All Adverse Events Research Articles

P09.54 Pneumonitis Following Durvalumab: A Real-World Analysis in Patients with Lung Cancer and Other Tumor Types

Durvalumab, a PDL-1 inhibitor is the standard of care as consolidation therapy after chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC) in the United States (US). Immune-mediated pneumonitis occurs with all checkpoint inhibitors, however patients with lung cancer may be particularly susceptible. In the PACIFIC trial supporting approval of durvalumab for this indication, any pneumonitis was reported in 34% of durvalumab-treated patients vs. 24% of placebo-treated patients. Pneumonitis represented 34% of all adverse events (AEs) in the study and led to treatment discontinuation in 6% durvalumab-treated patients (Antonia et al, NEJM 2018). Durvalumab is also approved in the US for recurrent urothelial cancer, but only 1% of patients experienced pneumonitis in the supporting trial. We conducted an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate post-marketing cases of pneumonitis reported in patients treated with durvalumab for NSCLC vs. other tumor types. The FAERS database, which contains anonymized reports of product-related AEs classified using the Medical Dictionary for Regulatory Activities and categorized as serious or non-serious, was queried for cases of pneumonitis in patients treated with durvalumab for oncology indications from the Food and Drugs Administration (FDA) approval date (May 1, 2017) through June 30, 2020. Cases occurring outside the US and cases for which the indication was not specified were excluded. The indication for use, reported demographics and AE outcomes were collected. The association of pneumonitis with indication and AE seriousness was evaluated by Chi-square test, using a two-sided α=0.05 to determine statistical significance. Median age in each subgroup was compared using the Mann-Whitney U test. Of the 733 durvalumab-associated AE cases retrieved, (532 [73%] for NSCLC, 201 [27%] for other tumor types), a total of 130 reports of any pneumonitis were identified. Pneumonitis accounted for 122 of 532 (23%) of all AEs reported in NSCLC vs. 8 of 201 (4%) in other tumor types (p<0.01). A greater proportion of pneumonitis cases were categorized as serious compared to non-pneumonitis cases (125 of 130 [96%] vs. 421 of 603 [70%], p<0.01). There was no difference between pneumonitis and non-pneumonitis cases in reported deaths (25 of 130 [19%] vs. 101 of 603 [17%]) or hospitalizations (57 of 130 [44%] vs. 242 of 603 [40%]). The median age of patients in pneumonitis cases was older than patients in non-pneumonitis cases (71 vs. 66 years, p<0.01). The proportion of durvalumab-associated AE cases reporting pneumonitis was greater for NSCLC vs. other tumor types and increased with age but was not associated with higher deaths or hospitalizations. Pneumonitis constituted a lesser proportion of total AEs in this real-world cohort compared to the PACIFIC trial. Limitations of this retrospective analysis include the potential for under-reporting of AEs to the FAERS database, the inability to establish causality, and the lack of a true denominator. Despite the limitations, these AE findings from a real-world dataset complement clinical trial safety data and support further investigation of interaction of chemoradiotherapy with checkpoint inhibitors in the pathogenesis of pneumonitis.

Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer

ABSTRACT Intravesical BCG is active against non-muscle invasive bladder cancer (NMIBC), but bladder cancer will recur and even progress in a significant number of patients. To improve the response rate, N-803, an IL-15 superagonist was administered in combination with BCG. To evaluate the safety and efficacy associated with the use of intravesical N-803 and BCG in patients with BCG-naïve NMIBC. This phase 1b clinical trial used a 3 + 3 dose-escalation design. Participants were enrolled from July 2014 and July 2015, with follow-up and analyses through January 15, 2021. Eligibility criteria included histologically confirmed non-muscle invasive urothelial carcinoma of intermediate or high risk who had not received prior treatment with intravesical BCG (ie, BCG-naïve). All 9 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Treatment was done once weekly for 6 consecutive weeks with bladder infusion of the standard dose of BCG, 50 mg/instillation, in combination with increasing doses of N-803 (100, 200, or 400 µg N-803 per instillation). No DLTs were noted in any of the dose cohorts. All adverse events (AEs) were manageable and less than grade 3. During the 2-year follow-up, all 9 participants were disease free. Furthermore, 6 y after treatment, all 9 participants (100%) were disease free with no evidence of disease progression and an intact bladder. This phase 1b trial found the combination of intravesical N-803 and BCG to be associated with modest toxic effects, low immunogenicity, and substantial prolonged antitumoral activity; phase 2 trials are in progress.

Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged &amp;gt;18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (&amp;gt;12-&amp;lt;18 years) and in two groups of pediatric patients (&amp;lt;6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

Fiirst-2: Prospective, Randomized Study Comparing Administration of Clotting Factor Concentrates with Standard Massive Hemorrhage Protocol in Severely Bleeding Trauma Patients

Introduction: Acute trauma coagulopathy (ATC) is associated with severe hemorrhage. ATC etiology is often multifactorial, with acquired fibrinogen deficiency and consumption of clotting factors recognized as major factors. The FiiRST-2 study will determine the impact of early co-administration of fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) on the total number of allogeneic blood products (ABPs) transfused compared to the current standard of care (ratio-based plasma resuscitation). Methods: FiiRST-2 is a multicenter (8 Canadian centers), pragmatic, randomized, parallel-control, superiority trial with a two-armed, two-stage design with an adaptive interim analysis. Research ethics board approval has been obtained and the study complies with the Declaration of Helsinki. Trauma patients &amp;gt;16 years old at risk of massive hemorrhage will be randomized to receive FC + PCC or standard of care (ratio-based plasma resuscitation + FC in response to low fibrinogen levels) (Table 1) until all units in the second massive hemorrhage protocol (MHP) pack have been administered, or earlier if the MHP is terminated. The primary endpoint is to demonstrate superiority with respect to the number of ABP units (RBCs [red blood cells] + plasma + platelets) transfused within 24 hours of arrival at the trauma bay/emergency department. Secondary endpoints include RBC units transfused within 24 hours, incidence of thromboembolic events, and ventilator-free days up to Day 28. Safety endpoints include all adverse events (AEs) and serious adverse events (SAEs) up to Day 28. It is projected to enroll 360 patients depending on the results of the Interim analysis. Results: An interim analysis will be performed after 120 patients have completed the study. The study is expected to start late 2020 and enrollment is expected to require about 2 years. Conclusions: FiiRST-2 will determine if early hemostatic therapy with FC + PCC is superior to standard MHP packs in bleeding trauma patients. Results could have a major impact on clinical practice and improve management and outcomes in this high-risk group of patients. Disclosures Da Luz: Octapharma Canada: Research Funding. Callum:Octapharma: Research Funding; Canadian Blood Services: Research Funding. Schwartz:Octapharma: Current Employment. Karkouti:Canadian blood services: Research Funding; Octapharma: Research Funding. OffLabel Disclosure: PCC and fibrinogen concentrate for acquired coagulopathic bleeding (off-label in the USA)

Safety and Preliminary Efficacy Results from a Phase II Study Evaluating Combined BRAF and MEK Inhibition in Relapsed/Refractory Multiple Myeloma (rrMM) Patients with Activating BRAF V600E Mutations: The GMMG-Birma Trial

Safety and Preliminary Efficacy Results from a Phase II Study Evaluating Combined BRAF and MEK Inhibition in Relapsed/Refractory Multiple Myeloma (rrMM) Patients with Activating BRAF V600E Mutations: The GMMG-Birma Trial

Comparison between Time-Limited,Venetoclax-Based and Continuous Bruton Thyrosine Kinase Inhibitors-Based Therapy in the Upfront Treatment of Chronic Lymphocytic Leukemia (CLL):a Systematic Review and Network Meta-Analysis

Background: Targeted agents (TAs) have shown impressive activity in the upfront treatment of chronic lymphocytic leukemia (CLL). However, TAs have rarely been compared in head-to-head clinical trials. With this background, a systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of TAs approved by the FDA and/or EMA for upfront therapy of CLL (i.e., ibrutinib, acalabrutinib, and venetoclax). Methods: A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted. Eligible studies consisted of randomized controlled trials (RCTs) assessing the efficacy or safety of TAs in previously untreated CLL patients. Outcomes considered were hazard ratios for progression-free survival (PFS), odds ratios for overall response rate (ORR) and adverse event rates. A given treatment was considered more effective than another one when a 95 % upper confidence interval (CI) for relative risk (RR) did not cross the value 1.0 (equivalent to a Bayesian probability for this pairwise comparison p≥97.5%). Results: Among relevant RCTs, 6 met criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions and were selected for analysis. Three studies were excluded because they lacked a common comparator arm (i.e., RESONATE2, ALLIANCE,and ECOG-ACRIN). Three trials were suitable for the base-case network analysis (i.e., ILLUMINATE, ELEVATE-TN, and CLL14). In aggregate, these trials included1336 patients and evaluated the combination of ibrutinib-obinutuzumab (IO) (ILLUMINATE trial;n=113), venetoclax-obinutuzumab (VO) (CLL14 trial;n=216) and acalabrutinib (A) single agent (ELEVATE-TN trial; n=179). Chlorambucil-obinutuzumab (CO) was the control arm across these studies (n=504). Since results of A plus obinutuzumab (AO)(n=179) in the ELEVATE-TN trial were based on a post-hoc analysis they were not included in the NMA. In terms of PFS, fixed-effect analyses comparing VO to IO (RR 1.52[0.82-2.81]), A to IO (RR 0.87 [0.47-1.61]) and A to VO (RR 0.57[0.32-1.03]) revealed that the upper limit of 95% CI for RR did exceed the 1.0 value (Fig 1). This implies a lack of significant difference in PFS for IO, VO, and acalabrutinib. Similarly, no differences with respect to ORR were found in the indirect comparison of different TAs: VO vs. IO (RR 0.98 [0.61-1.59]), A vs. IO (RR 0.90[0.55-1.48]) and A vs. VO (RR 0.92[0.60-1.40]). The analysis of treatment side effects was performed comparing in aggregate all adverse events (AEs). No differences in the frequency of AEs was observed across different TAs: VO vs. IO (RR 1.00 [0.63-1.58]), A vs. IO (RR 1.01[0.62-1.63]) and A vs. VO (RR 1.01[0.68-1.52]). The same applied when the analysis was restricted to events with grade 3-4 toxicity: VO vs. IO (RR 1.05[0.64-1.73]), A vs. IO (RR 0.73[0.43-1.24]) and A vs. VO (RR 0.69[0.44-1.09]). Conclusions: This systematic review and network meta-analysis did not identify significant differences in PFS between BTKi-and time-limited venetoclax-based treatments in CLL upfront therapy. Further trials are needed to ascertain the pros and cons of different targeted treatments. Meanwhile, treatment selection in routine clinical practice should be based on drugs' safety, cost, availability, and treatment objectives. Figure Disclosures Molica: Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Fecal Microbiota Transplant: Is It an Effective Option for Treating Steroid Refractory Acute Graft Versus Host Disease of Gut?

Introduction: One is left with very few options in patients with steroid refractory Gut Graft versus Host Disease (GVHD) which occurs post allogenic stem cell transplant (AlloSCT) with most of them increasing the financial burden, especially in resource poor countries like India and many others. Many studies looking in to the pathogenesis of Gut GVHD have confirmed the hypothesis that patients with less diverse faecal microbiome have a greater chance of developing intestinal GVHD and are more prone to succumb to transplant-related complications. Looking at the mechanism of cure in various diseases of the gut, led us to the thinking that reversal of intestinal dysbiosis could improve Gut GvHD. We used FMT as a second line treatment in few of our patients and got encouraging results. Our findings indicate the safety and effectiveness of FMT in acute Gut GVHD. Patient details: Please see image Materials and methods: Fecal material for FMT was taken from healthy donors who passed screening for transmissible disease. 100 gm of stool was prepared into a 200 ml solution and given once daily, serially for 4 days through naso-jejunal tube over 8 to 10 minutes. All patients received FMT as second line treatment after they were found non-responding or partially responding to steroids. All adverse events (AEs) that were first noted within 1 week of infusion of FMT were evaluated in terms of the safety. Response to FMT was evaluated at 14 days starting from the 1st FMT dose or at the time of maximum response whichever was first. Complete resolution of loose motions and gastrointestinal (GI) symptoms was considered as complete response (CR). Decrease in severity of GVHD by at least one stage was considered as partial response (PR). Results: All four patients include were treated between 2018 to 2020. All of them were diagnosed with GI acute GVHD (Gut ± upper GI) on the basis of clinical, scopy (colonoscopy ± endoscopy) findings and histopathology. Case 2 and Case 4 had liver GVHD simultaneously with Gut GVHD. The median time for initiation of FMT was at 52.5(14-90) days from the day of AlloSCT. Three patients (Case 2,3,4) had GVHD immediately post AlloSCT, while Case 1 had GVHD at day 90. All patients had stool microscopy, culture and a stool BIOFIRE test sent to rule out viral, bacterial and parasitic infections. Clostridium difficile infection was not observed in any of the patients. Three patients (Case 1,2,3) received single course (4 days serially) while case 4 required 2 courses 14 days apart. Case one had sigmoid colon involvement and we also gave him per rectal FMT via a flatus tube which was placed in his sigmoid colon. The procedure was well tolerated by all patients. No side effects related to FMT were suspected or confirmed in any patients. Three patients (Case 1,2,3) achieved CR with complete resolution of loose stools and GI symptoms. The median time to response was 4 days (3-5 days). We were able to reduce the dose and taper off steroids in all four patients. Case 4 showed partial response but again had aggravation of GVHD after each course of FMT. At last follow up, two (case 2 and 3) out of four patients were alive. Case 1 expired 2 months after resolution of GVHD due to anginal attack. Case 3 had a secondary graft failure but is still transfusion independent. Case 4 expired due to sever uncontrolled acute GI GVHD (colonic + upper GI). Conclusion: In summary, FMT can be considered as a potential, relatively safe and well tolerated option for treatment of acute Gut GVHD in AlloSCT patients. Further clinical trials with large number of patients are required to explore FMT as one of the effective options for treatment of acute GVHD. Despite the small number of patients, previous findings and our data corroborate that interventions to maintain intestinal diversity can improve outcomes of AlloSCT. Table Disclosures No relevant conflicts of interest to declare.

Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects.

BackgroundOur study aims to explore the effect of genetics on the pharmacodynamics (PD) and pharmacokinetics (PK) of cinacalcet in healthy Chinese subjects; to investigate the effect of dietary factors on cinacalcet, and to evaluate the safety of cinacalcet under fasting and non-fasting conditions using a bioequivalence trial.MethodsWe investigated the relationship of cinacalcet PK with single nucleotide polymorphisms (SNPs) of CYP3A4, CYP1A2 and CYP2D6, and of cinacalcet PD with SNPs of calcium-sensitive receptors (CASR) and vitamin D receptors (VDR) in 65 healthy Chinese subjects recruited to participate in this study. Our study was a phase I, open-label, randomized, two-period, two-sequence crossover, a single-center clinical study designed under both fasting and non-fasting conditions to investigate the effect of dietary factors on cinacalcet. Plasma cinacalcet concentrations were analyzed using a validated HPLC-MS/MS assay. Clinical laboratory tests evaluated safety. Thirteen SNPs of CASR, VDR, and CYP genes were selected for pharmacogenetic analysis.ResultsCYP3A4 rs4646437 was found to be associated with the PK of cinacalcet under fasting conditions (P<0.01). Subjects carrying T alleles of rs4646437 appeared to metabolize cinacalcet poorly. The Cmax and AUC of subjects in the non-fasting group were significantly higher (P<0.0001) than those in the fasting group. The Tmax, CL/F, and Vd/F in the fasting group were significantly higher (P<0.0001) than those in the non-fasting group. In the fasting group, the geometric least square mean ratios (T/R) of the Cmax and AUC0-t were 109.89% and 105.33%, and the corresponding 90% CIs were 98.36–122.79% and 98.04–113.15%, respectively. In the non-fasting group, the T/R of the Cmax and AUC0-t were 100.74% and 99.09%, and the corresponding 90% CIs were 92.65–109.54% and 94.79–103.58%, respectively. All adverse events (AEs) were mild, and no serious adverse events (SAEs) occurred during the bioequivalence trial.ConclusionsFollowing our investigation, we reached the following conclusions: CYP3A4 rs4646437 may affect cinacalcet PK; the reference and test preparations of cinacalcet were bioequivalent under fasting and non-fasting conditions and were safe to use; and dietary factors had a significant effect on the PK of cinacalcet, in that exposure to the drug increased when cinacalcet was taken after eating.

Patient Reported Experience with Treatment Modalities and Safety of Adjuvant Breast Radiotherapy - First Results of the Randomized HYPOSIB – Study

HYPOSIB is a multicentric randomized study investigating hypofractionated adjuvant radiotherapy with a simultaneous integrated boost (comparable to RTOG 1005). In the control arm, adjuvant radiotherapy could be administered either in conventional fractionation plus boost or as hypofractionated radiotherapy with a sequential boost. In the experimental arm, patients received a total dose of 40Gy to the breast and 48Gy in the boost volume in 16 fractions with integrated boost. Primary endpoint is disease-free survival. Per protocol, a yearly safety report for the data safety monitoring board (DSMB) is prepared. Amendment 6 of the study included a questionnaire for measurement of patient reported outcome and experience with therapy modalities. We report first results with regard to safety and patients´ satisfaction with therapy. There were 2,324 patients were recruited by 88 active study centers in Germany and Austria from June 2015 through January 2019. For the safety report, all adverse events (AE), severe adverse events (SAE) and acute skin toxicity were analyzed. After June 2018, the remaining recruited patients were asked to fulfil a questionnaire by the end of radiotherapy with questions about symptoms and about satisfaction with therapy and quality of care. The median follow-up at the time of the safety report for the year 2019 was 28 months. 3398 AEs including 152 SAEs had been reported. 12.7% SAEs were probably or likely associated with radiation therapy. The incidence of AEs/SAEs was comparable in the control arm (1741 AEs, 80 SAEs) and experimental arm (1657 AEs, 72 SAEs). Skin reactions grade 2+ (grade 2 in nearly all cases, very few grade 3) were reported in weeks 3/ 4/ 5/ 6/ 7 after start of radiotherapy in 5.7%/ 14.6%/ 23.1%/ 23.9%/ 16.5% in patients in the control arm as compared to 12.3%/ 15.8%/ 13.8%/ 13.8%/ 4.8% in the experimental arm. By the end of radiotherapy, patient reported symptoms (on a scale from 1 = no symptoms to 10 = massive symptoms) mainly concerned hot flushes (4.3 + 3.2), breast problems (4.2 + 2.7), skin problems (3.8 + 2,8) and other complaints (6.3 + 2.8). Radiotherapy was experienced less exhausting (4.3 + 2.4) than other therapy modalities (6.2 + 2.1). Patients felt well informed about radiotherapy and other modalities. Care during therapy was rated very good for all treatment modalities with the top rating for radiotherapy (9.5 + 1.2). The preliminary safety data of the HYPOSIB-trial prove the safety of adjuvant breast radiotherapy in this nationwide study. Acute skin reactions were less pronounced and occurred two weeks earlier in the HYPOSIB-arm than in the control arm. Patients should be informed that hypofractionated irradiation is already finished before the peak skin reaction occurs. Satisfaction of patients with therapy was generally high, especially with radiotherapy. Patient-reported symptom burden by the end radiotherapy may help to better tailor individual treatment.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

A Prospective, Multi‐Center, Clinical Trial of a 10‐kHz Spinal Cord Stimulation System in the Treatment of Chronic Pelvic Pain

BackgroundChronic pelvic pain (CPP) is a debilitating condition that often leads to disability and does not respond to conventional treatments. This study was conducted to evaluate the effects of paresthesia‐independent 10‐kHz spinal cord stimulation (SCS) in subjects with CPP.MethodsThis prospective, single‐arm pilot study enrolled subjects with clinical diagnoses of CPP and mean pain scores of ≥ 5.0 cm on a 10‐cm VAS. Subjects underwent trial stimulations with 10‐kHz SCS, and those who had successful trial stimulations (≥40% pain relief) received permanently implanted devices and were followed for 12 months.ResultsOf the 21 subjects who underwent the 10‐kHz SCS trial, 17 were successful and 14 subjects received permanent implants. No neurological deficits were observed in any subjects and all adverse events (AEs) were resolved without sequelae during the study period. Over 12 months, mean VAS scores decreased by 72% from baseline, and 10 of 13 subjects (77%) were responders (≥50% pain relief). Pain remission (VAS score ≤ 3.0 cm) was reported by 8 of 13 subjects (62%), and mean pain scores on the short‐form McGill Pain Questionnaire 2 decreased as well. Pain Disability Index scores declined by 29 points, and 85% of the subjects reported satisfaction.ConclusionsParesthesia‐independent stimulation with 10‐kHz SCS reduced pelvic pain in subjects with CPP and was not associated with any unexpected AEs. While larger, controlled studies are needed, results of this study suggest that this therapeutic modality could potentially treat patients with CPP while improving their quality of life.

The complication rate of intravascular ultrasound (IVUS) in a multicenter pediatric heart transplant population: A study of the international pediatric IVUS consortium.

Our purpose was to determine the complication rate from intravascular ultrasound (IVUS) in a large, multicenter cohort of pediatric heart transplant (PHT) patients. We retrospectively reviewed all PHT who underwent IVUS at 5 institutions (2006-2014). Rates of major and minor complications were calculated. All adverse events (AE) were graded from 1 to 5 using a previously published AE severity scale. There were 1380 catheterizations in 505 patients and 32 AE (2.3%); 9 major (0.6%) and 23 AE (1.7%). The major AE attributed to IVUS were all coronary artery vasospasm (7). Major and minor AE rates directly related to IVUS were 0.5% and 0.7%, respectively. Minor AE possibly attributable to IVUS included excessive fluoroscopy (3) and transient ST segment changes (7). Of AE related to IVUS, only 3 were of moderate severity. The rest were≤minor in severity. There were no reports of coronary artery dissection or death. Most AE during routine PHT coronary evaluation with IVUS were minor and not directly related to the use of IVUS. The number of coronary related AE was similar to a registry-based report of coronary angiography alone. Efforts to minimize IVUS-related complications should be focused on preventing coronary artery vasospasm.

Image-guided core biopsy of 2-cm or smaller renal tumors

PurposeThe purpose of this study was to retrospectively evaluate diagnostic yield, risk factors for diagnostic failure, and safety of image-guided core biopsy of renal tumors≤2cm. Materials and methodsEighty-four biopsies of 84 renal tumors (mean size, 1.5±0.4[SD] cm; range, 0.6–2.0cm) from 84 patients (53 men, 31 women; mean age, 61.7±12.7 [SD] years; age range, 34–87 years) were included. All adverse events (AEs) were evaluated based on the CIRSE classification. The 84 procedures were classified as diagnostic or nondiagnostic. Multiple variables related to the patients, tumors, and procedures were assessed to identify variables associated with diagnostic failure. ResultsAll 84 biopsies (100%) were technically successful, defined as penetration of the target and acquisition of some specimens. Eighty (80/84; 95.2%) biopsy procedures were diagnostic and four (4/84; 4.8%) procedures were nondiagnostic. Among 80 diagnosed renal tumors, 71/80 (88.8%) tumors were malignant (49 clear cell renal cell carcinomas [RCCs], 14 papillary RCCs, 3 chromophobe RCCs, 3 metastatic renal cancers, 1 lymphoma, and 1 unclassified RCC) and 9/80 (11.2%) lesions were benign (5 angiomyolipomas, 3 oncocytomas, and 1 inflammatory lesion). No significant differences existed in any variables between the two groups. A total of 57 (57/84; 67.9%) procedures resulted in 56 Grade 1, 2 Grade 2, and 1 Grade 3 AEs. ConclusionImage-guided biopsy of renal tumors≤2cm is safe and has a high diagnostic yield.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial

BackgroundIschemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke.MethodsPatients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram.ResultsIn total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups.ConclusionsThe results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported.Trial registrationChinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827. Retrospectively registered June 13, 2019.

543-P: A Randomised Control Trial to Evaluate the Efficacy of Chinese Traditional Medicine for the Treatment of Diabetic Peripheral Neuropathy

Background: Diabetic peripheral neuropathy (DPN) is a common complication in patients (pts) with diabetes. However, multinational data do not support any convincing efficacy of the current therapies for treating DPN. This necessitated the evaluation of safety and efficacy of alternative medicine to tackle DPN. Methods: A double-blinded RCT was conducted in 8 Chinese medicine hospitals in China, evaluating the safety and efficacy of 190 g Tangbi Waixi decoction (TW, intervention (Int)) compared with 19 g TW (control (Cont)). Change in Toronto Clinical Scoring System - Total Score (TCSS-TS) at 12 and 24 weeks follow-up was the primary outcome, with treatment ceasing at 12 weeks. Secondary outcomes included change in bilateral motor velocity (BMV) and sensory nerve conduction velocity (SNCV) of the common peroneal nerve (CPN). All pts received standard care for glycaemic management. The pts in the Int (n=317) and Cont (n=315) groups were analysed on ITT principle. All adverse events (AEs) were recorded. Results: The pts were mean 60 years old with median 10 yrs and 2 yrs of diabetes and DPN duration respectively at randomisation. With median TCSS-TS of 10 at randomisation in both groups, the median (95% CI) reduction in Int and Cont: at 12 weeks 2 (1.7, 2.3) and 3 (2.7, 3.3) respectively (median between group difference (MBGD): 1.0, p=0.011); at 24 weeks 3 (2.6, 3.4) in both groups. At 12 weeks, median (95% CI) CPN velocity increased in both Int and Cont - BMV Int vs. Cont: 2.7 (1.9, 4.9) m/s vs. 4.9 (2.7, 5.5) m/s, MBGD - 2.5 m/s (p=0.044); SNCV Int vs. Cont: 1.4 (0, 2) m/s vs. 2.7 (1.9, 4.9) m/s, MBGD - 0.7 m/s (p=0.26). Similar increase in CPN velocity was observed at 24 weeks in both groups. Overall 12% pts experienced at least one AE, with no difference between groups. Conclusion: Treatment of DPN with TW decoction significantly benefitted the pts and is safe, while lower dose of TW appears to be more effective than the higher does. Disclosure F. Guanjie: None. Y. Lin: None. S.K. Paul: Advisory Panel; Self; Sanofi. Research Support; Self; AstraZeneca, Genentech, Inc. H. Huang: None. T. Xianyu: None. Z. Yuehong: None. F. Zhaohui: None. Q. Xiaotang: None. D. Fang: None. S. Wang: None. M. Wang: None. H. Wei: None. Z. Ling: None. L. Zhenjie: None. Y. Fu: None. M. Wu: None. L. Anxiang: None. H. Jinzhu: None. Q. Li: None. Funding National Science and Technology Support Program (2015BAI04B09)

Efficacy, immunogenicity and safety of a trivalent live human-lamb reassortant rotavirus vaccine (LLR3) in healthy Chinese infants: A randomized, double-blind, placebo-controlled trial

BackgroundA randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy, immunogenicity and safety of a novel trivalent live human-lamb reassortant rotavirus vaccine (LLR3) against rotavirus gastroenteritis (RVGE). MethodsHealthy children aged 6–13 weeks were enrolled and randomized (1:1) to either 3 oral doses of LLR3 or placebo according to a 0, 1, 2 month schedule. The objectives were to evaluate vaccine efficacy (VE) against RVGE of any-severity, severe RVGE (sRVGE) and inpatient caused by rotavirus serotypes contained in the vaccine and not contained in the vaccine after the third dose. Immunogenicity was also assayed in a subgroup. All adverse events (AEs) were collected from 30 min after each dose for immediate reaction, even to the entire study period, including the serious AEs (SAEs) and intussusception. ResultsVE against RVGE of any-severity, sRVGE and inpatient caused by any serotype was 56.6% (95% CI: 50.7, 61.8), 70.3% (95% CI: 60.6, 77.6) and 74.0% (95% CI: 57.5, 84.1) respectively. VE against RVGE of any-severity, sRVGE caused by serotypes not contained in vaccine were 54.2% (95% CI: 47.5, 60.1) and 70.4% (95% CI: 60.4, 77.9). The rate of seroconversion and four-fold increase of rotavirus serotype G2-, G3-, and G4-specific IgA is 60.8%, 58.0%, and 60.6% in vaccine group, which was higher than 21.35%, 22.7%, and 23.1% in placebo group (p < 0.0001 for G2, G3, G4), as well as the Geometric Mean Titer (GMT). Through the entire trial, 65.91% and 67.79% of participants reported at least one AE, and 0.02% and 0.02% reported SAEs in the vaccine and placebo groups, respectively. Two intussusception cases were reported both in vaccine and placebo group. ConclusionsIn Chinese infants, LLR3 provided a substantial protection against RVGE of any-severity, sRVGE and inpatient caused by any serotype, and showed well immunogenicity and safety.

Short-Term Evaluation of the Real-World Efficacy and Safety of Dupilumab for the Treatment of Moderate-to-Severe Atopic Dermatitis: A Canadian Multicenter Retrospective Cohort Study [Formula: see text

Systemic therapy for atopic dermatitis (AD) has been challenging with limited safe and efficacious long-term treatment options. In 2017, dupilumab was approved in the United States, Europe, and Canada as the first targeted therapy for patients with moderate-to-severe AD. Despite promising efficacy and safety results in clinical trials, our understanding of dupilumab in clinical practice remains limited with few studies outside clinical trials in literature. The aim of this study is to evaluate the efficacy and safety of dupilumab in clinical practice and discuss any differences in results between clinical trials and real-world results. A retrospective chart review was conducted of consecutive patients receiving dupilumab treatment at two tertiary hospitals in Toronto, Canada, between December 2017 and May 2019. The primary efficacy endpoint was measured by Investigator's Global Assessment (IGA) score of 0/1 at 16 weeks and all adverse events (AEs) experienced by patients were recorded. Of the 93 patients included in the study, 51 (55%) reached IGA 0/1 and 38 (41%) experienced ≥1 AE. There were no severe AEs or discontinuation prior to 16 weeks due to an AE. These findings suggest a higher IGA-based efficacy profile with no newly identified safety concerns in patients treated with dupilumab at two tertiary hospitals in Toronto, Canada, compared to those in randomized controlled trials.

95 Early Clinical Experience with an Autologous Homologous Skin Construct to Treat Deep Partial-thickness and Full-thickness Burns

Abstract Introduction Split-thickness skin grafting (STSG) is the standard of care for treating deep burns. They often contract, have limited cosmesis, lack dermal appendages, and result in painful, conspicuous donor sites. An Autologous Homologous Skin Construct (AHSC) has been shown to result in full-thickness skin formation.1,2 This study examined the safety profile, graft take, and quality of healing of a pilot group of AHSC-treated burn wounds. Methods Following IRB approval and informed consent, patients with deep-partial/full-thickness burns requiring grafting underwent side-by-side treatment with AHSC and STSG. A 2cm2 full-thickness harvest was processed into AHSC at an FDA-registered facility, returned within 48 hours, and applied to a 4cm2 area alongside a STSG. AHSC donor site was closed primarily. Wounds were evaluated for healing with digital photography and investigator assessments for 90 days. All adverse events (AEs) were recorded. Results Eight patients with 12% TBSA [range 2–40%] burn wounds were treated; 5 Caucasian and 3 African American with an average BMI of 26.8. Injury was due to predominantly flame burn, with additional injury from grease, scald, contact, friction, and flash. Mean time between injury and AHSC treatment was 11 days [range 5–35 days]. All patients had graft take and complete epithelialization by the end of the study. Patients required one application of AHSC and no other additional surgical procedures at the application sites. The most common AEs for STSG-treated wounds included hypertrophic scarring, pruritus, and insomnia. One non-infected AHSC harvest site experienced a mechanical dehiscence. There were no other AEs related to AHSC treatment. Conclusions No related adverse events at the treatment sites were noted in this study. However, the size of the treatment area limited the ability to comment on the presence of complex dermal elements including hair follicles. Additional investigation with application to larger areas is warranted to evaluate the utility of AHSC for the treatment of acute burn wounds. Applicability of Research to Practice Novel therapy may provide an alternative treatment for burns requiring skin grafting however larger studies are needed.

First-in-human use of a marine oxygen carrier (M101) for organ preservation: A safety and proof-of-principle study.

The medical device M101 is an extracellular hemoglobin featuring high oxygen-carrying capabilities. Preclinical studies demonstrated its safety as an additive to organ preservation solutions and its beneficial effect on ischemia/reperfusion injuries. OXYgen carrier for Organ Preservation (OXYOP) is a multicenter open-label study evaluating for the first time the safety of M101 added (1g/L) to the preservation solution of one of two kidneys from the same donor. All adverse events (AEs) were analyzed by an independent data and safety monitoring board. Among the 58 donors, 38% were extended criteria donors. Grafts were preserved in cold storage (64%) or machine perfusion (36%) with a mean cold ischemia time (CIT) of 740minutes. At 3months, 490 AEs (41 serious) were reported, including two graft losses and two acute rejections (3.4%). No immunological, allergic, or prothrombotic effects were reported. Preimplantation and 3-month biopsies did not show thrombosis or altered microcirculation. Secondary efficacy end points showed less delayed graft function (DGF) and better renal function in the M101 group than in the contralateral kidneys. In the subgroup of grafts preserved in cold storage, Kaplan-Meier survival and Cox regression analysis showed beneficial effects on DGF independent of CIT (P=.048). This study confirms that M101 is safe and shows promising efficacy data.

Randomized, double-blind trial of F14512, a polyamine-vectorized anticancer drug, compared with etoposide phosphate, in dogs with naturally occurring lymphoma.

Purpose: F14512 is an epipodophyllotoxin derivative from etoposide, combined with a spermine moiety introduced as a cell delivery vector. The objective of this study was to compare the safety and antitumor activity of F14512 and etoposide phosphate in dogs with spontaneous non-Hodgkin lymphoma (NHL) and to investigate the potential benefit of F14512 in P-glycoprotein (Pgp) overexpressing lymphomas. Experimental Design: Forty-eight client-owned dogs with intermediate to high-grade NHL were enrolled into a randomized, double-blind trial of F14512 versus etoposide phosphate. Endpoints included safety and therapeutic efficacy. Results: Twenty-five dogs were randomized to receive F14512 and 23 dogs to receive etoposide phosphate. All adverse events (AEs) were reversible, and no treatment-related death was reported. Hematologic AEs were more severe with F14512 and gastrointestinal AEs were more frequent with etoposide phosphate. F14512 exhibited similar response rate and progression-free survival (PFS) as etoposide phosphate in the global treated population. Subgroup analysis of dogs with Pgp-overexpressing NHL showed a significant improvement in PFS in dogs treated with F14512 compared with etoposide phosphate. Conclusion: F14512 showed strong therapeutic efficacy against spontaneous NHL and exhibited a clinical benefice in Pgp-overexpressing lymphoma superior to etoposide phosphate. The results clearly justify the evaluation of F14512 in human clinical trials.