Browsing by Subject "drug safety"

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  • ALBINO Study Group; Maiwald, C.A.; Annink, K.V.; Rüdiger, M.; Benders, M.J.N.L.; Van Bel, F.; Allegaert, K.; Naulaers, G.; Bassler, D.; Klebermaß-Schrehof, K.; Vento, M.; Guimarães, H.; Stiris, T.; Cattarossi, L.; Metsäranta, M.; Vanhatalo, S.; Mazela, J.; Metsvaht, T.; Jacobs, Y. (2019)
    Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017. © 2019 The Author(s).
  • Vink, P.; Torrell, J.M.R.; Fructuoso, A.S.; Kim, Sung-Joo; Kim, Sang-Il; Zaltzman, J.; Ortiz, F.; Plana, J.M.C.; Rodriguez, A.M.F.; Rodrigo, H.R.; Marti, M.C.; Perez, R.; Roncero, F.M.G.; Kumar, D.; Chiang, Y.-J.; Doucette, K.; Pipeleers, L.; Morales, M.L.A.; Rodriguez-Ferrero, M.L.; Secchi, Antonio; McNeil, S.A.; Campora, L.; Di Paolo, E.; El Idrissi, M.; López-Fauqued, M.; Salaun, B.; Heineman, T.C.; Oostvogels, L. (2020)
    Background. The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy. Methods. In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2. Results. Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups. Conclusions. RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose. © The Author(s) 2019.
  • Shore, Neal D.; Tammela, Teuvo L.; Massard, Christophe; Bono, P.; Aspegren, John; Mustonen, Mika; Fizazi, Karim (2018)
    Background: ODM-201, a new androgen receptor antagonist for treatment of metastatic castration-resistant prostate cancer (mCRPC), demonstrated antitumour activity and acceptable tolerability in phase 1/2 trials. Objective: To determine the antitumour activity and safety profile of extended treatment with ODM-201 in men with mCRPC. Design, setting, and participants: ARADES and ARAFOR trials with ODM-201 enrolled chemotherapy-naïve and CYP17 inhibitor (CYP17i)-naïve mCRPC patients. Both trials had extended follow-up. Here we report results for chemotherapy-naïve and CYP17i-naïve patients from both trials (data cutoff October 2014 for ARADES and April 2015 for ARAFOR) after extended follow-up. Intervention: A total of 41 chemotherapy-naïve and CYP17i-naïve patients received oral ODM-201 twice daily (total daily dose of 1200, 1400 or 1800 mg). Outcome measurements and statistical analysis: Antitumour activity was assessed in terms of prostate-specific antigen (PSA) declines and PSA/radiographic progression. Safety was assessed until disease progression and/or drug discontinuation due to any intolerable adverse event (AE). Results and limitations: ODM-201 safety data after a median treatment time of 13.5 mo (95% confidence interval [CI] 9.7–15.6, interquartile range [IQR] 7.5–22.0) were similar to those reported in the main ARADES and ARAFOR trials. The overall AE incidence was 80.5% (n = 33/41), with 58.5% (n = 24/41) of patients experiencing only grade 1–2 AEs. The most common AEs were fatigue, back pain, diarrhoea, nausea, and pain in extremity. The median times to PSA and radiological progression were 12.4 mo (95% CI 6.3–18.2, IQR 5.5–22.0) and 15.3 mo (95% CI 9.5–not reached [NR], IQR 6.3–NR), respectively. Conclusions: Extended treatment with ODM-201 (1200–1800 mg/d) was well tolerated, with no new safety concerns, and provided evidence of sustained antitumour activity in chemotherapy-naïve and CYP17i-naïve patients with mCRPC. Patient summary: Prolonged treatment with high doses of ODM-201 was well tolerated and provided long-lasting disease control in patients with mCRPC. ODM-201 represents a therapeutic treatment option for mCRPC. The ARAFOR trial (including the follow-up stage) and the follow-up component of the ARADES trial are registered with ClinicalTrials.gov as trial numbers NCT01784757 and NCT01429064. Extended treatment with ODM-201 was well tolerated and provided long-lasting disease control in chemotherapy- naïve and CYP17 inhibitor-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). ODM-201 may represent an additional effective treatment option for mCRPC. © 2017 European Association of Urology
  • Fizazi, Karim; Massard, Christophe; Bono, P.; Kataja, Vesa; James, Nicholas; Tammela, T.L.; Joensuu, H.; Aspegren, John; Mustonen, M. (2017)
    Background: Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen receptor antagonist ODM-201, in phase 1/2 studies. Objective: To evaluate the safety and antitumour activity of prolonged ODM-201 treatment in patients with CRPC. Design, setting, and participants: The ARADES trial was a multicentre phase 1 (dose escalation) and phase 2 (dose expansion) trial; 134 patients with CRPC were stratified by previous chemotherapy to receive ODM-201. This paper reports extended follow-up in CYP17 inhibitor (CYP17i)-naïve patients. Intervention: Patients (n = 77) received oral ODM-201 twice daily at daily doses of 200–1800 mg. Outcome measurements and statistical analysis: Safety, measured as the occurrence of adverse events (AEs), prostate-specific antigen (PSA), and radiographic progression. Results and limitations: The safety profile of extended ODM-201 treatment (median treatment duration 8.2 mo, 95% confidence interval [CI] 5.6–11.0) was consistent with that reported at the time of the original data cutoff in the main ARADES trial, with no unexpected safety concerns over time. The majority of AEs (61.1%) were mild (grade 1); the most common AE was fatigue/asthenia (35.1% of patients), with no clear relationship to ODM-201. Median time to PSA progression was 25.2 mo (95% CI 11.3–25.2) for chemotherapy-naïve men and not reached (NR; 95% CI 5.5–NR) for chemotherapy-pretreated patients; a trend for improved antitumour response was observed for chemotherapy-naïve patients. The median time to radiographic progression was longer for chemotherapy-naïve (14.0 mo, 95% CI 8.1–33.3) than for chemotherapy-pretreated (7.2 mo, 95% CI 2.7–11.0) patients. Conclusions: Prolonged exposure to ODM-201 was well tolerated, with no additional safety concerns; disease suppression was sustained, especially in chemotherapy-naïve patients. These data support further development of ODM-201 in men with CYP17i-naïve CRPC. Patient summary: Extended ODM-201 therapy was well tolerated, with beneficial antitumour activity in men with advanced prostate cancer, indicating that ODM-201 may represent a new active treatment for men with CRPC. This extension trial is registered at ClinicalTrials.gov (www.clinicaltrials.gov) under identification number NCT01429064. Extended ODM-201 therapy showed encouraging antitumour activity in both chemotherapy-naïve and chemotherapy-treated men with metastatic castration-resistant prostate cancer (CRPC). Continued treatment with ODM-201 was well tolerated, with no unexpected safety concerns, and may represent a new, effective treatment option for men with CRPC. © 2017 European Association of Urology
  • Chen, Ingrid; Diawara, Halimatou; Mahamar, Almahamoudou; Sanogo, Koualy; Keita, Sekouba; Kone, Daouda; Diarra, Kalifa; Djimde, Mousse; Keita, Mohamed; Brown, Joelle; Roh, Michelle E.; Hwang, Jimee; Pett, Helmi; Murphy, Maxwell; Niemi, Mikko; Greenhouse, Bryan; Bousema, Teun; Gosling, Roly; Dicko, Alassane (2018)
    Methods: We conducted an open-label, nonrandomized, dose-adjustment trial of the safety of 3 single doses of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient adult males in Mali, followed by an assessment of safety in G6PD-deficient boys aged 11–17 years and those aged 5–10 years, including G6PD-normal control groups. The primary outcome was the greatest within-person percentage drop in hemoglobin concentration within 10 days after treatment. Results: Fifty-one participants were included in analysis. G6PD-deficient adult males received 0.40, 0.45, or 0.50 mg/kg of SLD-PQ. G6PD-deficient boys received 0.40 mg/kg of SLD-PQ. There was no evidence of symptomatic hemolysis, and adverse events considered related to study drug (n = 4) were mild. The mean largest within-person percentage change in hemoglobin level between days 0 and 10 was −9.7% (95% confidence interval [CI], −13.5% to −5.90%) in G6PD-deficient adults receiving 0.50 mg/kg of SLD-PQ, −11.5% (95% CI, −16.1% to −6.96%) in G6PD-deficient boys aged 11–17 years, and −9.61% (95% CI, −7.59% to −13.9%) in G6PD-deficient boys aged 5–10 years. The lowest hemoglobin concentration at any point during the study was 92 g/L. Conclusion: SLD-PQ doses between 0.40 and 0.50 mg/kg were well tolerated in G6PD-deficient males in Mali.
  • Howard, Ian; Cameron, Peter; Wallis, Lee; Castrén, Maaret; Lindström, Veronica (2020)
    Introduction In South Africa (SA), prehospital emergency care is delivered by emergency medical services (EMS) across the country. Within these services, quality systems are in their infancy, and issues regarding transparency, reliability and contextual relevance have been cited as common concerns, exacerbated by poor communication, and ineffective leadership. As a result, we undertook a study to assess the current state of quality systems in EMS in SA, so as to determine priorities for initial focus regarding their development. Methods A multiple exploratory case study design was used that employed the Institute for Healthcare Improvement's 18-point Quality Program Assessment Tool as both a formative assessment and semistructured interview guide using four provincial government EMS and one national private service. Results Services generally scored higher for structure and planning. Measurement and improvement were found to be more dependent on utilisation and perceived mandate. There was a relatively strong focus on clinical quality assessment within the private service, whereas in the provincial systems, measures were exclusively restricted to call times with little focus on clinical care. Staff engagement and programme evaluation were generally among the lowest scores. A multitude of contextual factors were identified that affected the effectiveness of quality systems, centred around leadership, vision and mission, and quality system infrastructure and capacity, guided by the need for comprehensive yet pragmatic strategic policies and standards. Conclusion Understanding and accounting for these factors will be key to ensuring both successful implementation and ongoing utilisation of healthcare quality systems in emergency care. The result will not only provide a more efficient and effective service, but also positively impact patient safety and quality of care of the services delivered. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
  • Nieminen, Tuomo (Helsingin yliopisto, 2017)
    All pharmaceutical products, including vaccines, can increase the risk of some undesired medical occurences (adverse events). Evaluating these risks post-licensure is essential for evaluating the safety of vaccines, since rare adverse events might go undetected in pre-licensure studies. This thesis introduces and applies a method for vaccine safety surveillance, suitable for monitoring the safety of vaccines in near real-time, utilizing electronic health care records. Adverse events are operationalized by diagnosis codes related to health care visits. Vaccine safety surveillance studies suspected, biologically plausible causal relationships between a vaccine and an adverse event. Information regarding such relationships are called safety signals. Safety surveillance can be seen as an observational study for which different study designs could be used. The popularity of vaccination, self-selection and changes in diagnosis coding practises, along with other possible sources of bias, present challenges for commonly used cohort designs. Self-controlled study designs such as the self-controlled case series (SCCS) eliminate time-invariant confounders and are therefore often more suitable for evaluating vaccine risks. This thesis introduces both a simple and a more general version of SCCS and explicitly describes the assumptions related to the method. A vaccine safety surveillance method involves a decision rule for generating safety signals. Natural goals of a safety surveillance method are to control the rates of false positive and false negative signals, as well as to generate a signal as soon as possible when an association between the vaccine and the adverse event exists. Statistical hypothesis testing can be used to derive the decision rules. This thesis describes the maximized sequential probability ratio test (maxSPRT), a hypothesis testing method designed for vaccine safety surveillance. Binomial maxSPRT (BmaxSPRT) is a variant of maxSPRT based on a self-controlled study design such as the SCCS. The BmaxSPRT method addresses hypotheses concerning the relative incidence of adverse events during specified risk and control periods. The derivation of the decision rules for BmaxSPRT, including the computation of critical values, is described in detail both mathematically and algorithmically in this work. As a proof-of-concept BmaxSPRT is retrospectively applied to Finnish register data. The relationships between the incidence of febrile seizures and three childhood vaccines, Measles-Mumps-Rubella (MMR), Pneumococcal (PCV) and the Rota virus vaccination (Rota) are studied. BmaxSPRT generated an expected safety signal related to MMR; the incidence rate of febrile seizures was higher during a period 0­­-13 days following MMR vaccination compared to a period 14-41 days following vaccination (relative rate RR = 1.59 at the time of signal). Results for PCV are inconclusive and the experiment highlights the need for more in depth analysis regarding PCV vaccinations and febrile seizures. The sensitivity of BmaxSPRT to the specifications of the risk and control periods is also studied in this thesis. The sensitivity analysis highlights the importance of careful consideration of the risk and control periods by quantifying the loss of power due to poor choices.