Targeting GPVI with glenzocimab in COVID-19 patients: Results from a randomized clinical trial.

BACKGROUND: Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets. METHODS AND PATIENTS: GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population. RESULTS: Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively. CONCLUSIONS: Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.

Safety and efficacy of platelet glycoprotein VI inhibition in acute ischaemic stroke (ACTIMIS): a randomised, double-blind, placebo-controlled, phase 1b/2a trial.

BACKGROUND: Antagonists of glycoprotein VI-triggered platelet activation used in combination with recanalisation therapies are a promising therapeutic approach in acute ischaemic stroke. Glenzocimab is an antibody fragment that inhibits the action of platelet glycoprotein VI. We aimed to determine and assess the safety and efficacy of the optimal dose of glenzocimab in patients with acute ischaemic stroke eligible to receive alteplase with or without mechanical thrombectomy. METHODS: This randomised, double-blind, placebo-controlled study with dose-escalation (1b) and dose-confirmation (2a) phases (ACTIMIS) was done in 26 stroke centres in six European countries. Participants were adults (≥18 years) with disabling acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or higher before alteplase administration. Patients were randomly assigned treatment using a central electronic procedure. Total administered dose at the end of the intravenous administration was 125 mg, 250 mg, 500 mg, and 1000 mg of glenzocimab or placebo in phase 1b and 1000 mg of glenzocimab or placebo in phase 2a. Treatment was initiated 4·5 h or earlier from stroke symptom onset in patients treated with alteplase with or without mechanical thrombectomy. The sponsor, study investigator and study staff, patients, and central laboratories were all masked to study treatment until database lock. Primary endpoints across both phases were safety, mortality, and intracranial haemorrhage (symptomatic, total, and fatal), assessed in all patients who received at least a partial dose of study medication (safety set). The trial is registered on ClinicalTrials.gov, NCT03803007, and is complete. FINDINGS: Between March 6, 2019, and June 27, 2021, 60 recruited patients were randomly assigned to 125 mg, 250 mg, 500 mg, or 1000 mg glenzocimab, or to placebo in phase 1b (n=12 per group) and were included in the safety analysis. Glenzocimab 1000 mg was well tolerated and selected as the phase 2a recommended dose; from Oct 2, 2020, to June 27, 2021, 106 patients were randomly assigned to glenzocimab 1000 mg (n=53) or placebo (n=53). One patient in the placebo group received glenzocimab in error and therefore 54 and 52, respectively, were included in the safety set. In phase 2a, the most frequent treatment-emergent adverse event was non-symptomatic haemorrhagic transformation, which occurred in 17 (31%) of 54 patients treated with glenzocimab and 26 (50%) of 52 patients treated with placebo. Symptomatic intracranial haemorrhage occurred in no patients treated with glenzocimab compared with five (10%) patients in the placebo group. All-cause deaths were lower with glenzocimab 1000 mg (four [7%] patients) than with placebo (11 [21%] patients). INTERPRETATION: Glenzocimab 1000 mg in addition to alteplase, with or without mechanical thrombectomy, was well tolerated, and might reduce serious adverse events, intracranial haemorrhage, and mortality. These findings support the need for future research into the potential therapeutic inhibition of glycoprotein VI with glenzocimab plus alteplase in patients with acute ischaemic stroke. FUNDING: Acticor Biotech.

Add-on therapies to metformin in type 2 diabetes: what modulates the respective decrements in postprandial and basal glucose?

BACKGROUND: Oral hypoglycemic agents (OHAs) are usually divided into postprandial and basal drugs. As their actions are probably more complex, it is important to ascertain which factors can modulate their effects. SUBJECTS AND METHODS: Thirty-one type 2 diabetes patients treated with metformin (glycosylated hemoglobin [HbA1c] 6.5-9%; median, 7.3%) and enrolled in two randomized controlled studies were allocated to either rosiglitazone (Group 1, n = 8) or glimepiride (Group 2, n = 7) and to either vildagliptin or sitagliptin (Group 3 considered as a whole, n = 16). All patients were investigated using continuous glucose monitoring at baseline and after 8-12 weeks of add-on therapy. Areas under the 24-h glycemic profile curves (AUCs) were determined for assessing postprandial (AUCpp), basal (AUCb), and total (AUCtotal) hyperglycemia. After calculation of decrements in AUCs (∂AUCs) from baseline to end of treatment periods, the following contribution ratios of postprandial and basal decrements to the overall glucose decrement were determined: ∂AUCpp/∂AUCtotal and ∂AUCb/∂AUCtotal (%). RESULTS: ∂AUCpp/∂AUCtotal and ∂AUCb/∂AUCtotal were negatively and positively, respectively, associated (R(2) = 0.195, P = 0.013) with baseline HbA1c. ∂AUCpp/∂AUCtotal was significantly higher (50.8 ± 4.8%) in patients with HbA1c <7.3% than in those with HbA1c ≥ 7.3% (27.0 ± 4.4%) (P = 0.001). After adjustment on baseline HbA1c, ∂AUCpp/∂AUCtotal was greater in Group 3 (44.0 ± 1.6%) than in Group 1 (32.1 ± 4%) and 2 (37.0 ± 3.1%) (P = 0.007). CONCLUSIONS: Gliptins, glitazones and sulfonylureas concomitantly act on basal and postprandial glucose even though gliptins are more efficient on postprandial glucose. HbA1c appears as a reliable factor for predicting the respective decrements of these two parameters and thus for guiding the choice between the aforementioned drugs.

Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice.

OBJECTIVE: To assess the improvements in symptoms, quality of life (QoL), discomfort and satisfaction in patients with symptomatic benign prostatic hyperplasia (BPH) treated with dutasteride in clinical practice. PATIENTS AND METHODS: In a prospective, multicentre open-label study, we evaluated the efficacy and safety in clinical practice of dutasteride, 0.5 mg/day for 24 weeks, in patients with symptomatic BPH. The primary endpoint was the proportion of patients achieving at least a 3-point decrease from baseline in the International Prostate Symptom Score (IPSS) after 24 weeks of treatment. The secondary endpoints included changes from baseline in measures of QoL (IPSS item 8 and BPH Impact Index score, BII), and patient discomfort and satisfaction (visual analogue scales, VAS) at 12 and 24 weeks. RESULTS: Of the 366 patients assessed, 72.5% achieved at least a 3-point reduction in IPSS at 24 weeks; the IPSS decreased from 15.3 at baseline to 10.2 at 12 weeks, and to 9.1 at 24 weeks. There were significant (P < 0.001) decreases in all the individual IPSS items at 12 and 24 weeks, with more marked improvements in voiding symptoms than storage symptoms. There were also significant (P < 0.001) improvements in the BII and VAS scores for patient discomfort and satisfaction at both times. CONCLUSIONS: Dutasteride treatment for 24 weeks significantly improved BPH symptoms, QoL and patient discomfort and satisfaction, and was well tolerated in clinical practice.

[Effect of dutasteride on reduction of intraoperative bleeding related to transurethral resection of the prostate]. / Effet du dutastéride sur la réduction des saignements per-opératoires liés a la résection transuréthrale de prostate.

OBJECTIVE: The pharmacological action of 5-alpha-reductase inhibitors (5-ARI) would reduce angiogenesis associated with benign prostatic hyperplasia (BPH), thereby decreasing peroperative bleeding during transurethral resection of the prostate (TURP). Dutasteride, a double inhibitor of 5-alpha-reductase iso-enzymes types 1 and 2, was not been previously studied in the context of reduction of peroperative bleeding related to TURP. MATERIAL AND METHODS: We conducted a multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy of dutasteride 0.5 mg per day, in peroperative bleeding related to TURP for BPH in patients over the age of 50 years with a prostatic volume greater than 30 cm3. Treatment was administered for 4 weeks before the operation. The primary endpoint was haemoglobin, expressed in grams, and expressed in relation to the weight of prostate resected, also expressed in grams. RESULTS: 59 patients were evaluated (32 treated with dutasteride and 27 treated with placebo). A significant difference in peroperative bleeding was observed between the dutasteride group (1.944 +/- 1.816 g of Hb/g of prostate resected) and the placebo group (1.401 +/- 1.021 g of Hb/g of prostate resected). Preoperative treatment was well tolerated. CONCLUSION: The working hypothesis of the study was not confirmed due to the low bleeding rate in the placebo group and the results suggest that a longer duration of treatment with dutasteride would reduce intraoperative and postoperative bleeding in TURP.

[Effect of dutasteride on reduction of plasma DHT following finasteride therapy in patients with benign prostatic hyperplasia]. / Effet du dutastéride sur la diminution de la DHT plasmatique en relais d'un traitement par finastéride chez des patients atteints d'une hypertrophie bénigne de prostate.

INTRODUCTION: Dihydrotestosterone (DHT) is a steroid hormone derived from testosterone, by the action of two distinct isoenzymes (type 1 and 2) of 5-alpha-reductase. Dutasteride is a specific selective inhibitor of the two isoenzymes, while finasteride is a selective inhibitor of type 2 -alpha-reductase. The working hypothesis is that the double 5-alpha-reductase inhibition induced by dutasteride therapy for 6 weeks should induce a supplementary reduction of plasma DHT levels compared to a parallel patient group continuing finasteride therapy over the same period. MATERIALS AND METHODS: In this prospective, two-centre, double-blind study, 21 patients previously treated by finasteride 5 mg for benign prostatic hyperplasia (BPH) for at least 6 months were randomized to receive either dutasteride 0.5 mg, or finasteride 5 mg daily for 6 weeks. RESULTS: The mean relative variation of plasma DHT was 67.3% +/- 16.16% in the dutasteride group and 30.3% +/- 59.8% in the finasteride group. The reduction of DHT was numerically greater and more constant in the dutasteride group than in the finasteride group at 6 weeks; such a tendency was already observed after two weeks of treatment with dutasteride. Nevertheless, these differences were not statistically significant. Both medications were well tolerated and the only treatment-related adverse event (epigastric pain) was reported in the finasteride group. CONCLUSIONS: The working hypothesis was therefore not statistically confirmed. It is difficult to conclude whether this reflects poor patient compliance with long-term finasteride for BPH or variability of response in patients with good compliance with treatment.