Cannabinoids in PLWHIV on Effective ART

Study Overview
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Brief Summary
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The purpose of this pilot study is to assess feasibility and to examine whether oral cannabinoids (capsules containing either Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) combined or CBD alone) are safe and well-tolerated in people living with HIV. Other aims are to determine whether oral cannabinoids may reduce HIV-associated inflammation. An exploratory objective is to determine whether oral cannabinoids may influence HIV persistence as well as the gastrointestinal microbiome.

Detailed Description
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Adults with well-controlled HIV (viral load suppressed for at least 3 years on effective antiretrovirals) will be randomized to receive Tilray oral capsules containing either THC and CBD (THC 2.5 mg / CBD 2.5 mg; TN-TC11M2) vs. CBD alone (CBD 200 mg; TN-C200M2). Participants will titrate up the number of capsules consumed based on their own individual tolerability, to a specified maximum daily dose, for a total treatment duration of 12 weeks. Participants will be assessed regularly via history and physical exam as well as through safety blood work monitoring (hematology and chemistry profiles, liver enzymes, renal function, HIV viral loads, CD4 and CD8 counts). Effect on mood and quality of life will be determined by WHO-QOL-HIV-BREF, EQ-5D and Profile of Mood States questionnaires. Blood work for immune activation and inflammatory profiles, as well as HIV reservoir, will also be drawn at regular intervals. This pilot study will provide information on feasibility (ie, time to recruitment of participants, whether participants continue the study for the full 12 week duration and complete the follow-up visits and questionnaires, whether treatment is safe and well-tolerated). It will also provide some preliminary data on the ability of TN-TC11M2 and TN-C200M2 oral capsules to reduce inflammation and possibly influence HIV persistence.

Official Title
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Cannabinoids in People Living With HIV on Effective Antiretroviral Therapy: A Pilot Study to Assess Safety, Tolerability and Effect on Immune Activation

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: TN-TC11M2 oral capsules (THC 2.5 mg/CBD 2.5 mg)
* Drug: TN-C200M2 oral capsules (CBD 200 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all of the following criteria within 4 weeks prior to the week 0 (Baseline 1) visit to be considered eligible for entry into the study: Documented HIV infection by Western Blot, EIA assays or viral load assays Male or female, Aged 18 or older Viral load <40 copies/ml for at least 3 years On ART for at least 3 years No cannabinoid use for at least 1 month prior to enrolment with negative baseline cannabinoid screen Able to communicate adequately in either French or English Able and willing to provide written informed consent prior to enrolment including access to relevant medical records Exclusion Criteria: Using cannabinoid-containing products outside of the study or within 4 weeks of study commencement Pregnant, breastfeeding or planning to become pregnant during the course of the study. Female participants must undergo a pregnancy test and obtain a negative result in order to qualify for study participation. Enrolled in a separate study involving administration of medication, vitamin, supplement or herbal product. Active intravenous drug users Active substance dependence Prior history of hypersensitivity to cannabis or cannabis-containing products Known or suspected allergy to sunflower lecithin oil Active opportunistic infection or malignant condition Unintentional weight loss of 10 % or more of body weight in the last 6 months Unstable angina or acute cardiac event in the past year Active psychiatric disorder or history of psychiatric depression (other than mild depression or anxiety); On antipsychotic medication Known or suspected family history of schizophrenia or severe personality disorder Serious cardiovascular disease such as ischemic heart disease, arrhythmias, poorly controlled hypertension, or severe heart failure Anemia (Hemoglobin <100 g/L) Active liver disease or unexplained persistent elevations of serum transaminases Co-infection with Hepatitis B or C (positive HBsAg or positive anti-HBc antibodies with a detectable HBV DNA viral load or positive anti HCV antibodies with a detectable HCV RNA viral load) Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) or alkaline phosphatase >2.5 x upper limit of normal (ULN) Active AIDS event in the last month as determined by the treating physician Renal dysfunction Unstable psychological or psychiatric condition as determined by the treating physician Holding employment which requires operation of heavy machinery or which requires undergoing drug screening (i.e., pilot or police officer) Concurrent use within the past 8 week of anabolic hormones, prednisone, IL-2 or other agents known to alter immune function.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1) THC and CBD combined<br>TN-TC11M2 oral capsules (THC 2.5 mg / CBD 2.5 mg) | Drug: TN-TC11M2 oral capsules (THC 2.5 mg/CBD 2.5 mg)<br>* Participants will start by taking 1 capsule twice daily for 1 week (5 mg THC/5 mg CBD) and increase the number of capsules as tolerated to a maximum of 6 capsules taken throughout the day by weeks 5-12 (15 mg THC/15 mg CBD total per day).<br>|
| Experimental: 2) CBD alone<br>TN-C200M2 oral capsules (CBD 200 mg) | Drug: TN-C200M2 oral capsules (CBD 200 mg)<br>* Participants will start by taking 1 capsule once daily for 1 week (200 mg CBD) and increase the number of capsules as tolerated to a maximum of 4 capsules taken throughout the day by weeks 5-12 (800 mg CBD total).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WHO toxicity scale | Proportions of participants in both groups without any signs of significant toxicity as determined by the WHO toxicity scale (i.e., number of participants with Grades 0-2 scores on the WHO toxicity scale) Proportion of participants in both groups without any signs of significant haematological, biochemical, hepatic, renal, cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal, dermatological or systemic toxicity (Grades 0-2) as determined by the World Health Organization Toxicity Grading Scale for Determining the Severity of Adverse events (Grades 0=no toxicity; Grade 1=mild, transient or mild discomfort vs. maximum score Grade 4=life-threatening, extreme limitation in activity, significant assistance required) Toxicity scores (Grade 0, 1, 2, 3, or 4) will be calculated and reported for each domain (hematology, biochemistry, hepatic enzymes, urinalysis, cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal, dermatological, systemic) | week 0-12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immune cell profile | Change in CD4 count and their subsets including naïve, central memory and effector memory, Treg and Th17 cells from week 0 to week 12 Change in immune cell profile (frequencies of CD4 T cell counts and their subsets such as naïve, central memory and effector memory T cells; T regulatory cells; Th17 cells) from week 0 to week 12 | week 0-12 | 
| Change in plasma inflammatory markers | Change in plasma inflammatory markers from week 0 to week 12 Change in concentration of plasma inflammatory markers (interferon-α, interleukin-1β, interleukin-6, interleukin-10, interleukin-17, Transforming Growth Factor-β, interferon-gamma-induced protein-10, d-dimer, C-reactive protein, lipopolysaccharide and soluble CD14) from week 0 to week 12 | week 0-12 | 
| Change in proportion activated CD4 and CD8 T cell lymphocytes | Change in CD8+CD38+HLADR+ and CD4+CD38+HLADR+ percentages from week 0 to 12 weeks Change in proportion activated CD4 and CD8 T cell lymphocytes (CD38+HLADR+) from week 0 to 12 weeks | week 0-12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Cannabinoids, HIV reservoir, Microbiome, CBD, THC, Inflammation, Immune activation