Off-label Therapy Research Articles

COMBINED BOLUS AND CONTINUOUS NEBULIZATION DURING MECHANICAL VENTILATION: DUAL THERAPY FOR RESPIRATORY FAILURE

TYPE: Abstract TOPIC: Critical Care PURPOSE: This study tests nebulizers configured to deliver multiple medications during continuous nebulization without interruption or circuit disconnection. METHODS: A prototype i-AIRE dual-medication port breath-enhanced jet nebulizer (BEJN) was compared to Aerogen Solo vibrating mesh nebulizers (VMN). VMN were stacked; one for infusion, the second for bolus drug delivery. Radiolabeled saline was infused over 4 hr at 5 & 10 mL/h with 3 mL and 6 mL radiolabeled saline bolus injections into the circuit at 30 and 120 min respectively. Inhaled Mass expressed as % of initial syringe activity (IM%/min) was monitored in real time with a ratemeter. All delivered radioaerosol was collected on a filter at the airway opening. Transients in aerosol delivery were documented. RESULTS: IM %/h during continuous infusion was linear, with BEJN and VMN delivering 3-4 %/hr. BEJN functioned without incident. VMN stopped nebulizing spontaneously 50% of the time but tapping restarted VMN function during 3 of 4 continuous runs and 7 of 9 bolus delivery runs. Bolus delivery IM% (mean ± SD): 22 ± 8%, 14 ± 11 % for BEJN and VMN, respectively. CONCLUSIONS: Simultaneous continuous and bolus nebulization without circuit disconnection is possible for both jet and mesh technology. CLINICAL IMPLICATIONS: Continuous nebulization of pulmonary vasodilators is an off-label therapy for critically ill patients with hypoxemia. This study indicates that additional drugs (bronchodilators/antibiotics) can be given by bolus nebulization without circuit disconnection. Monitoring of VMN devices may be necessary in case of spontaneous interruption of nebulization. DISCLOSURE: Stony Brook University owns patents on inhaled therapy in intubated patients licensed to InspiRx, Inc. Dr. Smaldone consults to InspiRx and is a member of the Advisory Board. Ms Cuccia has served as a consultant to InspiRx. Dr. Lee and Mr. McPeck have no KEYWORD: nebulization

Clinical utility of tumor next-generational sequencing (NGS) panel testing to inform treatment decisions for patients with advanced solid tumors.

3119 Background: There is limited information about the clinical utility of targeted NGS panel testing to inform decision-making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is an ongoing prospective study that enrolled over 4,500 solid tumor patients for NGS panel testing. We performed a retrospective survey of 21 medical oncologists enrolling OCTANE patients at a single academic institution to evaluate the impact of NGS testing on treatment decisions. Methods: Patients and treating oncologists were identified at the Princess Margaret Cancer Centre between 2016-2021. Tumor-only sequencing was performed using a custom hybridization capture panel of 555 cancer genes (Hi5) or a commercial 161-gene amplicon DNA/RNA panel (Oncomine Comprehensive v3). Oncologists were asked to review testing results for individual patients and complete a survey indicating whether NGS testing impacted treatment decisions. Mutations were defined as actionable based on clinical judgment and compared to classifications provided by OncoKB, an FDA-recognized precision medicine knowledgebase. The primary outcome of this study was rate of treatment change based on mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed effects model. Results: Two cohorts were surveyed, the first between 2017-2019 and the second in 2021. Of the 582 surveys sent, 394 (67.7%) were completed. Each physician completed a median of 19 surveys (range, 9-48). We found that 188 (47.7%) patients had a mutation classified as actionable by the oncologist, of whom 134 (71.3%) had ≥1 OncoKB-defined actionable mutation(s). 62/394 (15.7%) patients were matched to a treatment, of whom 37 were enrolled in a clinical trial, 13 received an approved drug, 4 were prescribed off-label therapy and 8 avoided ineffective treatment. 127/188 (67.5%) patients with actionable mutations did not receive treatment due to lack of available therapy, stability on current regimen, clinical deterioration or patient decision. Rate of treatment change was highest for bowel (15/37, 40.5%), breast (14/52, 27.5%), biliary tract (6/22, 27.3%) and lung (4/17, 23.5%) cancers. Treatment decisions were not associated with patient age, gender, physician clinical experience, physician gender, testing experience, OncoKB mutation level or time from biopsy to sequencing. There was no difference in overall survival between patients with matched vs. no matched treatment ( p = 0.55, median survival not reached). Conclusions: OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors. Patient, test, and physician characteristics were not significantly associated with treatment change.

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.

Background and ObjectiveThere is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers.MethodsWe conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant.ResultsPeak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events.ConclusionsEliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough.Clinical Trial RegistrationClinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01126-1.

Hyperbaric oxygen for COVID-19 patients with severe hypoxia prior to vaccine availability

Introduction: Few treatments have demonstrated mortality benefits among hospitalized hypoxic COVID-19 patients. We evaluated the use of hyperbaric oxygen (HBO2) therapy as a therapeutic intervention among hospitalized patients with a high oxygen requirement prior to vaccine approval. Methods: We extracted data on patients with COVID-19 hypoxia who required oxygen supplementation ranging from a 6L nasal cannula up to a high-flow nasal cannula at 100% FiO2 at 60L/minute with a 100% non-rebreather mask at 15 L/minute and were eligible for off-label HBO2 therapy from October 2020 to February 2021. We followed the Monitored Emergency use of Unregistered and Investigational Interventions or (MEURI) in conjunction with the consistent re-evaluation of the protocol using the Plan-Do-Study-Act (PDSA) tool [1]. We compared patient characteristics and used Fisher’s exact test and a survival analysis to assess the primary endpoint of inpatient death. Results: HBO2 therapy was offered to 36 patients, of which 24 received treatment and 12 did not receive treatment. Patients who did not receive treatment were significantly older (p < 0.01) and had worse baseline hypoxia (p = 0.06). Three of the 24 (13%) patients who received treatment died compared to six of 12 (50%) patients who did not receive treatment (RR ratio: 0.25, p = 0.04, 95% CI: 0.08 to 0.83). In the survival analysis, there was a statistically significant reduction in inpatient mortality in the treatment group (HR: 0.19, p = 0.02, 95% CI: 0.05-0.74). However, after adjusting for age and baseline hypoxia, there was no difference in inpatient mortality (hazard ratio: 0.48, p = 0.42, 95% CI: 0.08-2.86). Conclusions: The survival benefit of HBO2 therapy observed in our unadjusted analysis suggests that there may be therapeutic benefits of HBO2 in treating COVID-19 hypoxia as an adjunct to standard care.

MO1034: Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Alport Syndrome and Fsgs: A Case Series

Abstract BACKGROUND AND AIMS Most hereditary diseases of the glomerular filtration barrier still progress to end-stage renal failure (ESRF)—raising the urgent need for add-on therapies. Recent randomized clinical trials (RCTs) demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney diseases (CKD). SGLT2-mediated afferent arteriole vasoconstriction, additive to efferent arteriole vasodilatation by angiotensin-converting enzyme inhibitors (ACEis), is postulated to correct the haemodynamic overload of the glomerular filtration barrier. For that reason, we investigated the nephroprotective effect of SGLT2i in hereditary glomerular diseases. METHOD In 2020, this monocentric prospective case series was started in six patients with Alport syndrome or FSGS, who consented to off-label therapy with empagliflozin or dapagliflozin. To our knowledge, this is the first case series on the effect of SGLT2i in patients with hereditary causes of CKD. RESULTS We report data on the use of SGLT2i in a case series of patients with Alport syndrome and FSGS in respect of the early effect on the kidney function and safety of initiation of therapy. The follow-up was 3–11 months. The mean age was 40 years (standard deviation, SD ± 17), the mean duration of treatment was 4.5 months (SD ± 2.9). The mean serum creatinine before and after SGLT2i initiation was 1.46 (SD ± 0.42) and 1.58 (SD ± 0.55). The mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT2i was 1827 (SD ± 1560) and decreased to 1127 (SD ± 854) after SGLT2i initiation. The estimated glomerular filtration rate (eGFR) ‘dipped’ after initiation of SGLT2i in most patients. Overall, treatment was well tolerated, however, eGFR initially decreased by more than 30% in one patient with FSGS. The initial eGFR drop raises some safety concerns, which underlines the need to collect and evaluate the course of every patient with AS in which therapy with SGLT2i is started. CONCLUSION In conclusion, therapy with SGLT2i on top of ACEi was well tolerated and effective in terms of lowering albuminuria. As a proof of concept, SGLT2-mediated correction of the haemodynamic overload of the glomerular filtration barrier looks like a very promising therapeutic approach in hereditary diseases such as AS and FSGS. Specific RCTs are needed to confirm our findings in this genetically well-defined population with a tremendous unmet medical need for more effective, early on and safe nephroprotective therapies. Proteinuria is reported as a urinary albumin-creatinine ratio in mg/g creatinine. All male patients received SGLT2i additive to renin-angiotensin-aldosterone system (RAAS)-blockade. In the female patient, ACEi was stopped prior to the start of SGLT2i because of angioedema. In addition to ACEi and SGLT2i, one patient also received tacrolimus because of irritable bowel disease. (A) eGFR (CKD-EPI formula) at baseline and at follow-up. (B) UACr at baseline and at follow up. m, male; f, female; FSGS, focal segmental glomerulosclerosis; XLAS, X-linked Alport syndrome; IBD, irritable bowel disease; aHT, arterial hypertension; sHP, secondary hyperparathyroidism; eGFR, estimated glomerular filtration rate; UACr, urine-albumin-creatinine ratio; Crea, serum-creatinine

Real-World Analysis of Off-Label Use of Molecularly Targeted Therapy in a Large Academic Medical Center Cohort

The primary objective of this study is to quantify the use of off-label molecularly targeted therapy and describe the clinical situations in which off-label targeted therapy are used. A key secondary objective is to report the outcomes of patients treated with off-label use of targeted therapy. We searched the electronic health record between 2000 and 2020 at our center to characterize the volume, clinical settings, and outcomes associated with off-label use of targeted therapies in different types of solid tumors. Among 46,712 patients who received targeted therapies, we identified 119 instances of off-label use of targeted therapy. Colon cancer was the most common cancer type to receive off-label targeted therapy in 18 patients (15.1%), followed by 13 with non-small-cell lung cancer (10.9%), eight with cholangiocarcinoma (6.7%), and seven with glioblastoma (5.9%). The most frequent molecular rationale for off-label therapy came from a comprehensive next-generation sequencing test (53.7%). The most frequently mutated gene that provided the rationale for targeted therapy was BRAF (20.1%), with BRAFV600E being the most common molecular alteration overall (15.1%). The median duration of off-label targeted therapy was 3.58 months, and the overall survival of treated patients was 7.59 months. There were 37 patients (31.1%) treated for longer than 6 months, 23 patients (19.3%) who survived ≥ 2 years, and 13 patients who were still on therapy as of June 2020. In this large cohort study of patients with solid tumors, off-label use of targeted therapy was uncommon. With that said, a notable proportion of patients had treatment durations ≥ 6 months and survivals of ≥ 2 years.

Modern approaches to the diagnosis and treatment of polycystic ovary syndrome in adolescence

Тhe diagnosis of polycystic ovary syndrome (PCOS) in adolescence still raises many questions. The problem is that the characteristics of normal puberty often coincide with the symptoms of PCOS. The article presents the criteria of a normal menstrual cycle, clinical and laboratory hyperandrogenism. In the diagnosis of the latter, the most informative indicators are the determination of the index of free testosterone and androstenedione, and the assessment of free and total testosterone are relatively low sensitivity. Clinical hyperandrogenism in adolescents includes only severe acne and hirsutism. The level of antimullerian hormone has no independent significance. Irregular menstrual cycles during the first year after menarche represent a normal period of puberty. At the second and third year after menarche , menstrual cycles of less than 21 days and more than 45 days are considered irregular, and from the fourth year – less than 21 days and more than 35 days. From the second year after menarche, menstrual irregularities are considered to be more than 90 days for any cycle. Primary amenorrhea is indicated by the absence of menarche at 15 years, or 3 years after telarche. Ultrasound is not used as a criterion for PCOS in the first 8 years after menarche due to the high frequency of ovarian multifollicularity in adolescence. Therefore, adolescent girls in the presence of menstrual disorders and hyperandrogenism may be diagnosed with «PCOS. Phenotype B» (ultrasound signs are not taken into account). Adolescents who have signs of PCOS but do not meet the diagnostic criteria are at risk for PCOS. The most important stage of PCOS therapy is lifestyle modification, normalization of body weight and metabolic processes. Combined oral contraceptives in adolescents are more often prescribed not for direct purposes (contraception), but as off-label therapy not only at diagnosis, but also in the «risk group», which involves the treatment of irregular menstrual cycles and / or clinical hyperandrogenism. In the absence of the effect of lifestyle changes, proper nutrition to correct metabolic disorders in addition to combined oral contraceptives may be prescribed metformin, inositol and etc.

Safety of Off-Label Pharmacological Treatment in Pediatric Neuropsychiatric Disorders: A Global Perspective From an Observational Study at an Italian Third Level Children's Hospital.

Background: The acquisition of proper and relevant pediatric clinical data is essential to ensure tolerable and effective pediatric drug therapies. In the field of pharmacological treatment of neuropsychiatric disorders, the lack of sufficient high quality scientific evidence for pediatric age results in the frequent need to prescribe off-label drugs. With the aim of improving knowledge about safety profile of off-label drug prescription in children and adolescent with neurological and/or psychiatric disorders, we realized a multidisciplinary pharmacovigilance study. Materials and methods: An observational retrospective study was conducted to assess the safety of off-label pharmacological therapies in patients aged 0–18 years, admitted to the Neuropsychiatry Unit of the Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” between January 2016 and December 2018. Prescription patterns and adverse drug reactions were evaluated by a multidisciplinary team. Results: Overall, 230 patients were enrolled, 48% boys (N = 111), 52% girls (N = 119), average age of 10 years, and a total of 534 prescriptions was analyzed. 54.5% (N = 125) of patients had epilepsy, 37.5% (N = 86) suffered from psychiatric disorders, 8% (N = 19) had other neurological disorders. The prevalence of off-label prescriptions was 32% and 50% of the study population received at least one off-label drug. A total of 106 ADRs was detected: 57% of ADRs were due to drug-drug interactions, 30% were due to off-label prescriptions, 10% were due to overdose and 3% were due to improper use. No significant association between emerged ADRs and off label prescriptions was found (Fisher’s exact two-tailed test, p = 1.000). There was significant association between increasing number of administrated drugs and risk of ADRs (OR 1.99; IC95% 1.58–2.5; p = 0.000). Psychiatric disorders were associated with at least three times higher risk to be treated with an off-label drug (OR 3.30; IC95% 2.26–4.83; p = 0.000). Conclusions: This study shows that off-label prescribing in neuropsychiatric disorders does not pose a greater risk of ADRs than on-label prescribing and highlights unmet clinical needs in pediatric neuropsychopharmacology. The multidisciplinary approach can provide important contributions to improve therapeutic path of these already complex pathologies by careful monitoring of therapeutic appropriateness and drug interactions.

Epidemiological and Psychopharmacological Study About Off-Label Treatment in Child and Adolescent Psychiatric Emergencies: A Tertiary/Single Center Experience.

The study used an epidemiological and pharmacological description of child and adolescent psychiatric emergencies (CAPEs), during which psychotropic medications are frequently administered as off-label therapies. We retrospectively describe CAPE in 190 patients (mean age, 14.7 years) referring in the emergency department of a single tertiary center, from June 2016 to June 2018, focusing on off-label administration rate, most of all in emergency setting. An intrinsic fragility was observed in this population, where 28.4% of patients present a history of self-harm, 24.7% a concomitant neurodevelopmental disorder, and 17.3% a history of substance abuse. Psychomotor agitation was the most frequent referral reason, and it represents an unspecified clinical presentation of several conditions, while self-harm showed a stronger association with depressive disorders (55.2%).Globally, 811 medications were administered both as baseline therapy (67.8% of off-label rate) and/or in the emergency setting, where the off-label rate raised to 78.3%. Benzodiazepines had the highest rate of off-label use (98.2% as baseline therapy, 92.9% in acute context). Nevertheless, in 83.5% cases of acute administrations, a singular oral benzodiazepine (mostly lorazepam) guaranteed psychomotor agitation resolution, with a lower rate of adverse effects in contrast with atypical antipsychotics. Off-label drug use in CAPEs is a recurrent clinical practice. An international agreement about off-label drugs is crucial to obtain standard long-term pharmacoepidemiological, safety, and efficacy data. Pharmacological pediatric trials and international guidelines are also required to regulate pharmacological treatments of CAPEs, most of all in emergency settings.

Intractable Gastrointestinal Bleeding Events After Left Ventricular Assist Device Implantation

<h3>Introduction</h3> There is evidence that continuous-flow left ventricular assist device (CF-LVAD) support may cause gastrointestinal (GI) angiodysplasias. Bleeding events are the most common complications after LVAD implantation emphasizing the importance of GI bleeding management. <h3>Case Report</h3> A 63-year-old male patient underwent CF-LVAD implantation for advanced heart failure in 2014. Anticoagulation consisted of warfarin with a target INR of 2.0 to 3.0 and acetylsalicylic acid (ASA) 100 mg o.d. Recurrent anemia, managed by transfusions of over 500 units of packed red blood cells and iron supplementation, has been of major concern since 2014. Gastroscopy and colonoscopy were negative. Capsule endoscopy revealed jejunal angioectasias and ileal angiodysplasias. ASA was cessated, warfarin was temporarily stopped and INR was lowered to 1.8. Octreotide and erythropoietin were initiated. Hydrocortisone suppository was added and ligation for haemorrhoids was performed for rectal bleeding. As anaemia deteriorated, warfarin was permanently stopped in 2018; thus, patient has been maintained without anticoagulation for 3 years. LVAD pump speed was reduced to increase pulsatility. As computed tomography presumed jejunal bleeding, small bowel resection was performed. Angiodysplasia was histologically confirmed and off-label therapy was initiated with thalidomide and bevacizumab. Diffuse angiodysplasias of the colon and ileum were treated by argon plasma coagulation. Aminocaproic acid and tranexamic acid were administered. Meanwhile, LVAD pump speed was increased due to worsening of heart failure. Patient has experienced several self-terminating pump-stops since 2020, suspected to be caused by damaged insulation of the driveline. Due to his poor overall condition and unability to tolerate any forms of anticoagulation, neither heart transplantation, nor pump replacement could be performed. The patient died of LVAD stoppage in 2021. Pump thrombosis was excluded on autopsy. The breaches in the wire insulation causing pump-stops were confirmed by factory investigation. <h3>Summary</h3> In case of GI bleeding, hemostasis and LVAD pump management are crucial as the management of anticoagulation should balance between bleeding and risk for thromboembolism. Reduction in bleeding events emphasizes the importance of experimental therapies in case of intractable bleeding events.

Challenges and complexities in designing cluster headache prevention clinical trials: A narrative review.

ObjectiveTo provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies.BackgroundCurrent guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995.Methods/ResultsRandomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges.ConclusionsOptimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

Management of Delta Hepatitis 45 Years after the Discovery of HDV.

In 1977 the viral Delta agent was discovered and subsequently characterized as the hepatitis Delta virus (HDV). HDV infection is associated with HBV infection since the defective HDV needs HBV to infect and replicate in the liver. Even if not a frequent cause of chronic liver disease, HDV infection is responsible for an aggressive progression of hepatitis towards advanced liver disease. At present, no FDA approved treatment exists for this specific form of hepatitis. Interferon alfa has been recommended as off-label therapy by major scientific societies (AASLD, EASL and APASL) and has proved effective in about one quarter of patients. In recent years, new therapeutic approaches have been studied, and EMA has approved a new drug (bulevirtide) for Delta hepatitis. In this review, we encompass the 45-year journey of managing Delta hepatitis and address the most recent developments in treating this severe and aggressive liver disease.

Efficacy of Off-Label Therapy for Non-alcoholic Fatty Liver Disease in Improving Non-invasive and Invasive Biomarkers: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

ObjectiveTo evaluate the effects of vitamin E, pioglitazone, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with non-alcoholic fatty liver disease (NAFLD).DesignA network meta-analysis.Data SourcesPubMed, Embase, Cochrane Library, and Web of Science databases from their inception until September 1, 2021.Eligibility Criteria for Selecting StudiesRandomized controlled trials (RCTs) comparing the effects of four different drugs in patients with NAFLD were included. All superiority, non-inferiority, phase II and III, non-blinded, single-blinded, and double-blinded trials were included. Interventions of interest included vitamin E (α-tocopherol and δ-tocotrienol), pioglitazone, three kinds of GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide), four SGLT2 inhibitors (dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin), and comparisons of these different drugs, and placebos.Main Outcome MeasuresThe outcome measures included changes in non-invasive tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), controlled attenuation parameter (CAP), enhanced liver fibrosis (ELF) score, liver fat content (LFC), and keratin-18 (K-18)] and invasive tests [fibrosis score and resolution of non-alcoholic steatohepatitis (NASH)].ResultsTwenty-seven trials including 3,416 patients were eligible for inclusion in the study. Results refer to vitamin E, pioglitazone, GLP-1 receptor agonists, and SGLT2 inhibitors. First, placebos were used as a reference. δ-Tocotrienol was superior to placebo in decreasing the GGT level. Semaglutide, ipragliflozin, and pioglitazone induced a significantly higher decrease in the ALT level than a placebo. Semaglutide, pioglitazone, and dapagliflozin were superior to placebo in decreasing the AST level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than a placebo. Liraglutide was superior to placebo in decreasing CAP. Liraglutide, pioglitazone, and vitamin E induced a significantly higher increase in resolution of NASH than a placebo. As for pairwise comparisons, semaglutide and pioglitazone were superior to liraglutide in decreasing the ALT level. Semaglutide induced a significantly higher decrease in the ALT level than dulaglutide. Semaglutide was obviously superior to empagliflozin, liraglutide, dulaglutide, and tofogliflozin in decreasing the AST level. Pioglitazone induced a significantly higher decrease in the GGT level than ipragliflozin. δ-Tocotrienol was superior to liraglutide in decreasing the GGT level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than dulaglutide. Pioglitazone was superior to vitamin E in increasing the resolution of NASH. Furthermore, liraglutide treatment had the highest SUCRA ranking in decreasing CAP and ELF scores and increasing the resolution of NASH. Pioglitazone treatment had the highest SUCRA ranking in decreasing LFC and fibrosis scores. Tofogliflozin treatment had the highest SUCRA ranking in decreasing K-18, while dapagliflozin treatment had the highest SUCRA ranking in decreasing the GGT level. Semaglutide treatment had the highest SUCRA ranking in decreasing the levels of ALT and AST.ConclusionThe network meta-analysis provided evidence for the efficacy of vitamin E, pioglitazone, SGLT2 inhibitors, and GLP-1 receptor agonists in treating patients with NAFLD. To find the best guide-level drugs, it is necessary to include more RCTs with these off-label drugs, so that patients and clinicians can make optimal decisions together.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier: CRD42021283129.

Neridronate for transient osteoporosis of the hip in a child

Transient osteoporosis of the hip (TOH) is usually reported in middle-aged men or during pregnancy as a benign self-limiting condition. Nevertheless, its impact on quality of life in terms of pain and disability is considerable. Also, it can lead to insufficiency fractures or, more rarely, evolve into osteonecrosis. This condition is anecdotally described in the pediatric age and very little is known about how it may affect the growing bone. We herein describe a case of TOH in a 10-year-old child treated at our pediatric rheumatology service and summarize the pediatric cases of TOH previously reported in literature. There are two points of interest in our case report, the first one being the unusual complication of TOH with a femoral physis fracture and the second the complete recovery after the off-label therapy with bisphosphonates. We suggest that interventional medical treatment could be considered in selected cases of juvenile TOH, to prevent any possible irreversible damage on the femoral physis. As far as we know, this is the first report of neridronate employment in children affected by TOH.

Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy

Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

P592 Effectiveness and safety of thioguanine in thiopurine-naïve Inflammatory Bowel Disease patients

Abstract Background Currently thioguanine is considered as off-label rescue therapy for Inflammatory Bowel Disease (IBD) after conventional thiopurine failure. This study aimed to determine the safety, effectiveness and 12-month drug tolerability of thioguanine in thiopurine-naïve IBD patients. Methods We performed an analysis of our multicenter, retrospective cohort study including thiopurine-naïve IBD patients treated with thioguanine as first-line maintenance therapy without concomitant biological therapy. Clinical effectiveness was defined as a sustained clinical response (based on physician’s global assessment) without the (re-)initiation of concurrent biological therapy, corticosteroids or a IBD-related surgical intervention. All adverse events that occurred during follow-up were categorized by the Common Terminology Criteria for Adverse Events. Elevation of two concurrent liver tests were categorized as drug-induced liver injury. Results A total of 103 IBD patients (female 61%, Crohn’s disease 52%) were included with a median daily thioguanine dose of 20mg and median 6-thioguanine nucleotide (6-TGN) levels of 635 pmol/8x108 RBC (IQR 425–1100). Clinical effectiveness at 12 months was observed in 60 out of 99 patients (61%) and 80% of patients were still using thioguanine 12 months after initiation. Four patients did not reach the 12-month follow-up period but were in remission at time of data collection. Of the responding patients at 12 months 88% (N=53) remained responsive until the end of follow-up (median follow-up period 28 months, IQR 17–40 months). Forty-nine patients (48%) developed adverse events (grade 1 or 2), of which 24% graded as moderate (grade 2) and none as severe. Seven patients ceased therapy due to the occurrence of adverse events. Adverse events consisted mainly of elevated liver tests (26%) and gastrointestinal complaints (17%). An infection was documented in three patients, none of them requiring hospitalization. Pancytopenia occurred in two other patients with 6-TGN levels of respectively 2900 and 140 pmol/8x108 RBC. None of the included patients had signs of (noncirrhotic) portal hypertension or underwent a liver biopsy during follow-up. Conclusion This is the first cohort study that reports on the safety and effectiveness of first-line thioguanine maintenance therapy in IBD. Thioguanine therapy was, 12 months after initiation, still used by 80% and clinically effective in 61% of thiopurine-naive patients. Adverse events were relatively common but mainly mild (grade 1) and the discontinuation rate related to adverse events was lower than observed during conventional thiopurine therapy. No signs of (noncirrhotic) portal hypertension were reported

Tocilizumab use during Covid-19 should alert an orthopaedic surgeon for the surgical management of arthroplasty patients: A narrative review

The crisis of Covid-19 has shaken the world healthcare systems. The intensive care resources to manage the medical conditions associated with Covid-19 are consistently found to be inadequate with exploration and implementation of newer treatment avenues for an early recovery. Presently, the use of Tocilizumab (TCZ) in severe to critical affection of Covid-19 is being practiced as an off-label therapy. A narrative review of present knowledge regarding TCZ pharmacology, indications of its use, and potential side effects with clinical implications for an orthopedic surgeon is presented. The article discusses the clinicopathological factors required to be monitored during the perioperative management of an orthopedic patient who may have received TCZ for Covid-19 related illness. The implications of its usage should alert the orthopaedic surgeons for future management of their arthritic surgical patients. The commonly associated side effects and complications in the post-operative phase following an arthroplasty or any orthopaedic surgery are an area of concern and considerable uncertainty. In the post-Covid-19 recovery phase, when surgeons need to plan a surgical intervention then a thorough evaluation of their Covid-19 medical management history may be warranted. Practical guidelines for the management of arthritic surgical patients have been postulated. With an unregulated increased usage of TCZ during Covid-19 management, an orthopaedic surgeon should worry and needs to be aware of the possible consequences in the perioperative period for the post-surgery management. Future research to gain more insights will confirm the implied concerns.

Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children

BackgroundEarly start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2–12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children.MethodsAn observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018.Results22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063–7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported.ConclusionThe prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis.

Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism. The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects. We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported. Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects.

Efficacy and Safety of SGLT2 Inhibitors as Adjunctive Treatment in Type 1 Diabetes in a Tertiary Care Center in Saudi Arabia.

Background Adjunctive treatment with sodium-glucose co-transporters 2 inhibitors (SGLT2- I) has been successfully used in patients with type 1 diabetes mellitus (T1DM) in recent years to improve glycemic control and reduce body weight without increasing the risk of hypoglycemia; however, there is a scarcity of evidence for real-world experience in their use in T1DM Saudi patients. The purpose of this study was to evaluate the efficacy and safety of empagliflozin as off-label adjunctive therapy in Saudi patients with T1DM. Methods This study was a retrospective study for T1DM patients, who were prescribed empagliflozin as an adjunctive therapy. Baseline characteristics including age, changes in HbA1c, body weight, total daily insulin dose, lipid profile, and well as side effects such as urinary tract infections (UTIs) and diabetes ketoacidosis (DKA) were evaluated before and after initiation empagliflozin in 37 T1DM patients. Results The mean age was 25.8 ± 8.0 years, mean weight was 75.3 ± 14.8 kg, mean body mass index (BMI) was 28.1 ± 6.7 kg/m 2 , mean duration of diabetes was 10.1 ± 6.5 years, and mean HbA1c was 9.4 ± 1.4%. After a mean follow-up duration of 15.8 ± 6.0 months, the mean reduction in the HbA1c% from baseline was 0.82% ( p = 0.001) and mean weight reduction from baseline was 1.7 kg ( p = 0.097). The total daily insulin dose was decreased by 2.9 units. UTIs and DKA episodes were reported among 2.7% and 10.8% of the participants, respectively. Conclusion Empagliflozin in combination with insulin in overweight Saudi T1DM subjects resulted in a significant improvement in glycemic control, mild non-significant reduction in body weight, and a small but statistically significant reduction in the total daily insulin dose with a slight increase in the risk of DKA and UTIs. Further larger prospective studies are needed for better evaluation of the efficacy and safety of these agents in Saudi T1DM patients.