Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: Study protocol for a randomized control trial

Background: Patent ductus arteriosus (PDA) is one of most common complications in preterm infants. Although ibuprofen represents the first choice for the closure of PDA, this treatment can cause severe gastrointestinal and adverse renal effects and worsen platelet function. The successful closure of the PDA with paracetamol has been recently reported in several preterm infants, and the safety of paracetamol for this use has been suggested by the available data. Methods/design: We present the design of a randomized, multicenter, controlled study, whose aim is to assess the effectiveness and safety of intravenous paracetamol in comparison to intravenous ibuprofen for the treatment of PDA in preterm infants. A total of 110 infants born at 25 +0 to 31 +6 weeks of gestational age will be enrolled and randomized to receive paracetamol or ibuprofen (55 patients per group) starting at 24-72h of life. The primary endpoint of the study is the comparison of the PDA closing rate observed after a 3-day course with paracetamol or ibuprofen. The secondary endpoints include the closure rate of PDA after the second course of treatment with ibuprofen, the re-opening rate of the PDA, the incidence of surgical ligation, and the occurrence of adverse effects. Discussion: The results of this study will provide new information about the possible use of paracetamol in the treatment of PDA. Paracetamol could offer several important therapeutic advantages over current treatment options, and it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile. Trial registration: Clinicaltrials.gov NCT02422966. Eudract no. 2013-003883-30

Long-Term Treatment with Trazodone Once-A-Day (TzOAD) in Patients with MDD: An Observational, Prospective Study

Milena Shrashimirova,1,* Ivan Tyanev,2,* Wiesław J Cubała,3,* Adam Wichniak,4,* Claudia Vodickova-Borzova,5,* Alessandro Ruggieri,6,* Annalisa Bonelli,6,* Paola Lipone,6,* Alessandro Comandini,6,* Agnese Cattaneo6,* 1Diagnostic Consultative Center 14, Hospital VITA, Sofia, Bulgaria; 2Multiprofile Hospital for Active Treatment, Medical Clinic, Targovishte, Bulgaria; 3Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland; 4Third Department of Psychiatry and Sleep Disorders Center, Institute of Psychiatry and Neurology, Warsaw, Poland; 5Psychiatry and Neurology, Brain-Soultherapy.s.r.o, Kladno, Czech Republic; 6Global Medical Department, Angelini Pharma S.p.A, Rome, Italy*These authors contributed equally to this workCorrespondence: Alessandro Ruggieri, Global Medical Department, Angelini Pharma S.p.A, Viale Amelia 70, Rome, 00181, Italy, Tel +390691045309, Email [email protected]: This was an observational, prospective, single-group, multicentre, international study aimed to describe the clinical response, functional impairment, and quality of life (QoL) of patients suffering from major depressive disorder (MDD) and in treatment with Trazodone Once-A-Day (TzOAD) monotherapy, over a 24-week period.Patients and Methods: A total of 200 patients with a diagnosis of MDD who had been treated with TzOAD monotherapy were enrolled from 26 sites across 3 European countries (Bulgaria, Czech Republic, and Poland), including psychiatric private practices, and outpatient departments from general and psychiatric hospitals. Study assessments were completed by physicians and patients during routine visits within the normal practice of care.Results: Clinical response was assessed by Clinical Global Impressions – Improvement (CGI-I) responders’ percentage at 24 (± 4) weeks. The majority of patients (86.5%) reported an improvement on the CGI-I compared to baseline. Results of the study confirm the well-known safety and tolerability of TzOAD, as well as its effectiveness on depressive symptoms, such as improvement in QoL, sleep quality, and overall functioning accompanied by favourable adherence and low drop-out rate.Conclusion: To our knowledge, this is the first observational, long-term study in patients suffering from MDD, conducted with TzOAD. The improvement observed in clinical response, overall functioning, depressive symptoms, and QoL along the 24 weeks (+4) maintenance period and the very good retention rate, suggest that TzOAD may represent an effective and well tolerated treatment option for patients suffering from MDD.Keywords: major depressive disorder, trazodone, patient-reported outcome, real-world evidence, effectiveness, long-term follow-u

Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study

Background: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. Objective: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. Methods: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient’s improvement, and safety. Results: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were − 3.1, − 2.6, and − 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval − 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval − 1.54, − 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. Conclusions: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. Clinical Trial Registration: NCT03202979, date of registration: 29/06/2017

Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial

Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25+0\u201331+6 weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar. Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA. Trial registration:Clinicaltrials.gov: NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30.What is Known:\u2022 The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol.What is New:\u2022 Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect.\u2022 These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA