancy or breast-feeding
• Current serious illness requiring systemic treatment or hospitalization
• Any significant medical conditions that would put the individual at risk to participate, based on medical history, clinical examination, or any other protocol screening assessments. Exclusionary medical conditions include: significant renal insufficiency, unstable hypertension, unstable angina, poorly controlled diabetes mellitus, unstable cardiac arrhythmias, severe coronary artery disease, severe peripheral vascular disease, severe hepato-gastrointestinal disease, and oxygen-requiring chronic pulmonary disease.
• Untreated coinfection with hepatitis C virus (HCV), hepatitis B virus (HBV), or Treponema pallidum

• Any of the following laboratory findings at Screening:

  • Alanine aminotransferase >2 x upper limit of normal (ULN), aspartate aminotransferase >2 x ULN, and/or total bilirubin >1.5 x ULN
  • Note: Isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%.
  • Creatinine clearance ≤ 45 min/mL (measured or calculated based on institutional standards)
  • Eosinophil count >500 cells/µL

• Pre-existing gastrointestinal conditions:

  • Active or poorly controlled inflammatory bowel disease, including Crohn's disease or ulcerative colitis, or active microscopic colitis.
  • Ongoing infectious diarrhea, including unresolved Clostridioides difficile infection or another suspected or confirmed gastrointestinal infection.
  • Persistent or recurrent diarrhea at screening that limits usual daily activities, requires ongoing treatment but remains inadequately controlled, or is accompanied by dehydration, clinically significant electrolyte abnormalities, or unintentional weight loss.
  • Clinically significant malabsorption, short-bowel syndrome, or a high-output ostomy associated with difficulty maintaining hydration, electrolyte balance, or adequate nutrition.
  • Active or history of gastrointestinal bleeding, unresolved bowel obstruction, or unresolved complications of gastrointestinal surgery.
  • Any other gastrointestinal condition for which the clinical principle investigator (PI) and safety officer document that additional diarrhea would pose an unacceptable risk.
• Screening will include documentation of usual stool frequency and consistency, current gastrointestinal symptoms, relevant diagnoses and surgery, medications, hydration status, and available electrolyte and renal function results. Additional evaluation will be obtained when clinically indicated. Participants with an acute, potentially reversible condition will not be enrolled while the condition remains active. Rescreening may be considered after documented resolution and confirmation that all eligibility criteria are met. A history of a gastrointestinal diagnosis or surgery alone will not automatically exclude a participant if the condition is stable and none of the above criteria apply. Uncertain cases will require documented review by the clinical PI and safety officer before enrollment. These criteria will supplement the existing general medical exclusions

• Participants who are receiving any of the following medications should be excluded due to potential interactions with the study measures (i.e., chronic daily drug intake of ≥ 14 days or expected for ≥14 days):

  • Centrally active drugs that in the opinion of the physician may affect cognitive performance (e.g., clonidine, l-methyl dihydroxyphenylalanine (DOPA), guanidine, guanfacine, etc.)
  • Opioid containing analgesics

• For optional lumbar puncture (LP) procedure only. These criteria will not exclude participants from the study but will exclude them from undergoing option LP:

  • Prior adverse effect (AE) due to an LP (i.e., prior post-LP headache that did not resolve within 3 days or required blood patch)
  • Safety contraindications to LP (e.g., bleeding diathesis, anticoagulant use)
  • Requirements for LP: platelet count ≥50,000/µL, International Normalized Ratio (INR) \<1.5, and Prothrombin Time (PT) within the performing laboratory's normal reference range. An LP will not be performed if any of these requirements is not met.
  • For clinically stable participants, these laboratory assessments will be obtained within 14 calendar days before each LP. If an intervening illness, bleeding concern, medication change, or concern about changing laboratory values arises, the participant will undergo clinical reassessment and repeat laboratory testing within 24 hours before the procedure. The LP will be deferred until the results meet eligibility criteria and the procedural clinician determines that it is appropriate to proceed.
  • Before each LP, the procedural clinician will document review of the laboratory results, bleeding history, and medications that may increase bleeding risk. Medication-related contraindications and other LP safety exclusions will continue to apply. These requirements will be finalized with the study clinicians at both sites and incorporated consistently throughout the protocol. Participants who are ineligible for the optional LP may remain in the main study if they otherwise meet study eligibility criteria.
  • The investigators will exclude participants with suspected intracranial space-occupying lesions from the optional LP procedure. The investigators will review relevant history, neurological findings with a neurological examination performed by a licensed clinician and available neuroimaging. Optional research magnetic resonance imaging (MRI) participation will not substitute for clinically indicated pre-LP imaging.
  • A neurological examination, including fundoscopy will be performed by a qualified licensed clinician before every optional LP to assess for signs of raised intracranial pressure or other neurological contraindications. A normal funduscopic examination alone will not be considered sufficient to rule out raised intracranial pressure.
• For optional MRI only: Safety contraindications identified on MRI safety screening (e.g., implanted metal, stents, or other devices), based on institutional guidelines