Study Drug Administration Research Articles

Mosunetuzumab in Combination with Lenalidomide Has a Manageable Safety Profile and Encouraging Activity in Patients with Relapsed/Refractory Follicular Lymphoma: Initial Results from a Phase Ib Study

Mosunetuzumab in Combination with Lenalidomide Has a Manageable Safety Profile and Encouraging Activity in Patients with Relapsed/Refractory Follicular Lymphoma: Initial Results from a Phase Ib Study

Lenalidomide and Rituximab (ReRi) As Front-Line Chemo-Free Therapy for Elderly Frail Patients with Diffuse Large B-Cell Lymphoma. a Phase II Study of the Fondazione Italiana Linfomi (FIL)

▪INTRODUCTIONTreatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthracycline containing regimens.Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile.We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of a chemo-free combination of lenalidomide + rituximab in older (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to the simplified comprehensive geriatric assessment (sCGA) (Tucci A. et al., Leuk Lymphoma. 2015 Apr).PATIENTS AND METHODSPts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to sCGA.The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6 th cycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade >2 and of death for any cause during the treatmentThe study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study. With 34 responses the study would be able to demonstrate the initial hypothesis of an improvement of response rate from 45% (p0) to 65% (P1)RESULTSFrom August 2018 to June 2021, 68 newly diagnosed frail DLBCL were enrolled in 18 Italian centers. Median age was 83 years (range 70-91) and 73% had stage III/IV; 57% had High risk IPI (i.e. 3-5 risk factors). 64 pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 36 pts (56%). The median number of R2 cycles was 6 (1-6). Treatment was discontinued in 28 pts due to lymphoma progression (11 cases), extra-hematological toxicity (7), hematological toxicity (1), lost after 1 cycle and investigator choice after 5 cycles in CR in 1 case each, death in 7 cases (1 each for infection, pancytopenia, cachexia, ischemia and bowel infarction, and from unknown causes in 2 cases).At the end of 6 th R2 cycle 26 patients achieved a response (ORR 41%), 13 CR and 13 PR. After a median follow-up of 17 months, the overall survival, and progression free survival at 12 months were 69% (95CI 56-79%) and 55% (95%CI 42-66%), respectively. The duration of remission at 12 months was 72%.Regarding safety 46 events were reported including 31 extra-hematological toxicities > CTCAE grade 2: 7 cardio-vascular (1 resulting in death), 4 nervous system disorders (1 resulting in death), 10 gastro-intestinal, 3 infections, 6 skin and subcutaneous tissue disorders, 5 respiratory events (all resolved). The rate of grade 3-4 adverse events was higher than the highest allowed limit of 28.CONCLUSIONSThe Reri is the first study to evaluate activity and safety of a chemo-free therapy in patients with diffuse large B-Cell Lymphoma who are not eligible for conventional cytotoxic therapy. Even if this study was not able confirm the initial activity hypothesis, activity of the R2 combination was observed in a significant proportion of cases warranting further exploration of chemo-free approach of elderly frail patient with DLBCL. DisclosuresTucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Fabbri: Takeda: Honoraria; Servier/Pfizer: Honoraria; Takeda: Other: Travel, Accomodations, Expenses. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations. Luminari: Roche, Celgene, Teva Pharmaceuticals, Gilead Sciences, and Takeda Pharmaceuticals: Honoraria.

CLI120-001 Phase Ib Study of RVU120(SEL120) in Patients with AML and High Risk MDS: Updated Safety/Efficacy Results from Initial Dose Escalation

CLI120-001 Phase Ib Study of RVU120(SEL120) in Patients with AML and High Risk MDS: Updated Safety/Efficacy Results from Initial Dose Escalation

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

BackgroundMesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS.MethodsREALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143.FindingsNine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9).InterpretationA single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

СПЕЦИФИКА МОЛЕКУЛЫ МОРОКТОКОГА АЛЬФА: РЕЗУЛЬТАТЫ ПРОСПЕКТИВНОГО МНОГОЦЕНТРОВОГО НАБЛЮДАТЕЛЬНОГО ИССЛЕДОВАНИЯ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ У ПОДРОСТКОВ С ГЕМОФИЛИЕЙ A

The main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). The active use of biotechnological methods in the production of recombinant drugs contributes to the development and registration of new FVIII drugs. The results of clinical trials of drugs in children usually include a limited number of patients for a specific period of time. Post-marketing observational studies provide additional information on the results of using a new drug in patients in clinical practice. The objectives of the study were to collect and analyze data on the efficacy and safety of domestic recombinant FVIII with a deleted B-domain, moroctocog alfa (Octofactor, GENERIUM JSC) in the treatment of adolescents aged 12–18 years with hemophilia A in routine clinical practice. Materials and methods of research: a prospective multicenter open-label observational study of the results of using the Octofactor in adolescents with hemophilia A (№ OCF-HPA-N01) included 24 male patients with severe hemophilia A aged 12 to 18 years (mean age 14,8±1,7 years), who received moroctocog alfa in routine clinical practice. Enrollment in the study was carried out after the signing of the informed consent form by the parent of the minor patient and the minor patient aged 14 to 18 years, taking into account the results of the screening examination. The follow-up period was 52±4 weeks, which, presumably, was sufficient to achieve at least 100 days of moroctocog alfa administration. To assess the effectiveness, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the severity of spontaneous bleeding against the background of prophylactic treatment with moroctocog alfa, the number of injections and the dose of the study drug for prophylactic treatment, as well as for treatment at the request of one episode of bleeding, taking into account its severity; the researcher's determination of the response to treatment of acute hemarthrosis according to the scale of the World Federation of Hemophilia (2020). To assess safety, the frequency and characteristics of adverse events (AEs) associated with drug administration were analyzed, including the frequency of formation of an inhibitor to FVIII. Results: during the study, 59 bleedings were recorded, of which 21 (36%) were spontaneous and 38 (64%) were post-traumatic. Among spontaneous bleeding episodes, 5 (24%) episodes occurred within 48–72 hours after administration of the study drug. Spontaneous bleeding within 48–72 hours after administration of Octofactor was absent against the background of prophylactic treatment in most patients (81%) and was observed rarely during the observation period (1–3 times) in the remaining 19% of patients. The median number of bleeding within 48–72 h after study drug administration was 1 episode over the follow-up period. The proportion of mild to moderate bleeding was 97 [88; 100]% among all types of bleeding and 100 [84; 100]% among spontaneous bleeding within 48–72 hours after administration of the Octofactor drug. The median of a single dose of Octofactor for preventive treatment was 2000 [1500; 2000] IU or 31,7 [25,6; 38,5] IU/kg, and with treatment on demand ‒ 2000 [2000; 3000] IU or 34,1 [28,8; 38,5] IU/kg per single injection. To stop the resulting bleeding required 1 [1; 2] introduction in a single dose of 3000 [2000; 4000] IU; the average dose was 4490 ÷ 4993 IU. When doctors subjectively assess the response to treatment of acute hemarthrosis on the scale of the World Federation of Hemophilia, an excellent response was noted in 9 (27%) episodes, good and moderate ‒ in 2 (6%) and 22 (67%) episodes, respectively. Lack of response to treatment of acute hemarthrosis with moroctocog alfa was not revealed in the study. During the study, 23 AEs were recorded in 13 (54%) patients not related to the study drug. Conclusion: thus, the obtained results of the study indicates the efficacy and safety of the Octofactor both the prophylactic treatment and treatment of on-demand bleedings in 12 to 18 year old patients with severe hemophilia A.

A comparative study of propofol, thiopentone sodium, and ketofol as induction agents for electro convulsive therapy.

Background and Aims:Thiopentone and propofol are most commonly used induction agents for electro convulsive therapy (ECT). Recently, ketofol, an admixture of propofol and ketamine, is being tried in ECT. We aimed to compare propofol, thiopentone, and ketofol as induction agents during ECT regarding their effects on ECT-induced hemodynamic changes, seizure duration and recovery parameters.Material and Methods:This prospective randomized double blind study was conducted in 30 patients between 18 and 65 years with ASA status I and II scheduled for ECT. All patients received all study agents for first three sessions of ECT. The observations were compiled as Group K (Inj. Ketofol i.e., Inj. propofol 0.5mg/kg % Inj. ketamine 0.5mg/kg), Group P (Inj. propofol 1mg/kg), and Group T (Inj. thiopentone 3mg/kg). Heart rate (HR) and blood pressure (systolic, diastolic, and mean) was recorded at pre op, 0, 5, 10, and 20 min after ECT. The seizure duration, time to spontaneous eye opening, andobeying verbal commands and agitation score were recorded.Results:Statistically significant difference was seen in HR at 10 min after delivery of shock; in systolic BP at 2 min after shock; in diastolic BP after administration of study drug and immediately after shock and in mean arterial pressure at post induction, 0and2 min after shock with group T showing higher values compared to group K and P (p < 0.05). At all other times HR andBP was comparable in all the three groups. Seizure duration was more in group T than Groups P and K although the difference was statistically insignificant. Time to spontaneous eye opening and obey verbal commands was comparable in all groups. Mean agitation score was highest in group T than Groups P& Kwith Group P showing least value (p = 0.003).Conclusion:Propofol and ketofol showed superior hemodynamic stability than thiopentone but comparable seizure duration and recovery parameters. Thus, propofol and ketofol can be effectively used as induction agents for ECT although propofol is associated with lesser agitation than ketofol.

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

BackgroundIn the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks’ gestation) infants.MethodsPlasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).FindingsElevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.InterpretationElevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.FundingPENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

A METHOD FOR OBJECTIVE ASSESSMENT OF REST ACTIVITY PATTERNS AND LIGHT LEVELS IN THE ICU

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Patients in the intensive care unit (ICU), experience disturbed sleep due to environmental factors, as well as critical illness itself. Insufficient and fragmented sleep is linked to increased morbidity, mortality, and ICU length of stay. Despite these correlations, objectively measured sleep and circadian patterns are not routinely examined in ICU patients, and assessment methods are not standardized. In this study, we devised a method to use wrist actigraphy to examine rest-activity patterns and light in a medical ICU. METHODS: As part of an ongoing randomized placebo-controlled trial testing the effect of a sleep medication in preventing ICU delirium, we enrolled patients admitted to the medical ICU at Rhode Island Hospital. Patients were monitored with continuous actigraphy while they were in the ICU. We estimated sleep and wake durations using algorithms validated with polysomnography as well as maximum and average light levels. We summarized data for 2 defined periods across 24-hours based on timing of the investigational sleep aid and ICU routines in our hospital. “Subjective night” was defined from the time of study drug administration to 5:59 AM, and “subjective day” was defined from 6:00 AM to the next study drug treatment time. We used Wilcoxon Signed Ranks Tests to compare sleep and light measured between subjective night and day. RESULTS: Fifty-eight patients are included in these analyses, 45% of which are women. The mean age was 61 years, and the mean APACHE II score was 21. The mean actigraphy-recording days was 4.3. Median duration of subjective night was 513 minutes (IQR=472-526), and of subjective day was 708 minutes, (IQR=537-793; Z=-5.922, p<.0001). Patients spent a higher percentage of the subjective night asleep compared to subjective day (53.7% (IQR=32.8-72.4) vs. 32.9% (IQR=15.4-50.0), Z=-5.767, p<.0001), but estimated sleep duration did not differ between subjective night and day (median 280 minutes (IQR=175-362) vs. 216 minutes (IQR=82-342), Z=-0.664, p=.519). Mean and maximum illuminance were significantly lower during subjective night than day (median average lux 7.3 (IQR=3.0-14.0) vs. 53.8 (IQR=28.2-87.6), Z=-5.692, p<.0001; median maximum lux 116.8 (IQR=53.5-254.2) vs. 445.0 (311.8-643.4), Z=-4.854, p<.0001). CONCLUSIONS: In our study, estimated sleep percentages were higher during subjective night than day, but patients obtained similar amounts of sleep during the subjective day and night, indicating poor sleep consolidation. While patients experienced low light levels during the night, they also experienced low daytime light levels, potentially contributing to higher risk of circadian dysregulation and nighttime sleep disturbance. CLINICAL IMPLICATIONS: Our results provide evidence of disrupted rest-activity patterns in critically ill patients and of low daytime light levels in the ICU, highlighting the need for continued investigation into interventions to improve sleep quality in the ICU. DISCLOSURES: No relevant relationships by David Baek, source=Web Response No relevant relationships by Debasree Banerjee, source=Web Response No relevant relationships by Shi-Yo Chen, source=Web Response No relevant relationships by Jisoo Lee, source=Web Response No relevant relationships by Mitchell Levy, source=Web Response No relevant relationships by Amy Mathew, source=Web Responseauthor royalties relationship with UpToDate Please note: 2016-present Added 04/29/2021 by Katherine Sharkey, source=Web Response, value=Royalty

THE EFFECT OF TIME TO TREATMENT WITH ANTIARRHYTHMIC DRUGS ON OUTCOMES IN SHOCK REFRACTORY OUT-OF-HOSPITAL CARDIAC ARREST: A SECONDARY ANALYSIS OF THE ALPS RANDOMIZED CONTROLLED TRIAL

<h3>BACKGROUND</h3> The relationship between time to treatment in patients with out-of-hospital cardiac arrest (OHCA) and survival outcomes, and the interaction of time to treatment and antiarrhythmic drug effect, is not precisely known. We conducted a post-hoc analysis of the Resuscitation Outcomes Consortium Amiodarone, Lidocaine, Placebo (ROC ALPS) randomized controlled trial examining the association of time to treatment (drug or placebo) with survival and neurological outcome. A secondary objective was to determine whether this relationship was modified by treatment type (i.e., amiodarone versus lidocaine). <h3>METHODS AND RESULTS</h3> In the ROC ALPS trial, adults with non-traumatic OHCA and an initial rhythm of shock refractory ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) after at least one defibrillation were randomized to receive amiodarone, lidocaine, or placebo. We used logistic regression to examine the association of time to treatment (defined as a 911 call to study drug administration interval) with survival at hospital discharge and favourable neurological status at discharge (Modified Rankin Scale ≤ 3) for the three treatment groups. Time to treatment data were available for 2994/3026 (99%) of the patients. The proportion of patients who survived at hospital discharge decreased as time to drug administration increased in amiodarone (OR 0.91, 95% CI:0.90–0.93 per min increase in time interval), lidocaine (OR 0.93, 95% CI:0.91-0.96), and placebo (OR 0.91, 95% CI:0.90-0.93) treated patients. With short times to drug administration, survival was not different in lidocaine versus placebo, whereas survival was higher with lidocaine than placebo at later times after drug administration (Fig). The odds of survival at hospital discharge in the lidocaine group (as compared to placebo) changed significantly in relation to the time of drug administration in an adjusted analysis (OR 1.04, 95% CI:1.01-1.09, p=0.048). Comparing amiodarone to placebo, there was improved survival at discharge at all times of drug administration; there was no significant effect of time to drug administration (adjusted OR 1.00, 95% CI:0.95-1.03, p=0.84; unadjusted OR 0.99, 95% CI:0.95-1.03, p=0.67). Survival with good neurological outcome showed the same trends for all analyses. <h3>CONCLUSION</h3> In a post-hoc analysis of the ROC ALPS study, the probability of survival and favourable neurological outcomes decreased with a longer interval from a 911 call to receipt of amiodarone, lidocaine, or placebo. The effect of lidocaine but not amiodarone in increasing the probability of survival at hospital discharge and favourable neurological outcome varied based on the interval from 911 call to receipt of the drug.

Preoperative Single-Dose Intravenous Iron Formulation to Reduce Postsurgical Complications in Patients Undergoing Major Abdominal Surgery: A Randomized Control Trial Feasibility Study (PIRCAS Trial Pilot).

BackgroundPreoperative anemia is associated with an increased need for blood transfusion, complications, and prolonged hospital stay. Iron deficiency anemia (IDA) may be treated with oral or intravenous (IV) iron. IV iron repletes iron stores more rapidly. Its impact on perioperative blood transfusion, postoperative complications, patients’ recovery, and long-term quality of life is unclear. Newer agents, such as ferric carboxymaltose (FCM), are costly but have higher maximum approved doses and a very low incidence of anaphylactic-type reactions. This study aims to explore the feasibility of a randomized control trial to compare the preoperative treatment of IDA with IV FCM versus oral ferrous fumarate, in patients undergoing elective major abdominal surgery.Experimental designThis is an open-label pilot randomized controlled trial. A total of 30 adults with IDA scheduled for elective major abdominal surgery were recruited for the study. They were randomized into two groups to receive either oral iron or IV FCM. Primary outcomes are defined as the time from enrollment to study drug administration, recruitment rate, and follow-up rate up to three months. Secondary outcomes are hemoglobin rise from recruitment to surgery, perioperative blood transfusion, postoperative complications, EQ-5D-3L scores at baseline, and three months and adverse events related to IV FCM therapy.ResultsAll patients received study drugs within five days of enrollment; 30 patients were recruited within four months, 15 patients in each group. Two in each group were withdrawn for surgery postponement. All patients were followed up for three months and there was no crossover of patients. Per protocol, analysis was performed. No severe adverse events related to IV FCM therapy occurred. Both groups had similar baseline characteristics, similar hemoglobin rise from enrollment to the day of surgery [0.2 (+1.6) g/dL in the FCM group and 0.8 (+0.7) g/dL in the Oral Iron group, p=0.3] and similar mean units of perioperative blood transfused (recruitment to discharge) per patient [1.3 (+ 2.1) in the FCM group and 0.9 (+1.3) in the Oral Iron group, p=0.6]. Postoperatively, there was a similar hospital length of stay [11.5 (+13.6 days) in the FCM group and 9.0 (+9.8 days) in the Oral Iron group, p=0.6]; there were similar postoperative complications as reflected by the average Comprehensive Complication Index [12.8 (+19.6) in the FCM group and 22.6 (+30.7) in the Oral Iron group, p=0.3]; similar postoperative health-related quality of life as reflected by mean EQ-5D-3L scores at one month [70.4 (+21.8) in the FCM group and 84.5 (+12.1) in the Oral Iron group] and three months [80.0 (+18.4) in the FCM group and 85.9 (+10.7) in the Oral Iron group].ConclusionsA full-scale randomized controlled trial to evaluate the effectiveness of preoperative IV FCM compared to oral iron in patients with IDA undergoing major abdominal surgery is feasible.

Effect of Immunozin™ therapy on hematological and biochemical parameters of Sickle Cell Disease patients who presented with fatigue, acute bone pain, and acute chest syndrome in Nigeria

Introduction: Painful vaso-occlusive crises are frequent complications of sickle cell disease (SCD), which affects about 3% of the Nigerian population with a high mortality in children. Relevance of hematological and biochemical parameters to clinical symptoms of SCD are not often documented. Aims and Objective: This study aimed at determining the prevalence of fatigue, acute bone pains (ABP) and acute chest syndrome (ACS) and to assess the associating hematological and biochemical parameters before and after administration of ImmunozinTM. Materials and Method: This study was a double-blind, two-arm, randomized control pilot study with 30 SCD patients presenting with fatigue, acute bone pains (ABP) and ACS, each of whom was given the study agent. At the first visit, after thorough assessment of each patient had been undertaken and hematological parameters were measured, the study drug was administered to each patient accordingly. This process was repeated monthly for five more monthly visits when the study concluded. At each visit, venous blood sample was collected for hematological parameters, electrolytes, urea and creatinine analyses within 2 hours of collection. Results: Means (±sd) of age and BMI (Kg/m2 ) of the study subjects were 13.0 (5.6) and 16.1 (1.9) respectively with 26 (86.7%) of the patients underweight. At enrollment into the study, 25 (83.3%), 18 (60.0%) and 10 (33.3%) of the patients presented with ABP, fatigue and ACS respectively but at the end of study, post administration of study drug, 11 (36.7%), 8 (26.7%) and 7 (23.3%) presented with ABP, fatigue and ACS. At enrollment, females were less likely to present with moderate fatigue (χ²=2.03, P-value=0.15, OR=0.23, 95% CI: 0.05, 1.18), moderate ABP (χ²=0.09, P-value=0.77, OR=0.80, 95% CI: 0.18, 3.46) and moderate ACS (χ²=0.01, P-value=0.90, OR=0.40, 95% CI: 0.03, 4.96) compared to males. Only one patient each presented with fatigue and ABP at the end of study. The values of many hematological parameters, electrolytes, urea and creatinine significantly varied at the end of the study compared with enrollment values. A significant positive correlation (Pearson’s r=0.40, P-value=0.031) was observed between serum urea and ACS at enrollment, and astonishingly between fatigue and ABP (r=0.52, P-value=0.003) but no notable correlation between any of the clinical symptoms and other variables at the end of study. Conclusion: The significant reduction in proportion of patients with fatigue, ABP and ACS at the end of study, after administration of test drug may suggest the therapeutic consequence of the test drug among SCD patients. There is urgent need to conduct multi-center and multi-disciplinary studies to corroborate these findings.

Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial

There are an estimated 1·3-4·0 million cases of cholera and 20 000-140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001. Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20-40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3). Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings. Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyo.

MO283IMPACT OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, ON TETANUS- AND DIPHTHERIA-TOXOID VACCINATION-ELICITED IMMUNE RESPONSES IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Abstract Background and Aims VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of a proliferation-inducing ligand (APRIL), is in clinical development as a potential treatment for immunoglobulin A (IgA) nephropathy (IgAN). In a Phase 1 study, VIS649 was associated with dose-dependent reductions in serum IgA, IgG and IgM, which were reversible and showed a dose-response effect with respect to time-to-recovery. The aim of the present analysis was to determine if VIS649 suppression of APRIL influences antibody responses to tetanus and diphtheria toxoid vaccination. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). In one cohort within the study, participants were randomized in a 2:1 ratio to receive intravenous administration of VIS649 6.0 mg/kg or placebo, followed by a vaccine composed of tetanus and diphtheria toxoids (TENIVAC®, Sanofi Pasteur Limited), in order to evaluate the effect of VIS649 on recipients’ ability to generate a vaccine booster response (exploratory endpoint). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, received a single intramuscular dose of vaccine at the Week 4 visit, and were followed for 16 weeks in total on an outpatient basis. Blood samples were taken at regular intervals, and anti-tetanus toxoid and anti-diphtheria toxoid IgG, IgM and IgA quantitative ELISA assays were performed. Tetanus and diphtheria anti-toxoid IgG titers ≥0.1 IU/mL are generally considered to be protective. Results In the vaccination cohort, 15 participants were randomized and dosed with study drug or placebo, of whom 14 completed the study, and one participant who received VIS649 was lost to follow-up prior to receiving the vaccine. Both groups (placebo and VIS649) demonstrated increased tetanus anti-toxoid IgG titers following immunization, with a mean 7.9-fold increase in IU/mL at Week 6 for placebo recipients and a mean 6.4-fold increase in IU/mL for VIS649 recipients (Figure). At visits after Week 6, tetanus anti-toxoid IgG titers declined faster in the VIS649 group than in the placebo group (consistent with the reduction in total IgG associated with VIS649 administration) but remained above the protective threshold of 0.1 IU/mL for all participants throughout the study. Similar trends were observed for diphtheria anti-toxoid IgG titers, with a mean 5.5-fold increase in IU/mL at the Week 6 visit for placebo recipients and a mean 5.1-fold increase for VIS649 recipients (Figure). There was no evidence of tetanus- or diphtheria-toxoid elicited IgM responses in either the placebo or VIS649 groups, consistent with the recall nature of the vaccination. In a post hoc analysis, pre-existing serum tetanus/diphtheria anti-toxoid IgA titers fell between Day 1 and Week 4 in the VIS649 group, consistent with the overall suppression of total serum IgA, were boosted after vaccination in both groups, and declined faster in the VIS649 recipients thereafter. Conclusion VIS649 treatment did not interfere with participants’ ability to mount an antigen-specific serum IgG or IgA boost response to tetanus and diphtheria toxoid vaccination. There was no evidence of tetanus- or diphtheria-specific IgM responses in either the placebo or VIS649 groups, consistent with recall vaccination exposure. These data indicate that qualitative antibody responses are preserved during APRIL suppression.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

P358 An observational, prospective cohort study to evaluate the long term safety and effectiveness of intravenous CT-P13 (biosimilar of infliximab) in patients with Crohn’s Disease or Ulcerative Colitis

Abstract Background CT-P13 is the world’s first approved biosimilar infliximab for all indications of the reference infliximab. The purpose of this study was to assess long term safety and effectiveness of CT-P13 intravenous (IV) in patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC). We now present the result of safety and effectiveness of CT-P13 in patient with CD, UC for up to 5 years from this longitudinal, observational, prospective cohort Phase IV study. Methods The study was conducted from 17 April 2014 to 28 February 2020 in 22 and 21 study centres, in Korea and European Union, respectively. Patients were administered 5 mg/kg of CT-P13 by IV at weeks 0, 2 and 6 and every 8 weeks thereafter. The primary objective was to evaluate adverse events of special interest (AESI) including HBV reactivation, congestive heart failure, opportunistic infections, serious infection including sepsis, tuberculosis, serum sickness (delayed hypersensitivity reactions), hematologic reactions, systemic lupus erythematosus/lupus like syndrome, demyelinating disorders, lymphoma, hepatobiliary events, hepatosplenic T cell lymphoma (HSTCL), intestinal or perianal abscess (in CD), serious infusion reactions during a re-induction regimen following disease flare, sarcoidosis/sarcoid-like reactions, paediatric malignancy, leukaemia, malignancy, colon carcinoma, dysplasia (in UC), skin cancer, pregnancy exposure and bowel stenosis, stricture and obstruction (in CD). Results A total of 470 patients with inflammatory bowel disease (IBD) were analysed. Overall 352 (74.9%) patients have been continuously treated for more than 1 year and the mean duration of drug exposure was 26.3 months. The safety profile of CT-P13 and switching from the reference infliximab to CT-P13 was well-tolerated. A total of 329 (70.0%) patients experienced at least one treatment-emergent adverse event (TEAE). Adverse events of special interest of CT-P13 were analysed by safety analysis set (Table 1). Immunogenicity testing was optional and 72 (15.3%) patients had at least one ADA positive after first infusion of study drug. The incidence of TEAEs in ADA positive subset (83.3%) were slightly higher compared to the incidence of TEAEs in ADA negative subset (76.6%). The effectiveness results of clinical remission for each indication was generally well maintained after the study drug administration (Table 2). Conclusion The results show that CT-P13 was well-tolerated and efficacious in IBD patients. There was no new safety and effectiveness findings in patients who have been exposed to CT-P13 or patients who have switched treatment from the reference infliximab to CT-P13.

Exploratory circulating biomarker analyses: lenvatinib + pembrolizumab (L + P) in a phase 1b trial in unresectable hepatocellular carcinoma (uHCC).

4084 Background: In a phase 1b trial (NCT03006926), L + P had promising antitumor activity as first-line (1L) therapy in uHCC. We present exploratory biomarker analyses of circulating angiogenic factors and cytokines/chemokines related to the mechanism of action of L + P (ie, pharmacodynamic [PD] biomarkers), as well as biomarker correlations with clinical outcomes in patients (pts) with uHCC, from this trial. Methods: Pts received lenvatinib 12 mg/d (bodyweight [BW] &gt;60 kg) or 8 mg/d (BW &lt; 60 kg) PO + pembrolizumab 200 mg IV Q3W. Tumors were assessed using mRECIST or RECIST v1.1 per independent imaging review. Peripheral blood samples were collected before administration of study drug at baseline, cycle (C) 2, day (D) 1, C3D1, C4D1, and off-treatment. 43 Biomarkers were assayed in serum from 100 1L uHCC pts (excluding 4 pts from the dose-limiting toxicity part of the trial with prior sorafenib). Of these 43, 31 biomarkers (for which ≤20% of samples had measurements above/below the quantification limit of the assay) were included in the analyses. Changes in biomarker levels from baseline were evaluated via 1-sample Wilcoxon signed-rank test. Associations were explored between changes in biomarker levels and maximum tumor shrinkage (MTS) via the Spearman’s rank correlation test, objective response (OR; complete response + partial response) via the Wilcoxon rank sum test, and PFS via Cox regression analysis and log rank test. Data cutoff date for clinical endpoints was 7 August 2020. Results: Levels of PD biomarkers related to angiogenic signaling (VEGF increase/ANG2 decrease), FGF signaling (increase in FGF23/FGF19), and IFNγ signaling (increase in IFNγ, CXCL9/10/11) were changed significantly (adjusted P&lt; 0.05) with L + P (C2D1–C4D1; except for FGF19 at C3D1). Significant decreases of TIMP1 and increases of MCP1 were observed at C4D1 during treatment; these were associated with greater MTS. Greater decreases in TIMP1 and greater increases in MCP1 were observed in pts with OR vs others. Changes in levels of the PD biomarkers ANG2, IL10, and VEGFR2 were found to be associated with PFS by dichotomized analysis. With tertile 2 cutoff, median PFS for pts in the group with greater decreases of ANG2 was 13.9 months vs 9.6 months for pts in the group with lesser decreases of ANG2 (unadjusted P= 0.002; HR 2.65, 95% CI 1.39–5.08). Conclusions: These are the first exploratory biomarker analyses for the single-arm study of L + P in pts with uHCC. Changes in serum biomarkers associated with angiogenic-, FGF-, and IFNγ-signaling pathways indicated target engagement of L + P. Decreases in TIMP1 and increases in MCP1 were associated with MTS and OR. Associations were found between longer PFS and a greater decrease in levels of ANG2. Angiogenesis inhibition and modulation of cancer immune response were observed with L + P. Further validation from independent studies is warranted. Clinical trial information: NCT03006926.

Effect of Intravenous Acetaminophen on Mean Arterial Blood Pressure: A Post Hoc Analysis of the EFfect of Intravenous ACetaminophen on PosToperative HypOxemia After Abdominal SurgeRy Trial.

Acetaminophen is commonly used as part of multimodal analgesia for acute pain. The intravenous formulation offers a more predictable bioavailability compared to oral and rectal acetaminophen. There have been reports of hypotension with intravenous acetaminophen attributable to centrally mediated and vasodilatory effects. We tested the hypothesis that in adults having abdominal surgery the use of intravenous acetaminophen versus placebo for postoperative pain management is associated with a decrease in mean arterial pressure (MAP) after its administration. This is a substudy of eFfect of intravenous ACetaminophen on posToperative hypOxemia after abdominal surgeRy (FACTOR) trial (NCT02156154). FACTOR trial randomly assigned adults undergoing abdominal surgery to either 1 g of acetaminophen or placebo every 6 hours during the first postoperative 48 hours. Continuous monitoring of blood pressure was obtained by noninvasive ViSi Mobile device (Sotera Wireless, Inc, San Diego, CA) at 15-second intervals during initial 48 hours postoperatively. We excluded patients without continuous monitoring data available. The primary outcome was the MAP difference between MAP 5 minutes before study drug administration (baseline) and MAP 30 minutes poststudy drug administration initiation. We used a linear mixed effects model to assess the treatment effect on MAP change. The secondary outcome was MAP area under baseline (AUB) during the 30 minutes after treatment. In a sensitivity analysis of change in MAP from predrug to postdrug administration, we instead used postdrug MAP as the outcome adjusting for the baseline MAP in the model. Among 358 patients analyzed, 182 received acetaminophen and 176 placebo. The mean (standard deviation [SD]) of average MAP change was -0.75 (5.9) mm Hg for the treatment and 0.32 (6.3) mm Hg for the placebo. Acetaminophen was found to decrease the MAP from baseline more than placebo after drug administration. The estimated difference in mean change of MAP was -1.03 (95% confidence interval [CI] -1.60 to -0.47) mm Hg; P < .001. The sensitivity analysis showed postoperative MAP in the acetaminophen group was 1.33 (95% CI, 0.76-1.90) mm Hg lower than in the placebo group (P < .001). The median of MAP AUB was 33 [Q1 = 3.3, Q3 = 109] mm Hg × minutes for the treatment and 23 [1.6, 79] mm Hg × minutes for the placebo. Acetaminophen was found to increase the AUB with an estimated median difference of 15 (95% CI, 5-25) mm Hg × minutes (P = .003). Intravenous acetaminophen decreases MAP after its administration. However, this decrease does not appear to be clinically meaningful. Clinicians should not refrain to use intravenous acetaminophen for acute pain management because of worries of hypotension.

Efficacy and safety of single-dose DFN-15 for treatment of acute postsurgical dental pain: a randomized, double-blind, placebo-controlled study.

The analgesic efficacy and safety of DFN-15, a new oral liquid formulation of celecoxib with more rapid absorption than the capsule, were evaluated in the treatment of acute pain in adult patients after dental surgery. In this randomized, double-blind, placebo-controlled, dose-ranging study, 120 otherwise healthy adults who underwent the extraction of bilateral impacted mandibular third molar teeth and experienced moderate to severe pain postsurgery were randomly assigned, in a 1:1:1:1 ratio, to receive one dose of either placebo or DFN-15 at 3 doses: 62.5, 125, and 250 mg. Participants were evaluated at prespecified time points over 8 hours after study drug administration, using several instruments, including the 11-point Numerical Pain Rating Scale, 5-point Pain Relief Scale, and 5-point Treatment Satisfaction Scale. Rescue analgesic (oxycodone / acetaminophen) was permitted. The primary endpoint was the summed pain intensity difference (SPID) over the 6-hour postdose period (SPID6), which was compared between each DFN-15 dose and placebo using analysis of covariance. Other assessments of pain relief, use of rescue medication, and safety were also analyzed. All 3 doses of DFN-15 were significantly superior to placebo in SPID6 (least square mean difference over placebo: -756.6, -1120.7, and -1355.1, P < 0.0001 for all comparisons). In addition, DFN-15 was generally superior to placebo in other endpoints, including reduction of pain intensity, speed and magnitude of pain relief, treatment satisfaction, and rescue medication use. DFN-15 was similar to placebo in the incidence of adverse events with no apparent dose-related effects.

РЕЗУЛЬТАТЫ ОТКРЫТОГО МНОГОЦЕНТРОВОГО ПРОСПЕКТИВНОГО КЛИНИЧЕСКОГО ИССЛЕДОВАНИЯ ЭФФЕКТИВНОСТИ, БЕЗОПАСНОСТИ И ФАРМАКОКИНЕТИКИ МОРОКТОКОГА АЛЬФА У ДЕТЕЙ В ВОЗРАСТЕ ОТ 6 ДО 12 ЛЕТ С ГЕМОФИЛИЕЙ A

Currently, the main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). As a result of the development of new production technologies, recombinant FVIII are increasingly used for the treatment of hemophilia A. The justification for the use of new drugs in pediatric clinical practice requires careful preparation and clinical research studies of their efficacy and safety. The aim of this study was to evaluate the efficacy, safety and pharmacokinetics (PK) of domestic B-domain deleted recombinant factor VIII of Moroctocog alpha (Octofactor, GENERIUM JSC) in a cohort of children with hemophilia A aged 6 to 12 years in the framework of phase III clinical study of moroktocoga alpha in children 2 to 12 years old with hemophilia A. Materials and methods of the research: the age cohort of 6 to 12 years olds of an open multicenter prospective noncomparative study included 27 male children with severe hemophilia A (mean age 8,3±1,9 years). The study was carried out sequentially in 2 stages. Stage I included the study of PK parameters in 22 patients after a single study drug dose of 50 IU/kg. At stage II, the efficacy and safety of the drug was assessed in patients of stage I, as well as in additionally included 5 patients who received the study drug dose of 30±10 IU/kg per day every 2–3 days for 22±1 weeks of treatment. To assess the efficacy, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the number of injections and the dose of FVIII used for prophylaxis, as well as for treatment on demand of one episode of bleeding, taking into account its severity; number of patients with severe hemophilia A with residual FVIII activity &gt;/=1% 48–72 h after drug administration; the investigator's overall assessment of response to therapy on the acute hemarthrosis response scale. The main indicators for the analysis of PK properties were the area under the «concentration-time» curve, the half-life, the elimination constant, the increase in activity, and the degree of recovery of activity. To assess safety, the frequency of formation of an inhibitor to FVIII, the dynamics of vital and laboratory parameters, the frequency and characteristics of adverse events (AEs) associated with the administration of the drug were taken into account. Results: the area under the FVIII-time activity curve in the region of 0–48 h (AUC0-48) and with exponential extrapolation to infinity (AUC0-inf) was 731,82±264,94%*h and 756,11±270,16%*h, respectively. The half-life (T1/2) was 10,32±2,27 hours. In the examined age group, 78 bleeding were recorded, of which only 27 (35%) were spontaneous, including 24 (30%) episodes that occurred during 48–72 hours after the administration of drug under investigation. Haemorrhage within 48–72 hours after administration of the Octofactor drug was absent or was observed rarely (1–3 times) against the background of prophylactic treatment in most patients (88%), the median number of bleeding within 48–72 hours after administration of the study drug was 2 episodes per observation period. The proportion of spontaneous bleeding was the smallest in patients receiving a single prophylactic doses of the study drug 2000–3000 IU (7% of all bleeding), the largest proportion of spontaneous bleeding was observed in patients receiving a single prophylactic doses of the study drug 1000–2000 IU (70% of bleeding). The average single dose of Octofactor for preventive treatment was 1290,4±458,6 IU or 39,12±7,79 IU/kg, for on-demand treatment – 1641,7±722,4 IU per single injection. Of the 78 reported bleeding episodes, 68 (87%) required the study drug administration for relief, while the remaining 10 bleedings were selfcontained. On average, to stop bleeding, it took 1,5±0,8 injections of the drug on demand, median doses were 1 [1; 2], and average doses were 2434,3±1501,7 IU. During the study, 37 AEs were recorded in 15 (56%) patients. At the same time, 36 AEs (97%) were not associated with the drug under investigation, and one AE (allergic reaction), according to the researchers, was associated with the use of the drug. Thus, the analysis of data indicates the efficacy and safety of the Octofactor drug both the prophylactic treatment and treatment of on-demand bleeding in 6 to 12 year old patients with severe hemophilia A.

ANalgesic Efficacy and safety of MOrphiNe versus methoxyflurane in patients with acute myocardial infarction: the rationale and design of the ANEMON-SIRIO 3 study: a multicentre, open-label, phase II, randomised clinical trial

IntroductionThe unfavourable influence of morphine on the pharmacokinetics of ticagrelor resulting in weaker and retarded antiplatelet effect in patients with acute coronary syndrome (ACS) has been previously shown. Replacing morphine...