Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial.

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.

Intensive Safety Monitoring of Rituximab (Biosimilar Novex® and the Innovator) in Pediatric Patients With Complex Diseases.

Although rituximab is widely used off-label for complex pediatric diseases, safety reports are limited. We aimed to report evidence of its use in clinical practice, to describe the incidence of adverse drug reactions (ADR) to rituximab biosimilar Novex® and innovator, and to identify risk factors for the development of ADR in a real-life follow-up cohort of pediatric patients with complex diseases. We conducted a prospective, longitudinal, observational, single-centre study in patients that received rituximab for any complex disease, and as part of an intensive pharmacovigilance program. Demographic, pharmacological, clinical, and drug-related data were collected for all patients. ADR-free survival, including infusion-related reactions (IRR) and delayed ADR (dADR), was estimated using Kaplan-Meier curves. Risk factors were evaluated by multivariable Cox regression models. In total, 77 patients (<19 y.o.) received 187 infusions of rituximab Novex® (n = 155) or innovator rituximab (n = 32) for neurologic (Neu), immune-hematologic-rheumatic (IHR), oncologic (O) diseases, and hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation (SOT). We recorded 29 IRR and 58 dADR that occurred in 27 (35.1%) and 29 (37.7%) patients, respectively. The respiratory tract was the most affected during IRR (29.6%) and hypogammaglobulinemia (37.9 %) was the most frequent dADR. First versus subsequent infusions (HR 5.4, CI95% 2.4-12.1, p<0.05), sex (boys vs. girls, HR 0.3, CI95% 0.1-0.8, and p<0.05), and diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 2.3, CI95% 1.02-5.4, and p < 0.05) were significantly associated with the development of IRR. For dADR, risk factors were diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 0.4, CI95% 0.2-0.9, and p < 0.05) and cumulative body surface area-normalized dosage (HR 1.0003, CI95% 1.0001-1.0006, and p < 0.05). The present is the largest real-world safety assessment of rituximab in Latin-American children with complex diseases supporting its use based on the overall acceptable safety. Identification of risk factors may contribute to optimization of off-label rituximab treatment in pediatrics.

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.

BACKGROUND: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. METHODS: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. FINDINGS: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. INTERPRETATION: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. FUNDING: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Corrigendum to Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial [EClinicalMedicine 37 (2021) 100,959]".

[This corrects the article DOI: 10.1016/j.eclinm.2021.100959.].

Safety and clinical effectiveness of intravitreal administration of bevacizumab (Lumiere®) in patients with neovascular age-related macular degeneration.

The present study was an open-label, prospective, uncontrolled and multicenter clinical trial to investigate the safety and effectiveness of bevacizumab (Lumiere®) administered by the intravitreal route for the treatment of neovascular age-related macular degeneration (nAMD). A total of 22 patients without previous treatment with anti-vascular endothelial growth factor were recruited. Monthly therapy with 1.25 mg intravitreal bevacizumab was applied. Adverse events (AE), visual acuity (VA) and central retinal thickness (CRT) were assessed at baseline, day 1 and day 28 after each injection. A total of 87 AEs were reported; most of them were not serious (96.6%), expected (65.5%) and occurred after the third injection (56.3%). The most frequent AE was 'conjunctival hemorrhage' (29.9% of AEs), attributed to the injection procedure. Treatment was not suspended due to safety reasons in any case. After six months, a statistically significant gain of +8.2 (SD±8.8) letters and a CRT reduction of -75.50 µm (SD±120.3) were achieved with unilateral therapy. VA improvement and CRT reduction were also achieved with bilateral therapy, although to a lesser extent. The results of the present study suggested that therapy with a minimum of 3 doses of bevacizumab over a 6-month period was well tolerated and resulted in a sustained response regarding VA improvement and CRT reduction from the beginning of therapy compared with the baseline value. The study protocol was registered at clinicaltrials.gov (ref. no. NCT03668054).