Margarita Venegas

BACKGROUND: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. METHODS: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. RESULTS: those dying because of either TB or COVID-19 alone (p<0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). CONCLUSIONS: In our global cohort, death was the outcome in >10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes.

Abstract Background Alzheimer’s disease (AD) affects millions of Americans, with potential future increases without breakthroughs in treatment. IGC‐AD1, a novel formulation comprising of delta‐9 tetrahydrocannabinol (“THC”) and melatonin, is being studied in AD‐associated agitation. THC is predominantly metabolized by cytochrome P450 and specifically by CYP2C9. We present the comparison of Adverse Events (“AE”) between two polymorphisms of CYP2C9, intermediate (“IM”) and normal metabolizers (“NM”). Methods Thirteen Puerto Rican AD patients participated in a three‐cohort MAD, Phase‐1 safety, and tolerability trial (IND146069, NCT04749563). In Cohorts‐1, 2, and 3, one mL of IGC‐AD1 was administered QD, BID, TID, respectively, for 14‐days, with a minimum washout period of 4‐days between cohorts. CYP2C9 genotyping was assessed. Active Participants were grouped by phenotypes, Intermediate, or Normal. The IM group was assessed by genotype (*1/*2, *1/*3). Frequency of Adverse Events (“AE”s) was evaluated by group. Chi‐squared was used to compare differences between groups (SPSSv.28). Results Seven patients were IM (allele *1/*2 = 4, allele*1/*3 = 3), while five were NM. Both groups IM and NM presented somnolence (IM: 57%; NM: 80%, p = 0.63), hypertension (IM: 43%; NM: 20%, p = 0.50), dizziness (IM: 43%; NM: 40% p = 0.94), and falls (IM: 29%; NM: 40% p = 0.74). No serious adverse events were reported. Conclusion In this limited sample size and trial, there were no significant differences in AE frequencies between the two CYP2C9 phenotypes IM and NM, suggesting that IGC‐AD1 has a safety profile that does not vary greatly, based on these two CYP2C9 polymorphisms. This analysis and initial results are important because the pharmacokinetics of THC are different for IM and NM. We continue to study these and other polymorphisms of CYP2C9 to understand their impact on AEs as it is crucial for personalized treatment strategies for the aged AD population.

Abstract Background Blood pressure (BP) variability (BPV) is a risk factor for Alzheimer’s disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV. Method Participants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (&gt;140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily. Result Variability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1. Conclusion Preliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial.

Abstract Background Neuropsychiatric symptoms (NPS) are features of Alzheimer’s Disease (AD) and a main cause of institutionalization. NPS in AD include agitation, depression, anxiety, elation, apathy, disinhibition, irritability, delusions, hallucinations and aberrant motor behavior. The onset of NPS worsens functional deficits by accelerating patients' cognitive decline and in 80% of cases increases caregiver burden and distress. NPS are difficult to treat and currently used medications have black‐box warnings, and weak evidence of efficacy in dementia patients. Here, we present preliminary data for improvement in NPI scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1). Method Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. For all three Cohorts the NPI / NPI‐D were administered at baseline and EOT of each Cohort. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched‐pairs signed‐rank test (R‐Studio, dplyr ) was used to independently compare differences between mean NPI and NPI‐D scores at baseline and EOT. Result In Cohort‐1 mean NPI at baseline and EOT was 31.5 and 14.8 respectively (mean difference = ‐16.7, v = 55, p = 0.003). In Cohort‐2 mean NPI at baseline and EOT was 22.2 and 12.4 respectively (mean difference = ‐9.8, v = 48, p = 0.021). In Cohort‐3 mean NPI at baseline and EOT was 16 and 7.9 respectively (mean difference = ‐8.1, v = 35, p = 0.010). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐7, v = 15, p = 0.031; Cohort‐2: mean difference = ‐6.3, v = 43, p = 0.009; Cohort‐3: mean difference = ‐3.4, v = 30, p = 0.053). No changes in concomitant medication were observed. No serious AEs, no deaths, and no dropouts due to AEs were reported. Conclusion GC‐AD1 was safe and well tolerated and is potentially efficacious in reducing NPS and associated caregiver distress, clinically and statistically, in AD as measured by the NPI, warranting a larger placebo‐controlled study.

Abstract Background Agitation, common in AD, often associated with higher caregiver burden, increases in intensity and duration as the disease progresses. Although about 76% of AD patients suffer from agitation, only 6.9% of ongoing trials for AD target symptoms such as agitation. Here, we present preliminary data for improvement in NPI‐agitation (NPI‐ag) scores and associated caregiver distress (NPI caregiver distress, NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1). Method Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. In Cohort‐1 (QD), 9 participants (7‐active, 2‐placebo) with NPI‐ag and NPI‐D assessment at baseline were analyzed. In Cohort‐2 (BID), and Cohort‐3 (TID) six patients and five patients respectively had NPI‐ag and NPI‐D scores at baseline. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare separately the difference between the mean NPI‐ag and mean NPI‐D scores at baseline and EOT. Result In Cohort‐1 mean NPI‐ag at baseline and EOT was 4.71 and 3 respectively (mean difference = ‐1.75, 36.3%, V = 10, p = 0.047). In Cohort‐2 mean NPI‐ag at baseline and EOT was 4.33 and 1.5 respectively (mean difference = ‐2.83, 65.3%, V = 10, p = 0.049). In Cohort‐3 mean NPI‐ag at baseline and EOT was 4.2 and 1.4 respectively (mean difference = ‐2.8, 66.6%, V = 10, p = 0.04). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐1.57, 50%, v = 15, p = 0.028; Cohort‐2: mean difference = ‐2, 66.6%, v = 10, p = 0.049; Cohort‐3: mean difference = ‐1.45, 8.3%, v = 10, p = 0.049). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed. Conclusion IGC‐AD1 was safe and well tolerated and is potentially efficacious in reducing agitation and associated caregiver distress in AD as measured by the NPI, warranting a larger placebo‐controlled study.