28-day Dose Research Articles

P-538. People with HIV in the US switching to cabotegravir + rilpivirine long-acting (CAB+RPV LA) from oral antiretroviral therapy (ART) have numerous real-world benefits, including high adherence and treatment satisfaction

Abstract Background CAB+RPV LA is a complete HIV regimen which offers less frequent (monthly or every 2 months) dosing than daily oral ART. This real-world study provides additional utilization data of CAB+RPV LA and characterizes the experiences of people with HIV (PWH) receiving CAB+RPV LA in the US. Methods Data were obtained from the Adelphi HIV Disease Specific Programme™, a real-world, cross-sectional survey containing retrospective longitudinal data of healthcare professionals (HCP) and their PWH on CAB+RPV LA and over two periods (Jul 2021-Mar 2022 and Sept 2023-Feb 2024). HCPs reported demographics, clinical characteristics, and adherence for PWH on CAB+RPV LA aged ≥18 years. PWH surveys included treatment satisfaction, treatment preference and health-related quality of life (HRQoL) (HIV-specific PozQoL [score range 13-65], and EQ-5D-5L-US [score range 0-1]). Data were analyzed descriptively. Results HCPs (n=77) reported data for 237 PWH on CAB+RPV LA treatment for a median [IQR] of 1.0 [0.5, 1.7] years (n=202) at time of data collection, with 65% receiving CAB+RPV LA every 2 months (n=205). Mean age was 42 years, 20% were cisgender female, 43% were non-white (n=205) (Table 1). Top HCP-reported reasons for initiating CAB+RPV LA were tolerability (51%) and virologic potency (50%) (Figure 1). Top PWH-reported reasons for initiating CAB+RPV LA were “more convenient for my life” (43%) and “more convenient when travelling” (36%) (Figure 1). High levels of HCP-reported adherence were seen: 92% (n=205) of PWH received injections either early or within ± 7-day dosing window despite only 64% (n=103) of PWH reported to be completely adherent to prior oral ART. HCP-reported treatment satisfaction was high (93% satisfied/very satisfied). Of PWH who completed a survey, 95% (38/40) were satisfied/very satisfied with CAB+RPV LA. PWH had high HRQoL (PozQoL summary score 49.0 [SD 8.3; n=38] and EQ-5D-5L-US mean 0.88 [SD 0.14], n=39). PWH (82%) reported that fitting injection visits into their schedule was easy/extremely easy (Figure 2). CAB+RPV LA was preferred by 93%, and PWH reported numerous benefits of in-person visits to receive CAB+RPV LA (Figure 2). Conclusion PWH receiving CAB+RPV LA are adherent, highly satisfied, have high HRQoL, prefer LA regimens and reported benefits of in-person visits. Disclosures Andrew P. Brogan, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Tim Holbrook, BSc, Adelphi Real World: Employee|ViiV Healthcare: The Adelphi Real World Disease Specific Programme is wholly owned by Adelphi Real World; ViiV healthcare is one subscriber and paid for the analysis Fritha Hennessy, PhD, Adelphi Real World: Employee|ViiV Healthcare: The Adelphi Real World Disease Specific Programme is wholly owned by Adelphi Real World; ViiV healthcare is one subscriber and paid for the analysis Will Ambler, PhD, Adelphi Real World: Employee|ViiV Healthcare: The Adelphi Real World Disease Specific Programme is wholly owned by Adelphi Real World; ViiV healthcare is one subscriber and paid for the analysis Oliver-Thomas Carter, BSc, Adelphi Real World: Employee|ViiV Healthcare: The Adelphi Real World Disease Specific Programme is wholly owned by Adelphi Real World; ViiV healthcare is one subscriber and paid for the analysis Cindy Garris, MS, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee

IGF-1 Assessment During Weekly Somatrogon Treatment in Pediatric Patients With GH Deficiency.

In patients with GH deficiency (GHD) receiving GH treatment, IGF-1 concentrations are used by physicians to monitor treatment safety and efficacy and guide dosing decisions. Somatrogon is a long-acting GH approved as a once-weekly treatment for pediatric GHD. Somatrogon administration results in characteristic changes in the IGF-1 profile, with values measured at 96 hours postdose representing mean IGF-1 concentrations that best reflect overall somatrogon exposure. To develop a simple method to enable physicians to predict mean IGF-1 concentrations following somatrogon dosing, based on a single IGF-1 measurement taken at any point during the 7-day dosing interval. Data from phase 2 and phase 3 somatrogon studies were used to develop a 2-compartment pharmacokinetic model with delayed first-order absorption. An indirect-response pharmacokinetic/pharmacodynamic model was applied to the predicted somatrogon concentrations, and model simulations were used to predict IGF-1 and IGF-1 SD score (SDS) levels for participants in both studies. A total of 16,213 dosing records (from 42 and 109 participants in the phase 2 and 3 studies, respectively) were used for the simulations, generating predicted values for IGF-1 and IGF-1 SDS. Predicted values were scaled against the respective values at 96 hours (day 4). These values were used to create a table showing the adjustments required to predict mean IGF-1 and IGF-1 SDS values depending on time after dose. We developed a simple method enabling physicians to predict mean weekly IGF-1 values using IGF-1 values measured at any point in the dosing interval.

A Cross-Biomeasure Study to Optimize Antiretroviral Adherence Estimation.

Incomplete adherence to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) reduces effectiveness. Adherence biomeasures (i.e. drug concentrations in biological specimen) are more accurate than self-report. TDF/FTC's intracellular active metabolites (tenofovir-diphosphate; TFVdp and FTC-triphosphate; FTCtp) can be quantified in different types of blood samples to estimate adherence. To optimize adherence estimation, we investigated approaches to measure TFVdp and FTCtp in four blood matrices. Twelve HIV-negative, healthy volunteers were enrolled in a single center, open-label, 3-phase, directly observed therapy study. LC-MS/MS methods quantified TFVdp/FTCtp in dried blood spots, volumetrically accurate microsampling, upper layer packed cells and peripheral blood mononuclear cells (PBMCs). Non-compartmental analysis estimated half-lives and accumulation ratios. Correlations characterized relationships between clinical variables and exposure. Regression models were fit to determine concentrations associated with <4 and ≥4 doses/week; correct classification percentages were determined. Terminal half-life estimates of 3-4 vs 15-22 days distinguished between moderate-term (FTCtp in all samples; TFVdp in PBMCs) versus long-term (TFVdp in red blood cell-containing matrices) measures. Model-derived thresholds accurately categorized <4 and ≥4 doses/week when including both metabolites for 14- and 28-day dosing periods (81-91% and 82-85%, respectively). Within each classification and regression trees analyses containing both moderate- and long-term measures, dried blood spots exhibited highest accuracy to predict stable (74-94%) and changing (42-47%) adherence patterns. We demonstrate higher accuracy of moderate-term biomeasures to classify adherence over a 14-day period compared to long-term biomeasures to classify adherence over a 28-day period. Combined moderate- and long-term biomeasures predicted stable and changing adherence patterns, with dried blood spots exhibiting highest accuracy.

Effects of two carbonic anhydrase inhibitors on exercise performance in acute hypoxia.

Acute mountain sickness (AMS) occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole body exercise performance in acute hypoxia (fraction of inspired oxygen, [Formula: see text] = 0.15) between AZ, MZ, and placebo (PLA). Fifteen healthy participants completed five testing visits: day 1 for maximal exercise test, day 2 for familiarization, and days 3-5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial (TT) performed after a 2-day dosing protocol of either AZ (250 mg three times a day), MZ (100 mg twice a day), or PLA (three times a day); the order was randomized and double-blinded. Before exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared with PLA [capillary hydrogen ions (H+) 47 ± 3, 43 ± 2, and 39 ± 2 nmol for AZ, MZ, and PLA respectively, P < 0.01]. Time to complete 5 km with PLA (562 ± 32 s, P < 0.01) was significantly faster than AZ and MZ (577 ± 38 vs. 581 ± 37 s, respectively), with no differences between AZ and MZ (P = 0.96). There were no differences in average ventilation (124 ± 27, 127 ± 24, 127 ± 19 L/min) and oxyhemoglobin saturation (87 ± 2, 88 ± 2, 88 ± 3%) between AZ, MZ, and PLA, respectively (P > 0.05). Overall, both AZ and MZ impair whole body exercise performance in acute normobaric hypoxia.NEW & NOTEWORTHY Administration of acetazolamide (AZ) and methazolamide (MZ) both resulted in a significantly slower 5-km time trial in acute normobaric hypoxia compared with a placebo. Both drugs lead to a partially compensated metabolic acidosis, but ventilation and oxyhemoglobin saturation were not different across the conditions. Overall, acetazolamide and methazolamide both impaired whole body exercise performance in acute normobaric hypoxia but potentially have different mechanisms of action.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

Effect of preoperative Silodosin on facilitating access sheath placement in retrograde intrarenal surgery. A randomized controlled studys

ABSTRACT Introduction to evaluate the effect of preoperative Silodosin on ureteric dilatation to facilitate ureteral access sheath (UAS) placement and reduction of ureteral wall injury in retrograde intrarenal surgery (RIRS). Methods one hundred and twenty patients with renal or ureteric stones were randomly allocated into 2 equal groups. Group A represents patients who received a 7-day preoperative single dose Silodosin before RIRS while Group B represents patients who received a placebo for the same regimen. Our primary outcome was to assess the success rate of (UAS) placement. Our secondary outcomes were to evaluate the perioperative complication rate, stone-free rate, hospital stay, and cost analysis. Results In our study, Silodosin showed a higher success rate for (UAS) insertion compared to placebo with a statistically significant difference (p-value = 0.04). Spontaneous UAS insertion in the Silodosin group was 58.3%, which was increased with active ureteric dilatation to 98.3%. Preoperative Silodosin led to less postoperative pain and analgesics requirements without impacting postoperative hospital stay or stone-free rate. There was less ureteric injury incidence in the Silodosin group compared to placebo with a statistically significant difference (p-value = 0.002). Conclusion Preoperative Silodosin facilitates UAS insertion with a protective role against ureteric injury compared to placebo.

Atomoxetine and spironolactone combine to reduce obstructive sleep apnea severity and blood pressure in hypertensive patients.

Norepinephrine reuptake inhibitors such as atomoxetine (ato) can improve OSA by increasing pharyngeal muscle activity. Mineralocorticoid antagonists such as spironolactone, may potentiate the reduction of OSA severity and reduce blood pressure. We evaluated whether adding spironolactone to atomoxetine (ato-spiro) improved responses in hypertensive OSA patients. Twenty-one patients with an apnea-hypopnea index (AHI) between 10 and 50 events/h and a history of hypertension were recruited and crossed-over in random order to ato 80mg and ato-spiro 80/50mg for 1 week after a 3-day low dose run-in period. Two dropped out due to drug related side effects. Polysomnography and 24-hour blood pressure (BP) monitoring were performed at baseline and after each treatment period. AHI decreased on both ato and ato-spiro from a baseline median(IQR) of 20.3(18.8 to 28.5) to 8.2(7 to 13.1) and 6.2(5.7 to 14.1), respectively (p < 0.001 for both). Systolic BP (mmHg) fell by mean(95%CI) -4.5(-13.8 to 4.8, p = 0.33) on ato and - 10.3(-19.2 to -1.5, p = 0.02) on ato-spiro, and diastolic BP dropped by -3.0(-8.0 to 2.0, p = 0.23) on ato and - 5.0(-9.1 to -0.9; p = 0.02) on ato-spiro. Both ato and ato-spiro led to a significant shift from apnea to hypopnea predominance (p < 0.001), and significant reductions in hypoxic burden (p ≤ 0.001) and REM sleep (p ≤ 0.001). Both ato-spiro and ato alone decreased OSA severity similarly, but ato-spiro led to even greater, statistically significant and clinically meaningful falls in systolic and diastolic BP. BP reductions were likely due to ato-related improvements in upper airway patency and hypoxemia, and to spiro-related reduced fluid retention. These findings show promise for ato-spiro as an oral treatment for hypertensive OSA patients. REGISTERED AT CLINICALTRIALS.GOV: NCT04905979.

Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men

This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50–70 years; body mass index, 18.5–28 kg/m2) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported. Substantial changes in serum and urine polyamine concentrations were not observed following hpSPD supplementation, suggesting effective homeostatic control of full-dose highly purified spermidine supplements with no evidence of adaptation of spermidine metabolism at 40 mg/day. These findings suggest that hpSPD at 40 mg/day for up to 28 days is safe and well-tolerated in healthy older men. The study is consistent with preclinical results and provides important evidence supporting the safety of high-purity spermidine supplementation, enabling further research with single-molecule spermidine to investigate its potential biology for improving human health. This trial was registered at clinicaltrials.gov (NCT05459961).

Case of Vibrio vulnificus Infection in Orechromis niloticus during Suspension of Recirculating Aquaculture System

During a suspension of a GIFT tilapia broodstock recirculating aquaculture system (RAS), a significant fish mortality event occurred. To determine the cause, four bacterial strains were isolated from affected fish and identified as Vibrio vulnificus through 16S rDNA sequencing. Virulence assays confirmed the pathogenicity of these strains, with the most virulent, CS-4, selected for a further analysis. Antimicrobial testing revealed CS-4’s sensitivity to 19 antibiotics, including meloxicillin and Gentamicin. Challenge tests indicated varied 7-day Lethal Dose 50 (LD50) values for CS-4 depending on the infection route, with immersion after skin injury being the most lethal. Additionally, the effects of salinity, crowding with air exposure, and nitrite on tilapia mortality were evaluated. The results showed that salinity stress increased the mortality rate of tilapia infected with V. vulnificus through immersion, and that salinity stress and V. vulnificus infection had a synergistic effect. A 20 min crowding with air exposure stress reduced the mortality rate of Nile tilapia infected with V. vulnificus. Nitrite stress had little effect on the mortality rate of tilapia infected with V. vulnificus. The results of the risk factor analysis indicated that salinity was the main factor affecting tilapia mortality caused by V. vulnificus infection. This study will serve as a valuable reference for the future management of similar RAS.

A randomized, double-blind, placebo-controlled trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis

BackgroundSpasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. MethodsThis was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. ResultsOf 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were −0.23 for nabiximols and −0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. ConclusionDespite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. Clinical trial registration number (ClinicalTrials.gov): NCT04657666

Low-dose overlap initiation with split tablets of buprenorphine in intubated intensive care unit patients with opioid use disorder

BackgroundAs the opioid public health crisis evolves to include fentanyl and other potent synthetic opioids, more patients are admitted to the hospital with serious complications of drug use and frequently require higher levels of care, including intensive care unit (ICU) admission, for acute and chronic conditions related to opioid use disorder (OUD). This patient population poses a unique challenge when managing sedation and ensuring adequate ventilation while intubated given their high opioid requirements. Starting a patient on medications such as buprenorphine may be difficult for inpatient providers unfamiliar with its use, which may lead to undertreatment of patients with OUD, prolonged mechanical ventilation and length of stay.MethodsWe developed a 7-day buprenorphine low dose overlap initiation (LDOI) schedule for patients with OUD admitted to the ICU (Table 1). Buprenorphine tablets were split by pharmacists and placed into pre-made blister packs as a kit to be loaded into the automated medication dispensing machine for nursing to administer daily. An internal quality review validated the appropriate dosing of split-dose tablets. To simplify order entry and increase prescriber comfort with this new protocol, we generated an order set within our electronic health record software with prebuilt buprenorphine titration orders. This protocol was implemented alongside patient and healthcare team education and counseling on the LDOI process, with follow-up offered to all patients upon discharge.ResultsHere we report a series of 6 ICU patients started on buprenorphine using the LDOI schedule with split buprenorphine tablets. None of the 6 patients experienced precipitated withdrawal upon buprenorphine initiation using the LDOI schedule, and 5/6 patients were successfully extubated during the buprenorphine initiation. Four of six patients had a decrease in daily morphine milligram equivalents, with 3 patients transitioning to buprenorphine alone.ConclusionInitiating buprenorphine via LDOI was found to be successful in the development of a protocol for critically ill patients with OUD. We examined LDOI of buprenorphine in intubated ICU patients and found no events of acute precipitated withdrawal. This protocol can be used as a guide for other institutions seeking to start critically ill patients on medication treatment for OUD during ICU admission.

A genetically engineered epothilone analog as a novel oral microtubule inhibitor: A clinical study of utidelone capsule for advanced breast cancer.

e13115 Background: Utidelone, a genetically engineered epothilone analog, is a potential best-in-class novel microtubule stabilizing agent. Utidelone injection was approved for advanced breast cancer in China in 2021. Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral formulation-Utidelone Capsule (UTD2). As of now, there has been no oral microtubule stabilizing agent approved in China and the United States. UTD2 may benefit patients in various aspects including effectiveness, safety, better compliance, reduced medical cost, and facilitation of combination therapy, especially with other oral anti-cancer drugs. This is the first clinical study in China to investigate the efficacy and safety of UTD2 monotherapy for treatment of advanced breast cancer. Methods: This is an ongoing open-label, multi-center study (NCT05700084) consisting of three parts: dose escalation, bioavailability and food effect, and in combination with capecitabine for treatment of metastatic breast cancer. Here we report the preliminary results from single center for part I with determination of DLT and MTD as the primary objective, and efficacy, PK profile and safety in patients with pretreated metastatic breast cancer as the secondary objectives. Eligible patients are aged 18-70 years with confirmed advanced breast cancer refractory to prior standard therapies, and have an ECOG PS of 0-1, life expectancy ≥12weeks. Patients are treated with UTD2 monotherapy, at starting dose of 50 mg/m2/d-5day for two patients, with planned escalation (3+3) to 75 mg/m2/d-5day and 75 mg/m2/d-7day, then to 85 mg/m2/d-7day or down to 70 mg/m2/d-7day in a 21-day cycle. Results: As of 25th January 2024, 5 advanced breast cancer patients were enrolled, who had received prior treatment in advanced settings. Dose escalation is ongoing, and 75mg/m2/d-7day cohort is under evaluation. Four patients were evaluated for efficacy with an outcome of 2 PR (each for 50 and 75mg/m2/d-5day dose) and 2 SD (75mg/m2/d-5day dose) with treatment durations of 2 to 8 cycles. Most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included peripheral sensory neuropathy (PN), dizziness and loss of appetite. There were two patients encountered Grade 3 TEAEs including one with PN and one with diarrhea/insomnia, that recovered through dose reduction or supportive treatment. No grade 4/5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: These preliminary results suggested promising efficacy with a manageable safety profile of UTD2 in pretreated metastatic breast cancer patients. This study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT05700084 .

Durable complete response and overall survival in patients with heavily pretreated, poor-prognosis non-Hodgkin lymphoma to immunoactivating AVM0703 with few and mild drug-related adverse effects.

7077 Background: In 2022, the majority of new cancer drugs in clinical development are aimed at targets that are already saturated with approved drugs1. This is of concern to patients, payers, sponsor/investors, and regulatory agencies. AVM0703 activates a unique immune response mobilizing an endogenous gamma delta TCR+ and invariant TCR+ bispecific Natural Killer T-like cell (γδTCR+iTCR+NKT) (PCT/US21/19773), that has demonstrated clinical anti-cancer activity against a variety of solid and blood cancers. The potential for AVM0703 to fill a gap in the “no-option” R/R NHL treatment landscape led to the launch of the AVM0703-001 clinical trial (The OPAL Study, NCT04329728). 1) Fougner C et al. Herding in the drug development pipeline. Nat Rev Drug Discov. 2023 Aug;22(8):617-618. Methods: An open-label phase 1 trial evaluating the safety and preliminary efficacy of AVM0703 was completed in patients with hematological malignancies. AVM0703 was administered as a single intravenous (IV) infusion to patients enrolled into a 3+3 dose escalation design. Consolidation therapy of investigator’s choice was allowed, preferably 28 days after AVM0703. For each cohort, 3-6 patients were treated, and dose escalation permitted only after the cohort completed a 7-day dose limiting toxicity (DLT) assessment period with no more than 1 DLT. Patients ≥12 years and &gt;40 kg diagnosed with WHO classified lymphoid neoplasms with R/R disease ineligible for transplant or CAR-T were included. The database has not been formally locked and a cutoff date of Dec 13, 2023, is used for presentation of these Phase 1 results. Results: In summary, 17 patients, 39-86 years of age (median 64) with a median of 4 prior lines (range: 1 to 10) received AVM0703 at 6, 9, 12, 18 and 21 mg/kg. Fifteen (88%) were poor prognosis and 4 had CNS involvement. Only 13 of 17 (76.5%) experienced study-drug related adverse events (AEs) during the DLT period; 15 AEs were grade 1 (78.9%), 2 were grade 2 (10.5%), and 2 were grade 3 (10.5%). The most common AEs were insomnia (N=5), hyperglycemia (N=3), and pruritis (N=2). The total number of All-grade TEAEs recorded in 17 patients was 114 within 30 days post dose, with 98.2% of grades 1-3. Median overall survival (OS) in all dose cohorts was 13.3 months, with 8 of 17 patients alive as of 13 Dec 2023. The recommended Phase 2 dose (RP2D) was determined as 18 mg/kg. For the 18 mg/kg group (N=6), long term durable responses were obtained in 66% (3 CR, 1 PR) with an additional patient converting to late CR, nine months survival was 100%, and median OS has not been reached with follow up between 15.9 and 27.8 months (83% still alive). No safety signals have been identified. Conclusions: RP2D AVM0703, with consolidation therapy at day 28 median (range 7 to 240 days) showed no concerning safety signals and promising long-term survival. Clinical trial information: NCT04329728 .

Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.

Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis.

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

Single-dose Intraoperative Methadone for Pain Management in Pediatric Tonsillectomy: A Randomized Double-blind Clinical Trial.

More than 500,000 elective tonsillectomies are performed in U.S. children annually. Pain after pediatric tonsillectomy is common, often severe, and undertreated. There is no consensus on the optimal management of perioperative tonsillectomy pain. Methadone, with an elimination half-life of 1 to 2 days, has a longer duration of effect than short-duration opioids such as fentanyl. The primary objective of this study was to investigate the intraoperative use of methadone for pediatric tonsillectomy. It tested the hypothesis that methadone would result in less postoperative opioid use compared with short-duration opioids in children after tonsillectomy. This double-blind, randomized, parallel group trial in children (3 to 17 yr) undergoing tonsillectomy compared single-dose intravenous methadone (0.1 mg/kg then 0.15 mg/kg age-ideal body weight, in a dose escalation paradigm) versus as-needed short-duration opioid (fentanyl) controls. Opioid use, pain, and side effects were assessed in-hospital and 7 days postoperatively via electronic surveys. The primary outcome was total 7-day opioid use in oral morphine equivalents per kilogram (kg). Secondary outcomes were opioid use in the postanesthesia care unit, daily pain scores, and total number of 7-day opioid doses used. Data analysis included 60 children (20/group), age 5.9 ± 3.7 yr (mean ± SD; median, 4; range, 3 to 17). Total 7-day opioid use (oral morphine equivalents per kg median [interquartile range]) was 1.5 [1.2, 2.1] in controls, 0.9 [0.1, 1.4] after methadone 0.1 mg/kg (P = 0.045), and 0.5 [0, 1.4] after methadone 0.15 mg/kg (P = 0.023). Postanesthesia care unit opioid use (oral morphine equivalents per kg) in controls was 0.15 [0.1, 0.3], 0.04 [0, 0.1] after methadone 0.1 mg/kg (P = 0.061). and 0.0 [0, 0.1] after methadone 0.15 mg/kg (P = 0.021). Postoperative pain scores were not different between groups. No serious opioid-related adverse events occurred. This small initial study in children undergoing tonsillectomy found that single-dose intraoperative methadone at 0.15 mg/kg age ideal body weight was opioid-sparing compared with intermittent fentanyl.

Comparison of the Efficacy of 12-day Concomitant Quadruple Therapy versus 14-day High dose Dual Therapy as a First-line H. pylori Eradication Regimen.

Helicobacter pylori (H. pylori) is the most prevalent infection in the world and is strongly associated with gastric adenocarcinoma, lymphoma and gastric or duodenal ulcers. Different regimens have been used for H. pylori eradication. We aimed to compare the efficacy of two different regimens as first-line H. pylori eradication regimens, in an area with high antibiotic resistance. In this RCT, we assigned 223 patients with H. pylori infection, who were naïve to treatment. They were randomly divided into two groups to receive either 12-day concomitant quadruple therapy (consisting of pantoprazole 40 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours) or 14-day high dose dual therapy (consisting of esomeprazole 40 mg and amoxicillin 1 g TDS). H. pylori eradication was assessed eight weeks after the end of treatment. H. pylori eradication rate by PP analysis for 12-day concomitant quadruple therapy and 14-day high dose dual therapy were 90.4% and 79.1%, respectively (p=0.02). According to ITT analysis, the eradication rates were 86.2% and 76.3%, respectively (p=0.06). Adverse drug reactions were 12.3% in high dose dual therapy and 36.8% in concomitant quadruple therapy (p<0.001). Twelve-day concomitant therapy seems to be an acceptable regimen for first-line H. pylori eradication in Iran, a country with a high rate of antibiotic resistance. Although, high dose dual therapy did not result in an ideal eradication rate, but it had fewer drug side effects than the 12-day concomitant regimen.

Real-world use of long-acting cabotegravir and rilpivirine: 12-month results of the inJectable Antiretroviral therapy feasiBility Study (JABS).

The inJectable Antiretroviral feasiBility Study (JABS) aimed to evaluate the implementation of long-acting regimens in a 'real world' Australian setting, with inclusion of participants with complex medical needs, social vulnerability and/or historical non-adherence. JABS was a 12-month, single-centre, single-arm, open-label phase IV study of long-acting cabotegravir 600 mg plus rilpivirine 900 mg administered intramuscularly every 2 months to adults with treated HIV-1 infection. The primary endpoint was the proportion of attendances and administration of injections within a 14-day dosing window over 12 months, out of the total prescribed doses. Secondary endpoints included proportions of missed appointments, use of oral bridging, discontinuations, virological failures, adverse events and participant-reported outcomes. A multidisciplinary adherence programme embedded in the clinical service known as REACH provided support to JABS participants. Of 60 participants enrolled by May 2022, 60% had one or more complexity or vulnerability factors identified, including absence of social supports (50%), mental health issues, alcohol or drug use (30%) and financial hardship or instability (13%), among others. Twenty-seven per cent of participants had historical non-adherence to antiretroviral therapy. Out of 395 prescribed doses, 97.2% of injections were administered within correct dosing windows at clinic visits. Two courses of short-term oral bridging were required. The rate of injection site reactions was 29%, the majority being grade 1-2. There were no virological failures, no serious adverse events and only one injection-related study discontinuation. High baseline treatment satisfaction and acceptability of injections increased by month 12. Those with vulnerability factors had similar adherence to injections as those without such factors. Ninety-eight per cent of the participants who completed 12 months on the study have maintained long-acting therapy, virological suppression and retention in care. Long-acting cabotegravir plus rilpivirine was associated with very high adherence, maintenance of virological suppression, safety and treatment satisfaction in a diverse Australian clinic population, comparable to results of phase III randomized clinical trials. Individuals with vulnerability factors can achieve adherence to injections with individualized support. Long-acting therapies in this group can increase the subsequent engagement in clinical care.

Abstract CT105: Early clinical experience with a novel first-in-class G-quadruplex experimental anti-cancer drug

Abstract The human genome contains G-rich regions that are over-represented in many cancer gene promoters. These can form higher-order G-quadruplex arrangements under the influence of an appropriate and selective small molecule compound. The resulting ligand-G-quadruplex complex may be resistant to polymerase read-through and thus results in transcriptional down-regulation of target genes. QN-302, based on a tetra-substituted naphthalene diimide chemotype, is a potent and selective G-quadruplex-binding compound that has been designed and initially developed at University College London. It displays single-digit cell growth inhibition in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. RNA-seq analysis shows that it is a pan-quadruplex agent, down-regulating the expression of multiple G-quadruplex-promoter cancer genes and pathways in PDAC. It also shows in vivo anti-tumor activity in several animal models for PDAC, with low toxicity observed at therapeutic doses. QN-302 was licensed to Qualigen Therapeutics Inc in January 2022. It was granted Orphan Drug designation by the FDA in December 2022 for PDAC. This was followed by extensive regulatory toxicological and pharmacological studies together with successful scale-up synthesis, purification and formulation. QN-302 was granted IND clearance in August 2023 by the FDA for phase 1 clinical trials in advanced or metastatic solid tumors. This Phase 1a clinical trial is being conducted in two USA cancer centers (START Midwest, Grand Rapids, MI and Honor Health, Scottsdale, AZ) using a protocol based on 28-day once-weekly dose escalation and evaluation of three potential biomarkers, two of which have been suggested by transcriptomic analysis as being indicative of G-quadruplex-induced drug response and accompanying decrease of anti-tumor activity. So far 1 Cohort (3 patients) has been dosed at the lowest dose of 1.62 mg of QN-302 as part of this Phase 1a clinical trial. Patient #1, a male patient of metastatic pancreatic cancer, is currently in Cycle 4 of therapy showing Stable Disease and no AEs or SAEs reported. Patient #2, a female patient of metastatic colorectal cancer, completed Cycle 2 after which she showed progression upon CT Scan before entering Cycle 3 and was taken off study. Patient #3, a male patient of metastatic PDAC, is currently ending Cycle 2, about to enter Cycle 3, showing Stable Disease upon CT scan. All patients dosed showed no AEs, SAEs or side effects. They were also clinically observed to have improved QOL compared to prior SOC while on therapy with QN-302, This presentation will outline this unique approach and summarize safety, tolerability, PK/PD data and any early clinical data as described above including preliminary biomarker data now that clinical evaluation has commenced. The advantages and challenges of QN-302 will also be discussed. Citation Format: Tariq Arshad, Stephen Neidle, Sreenivasa Chandana, Erkut Borazanci. Early clinical experience with a novel first-in-class G-quadruplex experimental anti-cancer drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT105.

Nurse-Led Brief Intervention for Enhancing Safe Sex Practice Among Emerging Adults in Hong Kong Using Instant Messaging: Feasibility Study.

The incidence of sexually transmitted infections has been increasing throughout the world. Additionally, substantial changes in emerging adults' attitudes toward sex and the popularization of premarital sex could further affect the diagnosis and treatment of sexually transmitted infections. With the high acceptability and effectiveness of instant messaging (IM) interventions for health promotion, there is potential for such interventions to improve condom use knowledge and promote safer sex practice. The study evaluates the feasibility of a nurse-led IM intervention to promote safer sex practices in emerging adults. A 30-minute adaptive IM intervention and a 5-day booster dose of daily messages after 2 weeks through WhatsApp (Meta Platforms, Inc) were conducted with emerging adults in local universities in Hong Kong aged between 18 and 29 years with previous sexual experience. A questionnaire was distributed 1 week after the intervention that measured the consistency in condom use, the change in condom use knowledge and attitudes, and the acceptability of the intervention. The feasibility of the intervention was assessed by Bowen's feasibility framework. A total of 20 participants completed the intervention and questionnaire. Results showed (1) high satisfaction level (mean satisfaction score: 9.10/10), (2) high demand of the intervention (retention rate: 95%), (3) smooth implementation of the intervention, (4) high practicality (13/20, 65% of the participants viewed IM to be an effective means of intervention), (5) potential integration of the intervention, and (6) significant mean increase in condom use knowledge and attitudes (mean increase 9.05; t19=3.727; 95% CI 3.97-14.13; P=.001). The IM intervention was feasible, acceptable, and had potential impacts on improving safer sex practices. These findings will support the future development of IM interventions in the arena of sexual health promotion.