Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

[A CASE OF ANAPHYLAXIS INDUCED BY VITAMIN B1 DERIVATIVE IN VITAMIN B INFUSION FORMULATION FOR INTRAVENOUS INJECTION].

A woman in her 20s presented to our clinic with a lower gastrointestinal infection. When we administered intravenous antibacterial and vitamin infusions, she developed anaphylaxis. We performed skin tests to investigate the cause, and an intradermal test was positive for a 1% intravenous vitamin complex. We then performed a component-specific test, which was positive for thiamine disulfide phosphate, a vitamin B1 derivative. We therefore diagnosed anaphylaxis due to thiamine disulfide phosphate. No previous reports have described cross-reactivity between vitamin B1 derivatives. In our case, however, the patient tested positive for fluthiamine hydrochloride, suggesting cross-reactivity. Intravenous vitamin complexes are used in daily clinical practice and should be administered with caution because of the possibility of anaphylaxis, although it occurs infrequently.

Efficacy of thiamine supplementation in improving depressive symptoms-evidence-based review / Eficacia de la suplementación con tiamina para mejorar los síntomas depresivos-revisión basada en la evidencia

Objetivos: Revisar la evidencia existente con respecto a la efectividad de la suplementación con tiamina en pacientes consíntomas depresivos en cuanto a su mejoría, en comparación con la toma de fármacos psicotrópicos aislados o placebos. Diseño: Revisión sistemática; Emplazamiento: Atención primaria. Método: Pregunta de investigación: Población – Adultos con síntomas depresivos; Intervención – Suplementación contiamina aislada o asociada a psicofármacos; Comparación: uso de placebo o fármacos psicotrópicos; Resultado – Mejoría delos síntomas depresivos (según DSM-V). La búsqueda se realizó utilizando los términos MeSH (("Depression" OR"Depression Disorder") AND "Thiamine"”) en las fuentes seleccionadas. Se excluyeron todos los artículos de opinión,artículos de revisión clásicos y estudios ya incluidos en metanálisis o revisiones sistemáticas seleccionadas. Se utilizó laescala Strength of Recommendation Taxonomy (SORT) para asignar niveles de evidencia y fuerzas de recomendación.Resultados: La investigación resultó en 3 artículos que cumplieron con los criterios de inclusión y de los cuales se extrajeronlas conclusiones.Conclusiones: Se demostraron beneficios estadísticamente significativos de la suplementación con tiamina en algunos delos parámetros evaluados. Sin embargo, a la suplementación con tiamina se le asignó una Fuerza de Recomendación B porla Escala SORT, ya que los estudios existentes de calidad moderada son pocos, aunque orientados al paciente, y no handemostrado ser suficientes o consistentes para recomendar la generalización del uso de tiamina. Se necesitan más ensayosclínicos controlados de buena calidad científica para responder adecuadamente a esta pregunta de investigación.(AU)

Objective: to review the existing evidence regarding the effectiveness of thiamine supplementation in improving depressivesymptoms in adult patients, compared to taking psychoactive drugs alone or placebo. Design: Systematic ReviewSite: Primary Care. Methods: Research question: Population – Adults with depressive symptoms; Intervention – Thiamine supplementationalone or associated with psychotropic drugs; Comparison: use of placebo or psychotropic drugs; Outcome – Improvementof depressive symptoms (according to DSM-V). The search was performed using the MeSH terms (("Depression" OR"Depression Disorder") AND "Thiamine"") in the selected sources. All opinion articles, classic review articles, and studiesalready included in meta-analyses or previously selected reviews were excluded. The strength of recommendationtaxonomy scale (SORT) was used to assign levels of evidence and strength of recommendation.Results: The search resulted in 3 articles that met the inclusion criteria, from which conclusions were drawn. Conclusions: Statistically significant benefits of thiamine supplementation were demonstrated in some of the evaluatedparameters. However, thiamine supplementation was assigned a Strength of Recommendation B by the SORT Scale, asexisting studies of moderate quality are few, albeit patient oriented, not proving to be sufficient or consistent torecommend the generalization of the use of thiamine. More controlled clinical trials of good scientific quality are needed toadequately answer this research question.(AU)

Furosemide-related thiamine deficiency in hospitalized hypervolemic patients with renal failure and heart failure.

BACKGROUND: We aimed to describe the thiamine status in hospitalized hypervolemic heart failure (HF) and/or renal failure (RF) patients treated with furosemide and to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF. METHODS: Patients who were diagnosed as hypervolemia and treated with intravenous furosemide (at least 40mg/day) were included in this prospective observational study. Whole blood thiamine concentrations were measured 3 times during hospital follow-up of patients. RESULTS: We evaluated 61 hospitalized hypervolemic patients, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00±10.39 (45-90) years. The baseline and post-hospital admission days 2 and 4 mean thiamine levels were 51.71±20.66ng/ml, 47.64±15.43ng/ml and 43.78±16.20ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p=0.029). There was a significant decrease in thiamine levels in patients who had HF (p=0.026) and also, thiamine was significantly lower in HF patients who had previously used oral furosemide before hospitalization. However, these findings were not present in patients with RF. CONCLUSIONS: Thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion.

Unanswered questions on the use of hydrocortisone, ascorbic acid, and thiamine therapy in sepsis and septic shock.

PURPOSE: To evaluate current evidence on the utility of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy for the management of septic shock. SUMMARY: The following keyword search terms were utilized in PubMed to identify relevant articles: ascorbic acid, thiamine, hydrocortisone, shock, and critical care. Articles relevant to HAT therapy in patients with septic shock were selected. Retrospective cohorts and randomized controlled trials were included in this review; case reports/series were excluded. Data from included studies illustrating the use of HAT therapy for the management of sepsis and septic shock, including data on time to HAT therapy initiation, severity of illness at baseline, duration of vasopressor therapy, progression of organ failure, and mortality, were evaluated. CONCLUSION: The utilization of HAT therapy for the management of sepsis and septic shock remains controversial. Hemodynamic benefits have been shown to be most pronounced when HAT therapy is initiated earlier. Future studies directed at earlier initiation may be necessary to confirm this theory.

Evaluation of the safety of 500 mg intravenous push thiamine at a tertiary academic medical center.

Background: Thiamine, also known as vitamin B1, is an essential water-soluble micronutrient. Although thiamine has minimal safety concerns, parenteral administration has been associated with rare cases of anaphylactic shock, cardiac arrest, and injection site reaction. The objective of this analysis is to evaluate the incidence of anaphylaxis and injection site reactions associated with the administration of thiamine 500 mg as an intravenous (IV) push in adult patients. Method: This single-center, retrospective analysis was performed at Brigham and Women's Hospital in Boston, Massachusetts. Electronic health records were used to identify all adult patients who were ordered for thiamine 500 mg IV push between July 1, 2020, and December 31, 2020. For the major and minor endpoints, anaphylaxis and injection site reactions were assessed, respectively. Descriptive statistics were used as appropriate. Results: A total of 463 doses of thiamine in 69 patients were evaluated. Thiamine was administered peripherally for 392 (84.7%) doses and centrally for 68 (14.7) doses. No anaphylactic reactions were observed. A total of 4 injection site reactions (0.86%) were noted with 4 unique doses. All reactions were classified as low-grade based on our institutional grading system. All injection site reactions were classified as "possible" (Naranjo score of 1-4). Conclusion: Administration of IV push 500 mg thiamine was not associated with anaphylactic events and was associated with a low rate of injection site reactions.

Evaluation of the Safety of Intravenous Thiamine Administration in a Large Academic Medical Center.

BACKGROUND/OBJECTIVE: Previous literature describes increased incidence of infusion-related reactions when administering thiamine doses greater than 100 mg as an intravenous (IV) push. The purpose of this evaluation was to assess the safety of administering higher doses of thiamine as IV push compared to infusion. METHODS: A single-center, retrospective review was performed from June to October 2017. Included patients were aged 18 years or older and received 1 dose of IV thiamine 200 mg or greater. Patients were divided into 2 groups: group 1 included patients who received 200-mg IV push and, group 2 included patients who received any dose greater than 200 mg. The primary objective was to quantify and compare rate of adverse reactions between the 2 groups. Institutional thiamine prescribing practices were examined. Wilcoxon Rank Sum and Fischer exact tests were performed. RESULTS: Sixty-six percent of patients were male, and the median age was 55 years (interquartile range [IQR]: 44-63). Fifty percent received 200-mg IV push, 20% received a combination of IV infusion and IV push, and 30% received IV infusion. Adverse reactions possibly due to thiamine administration occurred in 4 (2.0%) patients. One patient received 200 mg via IV infusion, while 3 received 200 mg via IV push. There was no significant difference in adverse reaction rate between IV push and IV infusion administrations (P = .640). CONCLUSION: Our results support administering thiamine doses of 200 mg or less as an IV push. Given lack of robust safety data, it is recommended to continue to dilute doses greater than 200 mg and infuse over 30 minutes.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial.

IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.

Safety of intravenous push thiamine administration at a tertiary academic medical center.

OBJECTIVES: Intravenous (IV) thiamine, administered using both diluted solution for infusion and undiluted solution for IV push, is used to correct low levels of thiamine. Although thiamine has a good safety profile, its IV administration is associated with rare cases of anaphylaxis. The objective of this analysis was to evaluate the incidence of anaphylaxis and IV site reactions associated with IV push thiamine. DESIGN: A single-center, retrospective chart review was performed using electronic health records. SETTING AND PARTICIPANTS: All adult patients who received undiluted IV push thiamine between June 1, 2015, and July 31, 2017, were included. Patient demographics, IV access site, allergy history, and antihistaminic medication use before thiamine administration were collected. OUTCOME MEASURES: Anaphylaxis was assessed while infiltration and phlebitis were evaluated using a standardized institutional grading system. All documented adverse events were adjudicated with the Naranjo Nomogram for adverse drug reaction assessment. RESULTS: A total of 8606 administrations in 2595 patients were evaluated; 5560 doses were administered peripherally, 1643 doses were administered centrally, and the line of administration was not documented for the remaining doses. Administrations included 7605 doses of 100 mg, 433 of 200 mg, 549 of 250 mg, and 19 of 500 mg. No anaphylactic or anaphylactoid reactions were observed. A total of 26 injection site reactions (0.30%) were noted in 19 patients (phlebitis, 12 events and infiltration, 14 events). Assessment with the Naranjo Nomogram classified 18 reactions to have a possible likelihood and 8 reactions to have a probable likelihood of being caused by IV push thiamine administration. CONCLUSION: Administration of IV push thiamine was not associated with any anaphylactic event and had a low incidence of IV site reactions. IV push thiamine in doses up to 250 mg appeared to be safe. There may be an indication for its safe administration with doses up to 500 mg, although more research is needed.

Administration of Corticosteroids, Ascorbic Acid, and Thiamine Improves Oxygenation after Thoracoscopic Esophagectomy.

PURPOSE: The activity of corticosteroids, ascorbic acid, and thiamine against oxidative and inflammatory responses was evaluated in patients undergoing esophagectomy. This study was undertaken to investigate the effect of this combined therapy on lung dysfunction following esophagectomy. METHODS: In this retrospective before-after study, we compared the clinical course of consecutive patients undergoing thoracoscopic esophagectomy treated with the combination of corticosteroids, ascorbic acid, and thiamine between June and December 2018 with a control group treated with corticosteroids alone between January 2016 and May 2018. Outcomes included oxygenation (arterial partial pressure of oxygen (PaO2)/fractional concentration of inspired oxygen (FiO2) ratios), duration of mechanical ventilation and intensive care unit (ICU) length of stay. RESULTS: In all, 17 patients were included in this study (6 in the combination therapy group and 11 patients in the control group). Mean PaO2/FiO2 ratios in the combined therapy group were significantly higher than in the control group at all points during the observation period (p <0.001). In the combined therapy group, the duration of mechanical ventilation and ICU stay were significantly shorter (p <0.001, p = 0.009). CONCLUSIONS: This study suggests that combined therapy including corticosteroids, ascorbic acid, and thiamine may be effective in improving oxygenation after esophagectomy. Additional studies are required to confirm these preliminary findings.