Development of IFNß-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis.

IFNß (recombinant interferon Beta) has been widely used for the treatment of Multiple sclerosis for the last four decades. Despite the human origin of the IFNß sequence, IFNß is immunogenic, and unwanted immune responses in IFNß-treated patients may compromise its efficacy and safety in the clinic. In this study, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of IFNß-1a. Two de-immunized versions of IFNß-1a were produced in CHO cells and designated as IFNß-1a(VAR1) and IFNß-1a(VAR2). First, the secondary and tertiary protein structures were analyzed by circular dichroism spectroscopy. Then, the variants were also tested for functionality. While IFNß-1a(VAR2) showed similar in vitro antiviral activity to the original protein, IFNß-1a(VAR1) exhibited 40% more biological potency. Finally, in vivo assays using HLA-DR transgenic mice revealed that the de-immunized variants showed a markedly reduced immunogenicity when compared to the originator.

Interferon Beta-1a versus Glatiramer Acetate: Changes of Innate Immunity in a Group of Women with Multiple Sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.

Effect of Dimethyl Fumarate vs Interferon ß-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial.

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon ß-1a (IFNß-1a) in POMS. Design, Setting, and Participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Interventions: Patients were randomized to DMF or IFNß-1a. Main Outcomes and Measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNß-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNß-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNß-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNß-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNß-1a; the rate ratio for DMF vs IFNß-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNß-1a. Conclusions and Relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon ß-1a. DMF was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-ß1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. METHODS: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-ß1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. INTERPRETATION: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). FUNDING: WHO.

Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a.

BACKGROUND AND PURPOSE: In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon beta-1a (sc IFN ß-1a) versus placebo. This post hoc analysis evaluated the effect of sc IFN ß-1a on spatio-temporal evolution of disease activity, assessed by changes in T2 lesion distribution, in specific brain regions of such patients and its relationship with conversion to MS. METHODS: Post hoc analysis of baseline and 24-month magnetic resonance imaging data from FCDE patients who received sc IFN ß-1a 44 µg once or three times weekly, or placebo in the REFLEX trial. Patients were grouped according to McDonald MS status (converter/non-converter) or treatment (sc IFN ß-1a/placebo). For each patient group, a baseline lesion probability map (LPM) and longitudinal new/enlarging and shrinking/disappearing LPMs were created. Lesion location/frequency of lesion occurrence were assessed in the white matter. RESULTS: At Month 24, lesion frequency was significantly higher in the anterior thalamic radiation (ATR) and corticospinal tract (CST) of converters versus non-converters (p < 0.05). Additionally, the overall distribution of new/enlarging lesions across the brain at Month 24 was similar in placebo- and sc IFN ß-1a-treated patients (ratio: 0.95). Patients treated with sc IFN ß-1a versus placebo showed significantly lower new lesion frequency in specific brain regions (cluster corrected): ATR (p = 0.025), superior longitudinal fasciculus (p = 0.042), CST (p = 0.048), and inferior longitudinal fasciculus (p = 0.048). CONCLUSIONS: T2 lesion distribution in specific brain locations predict conversion to McDonald MS and show significantly reduced new lesion occurrence after treatment with sc IFN ß-1a in an FCDE population.

Induction of CD73 prevents death after emergency open aortic surgery for a ruptured abdominal aortic aneurysm: a randomized, double-blind, placebo-controlled study.

Mortality remains high after emergency open surgery for a ruptured abdominal aortic aneurysm (RAAA). The aim of the present study was to assess, if intravenous (IV) Interferon (IFN) beta-1a improve survival after surgery by up-regulating Cluster of differentiation (CD73). This is a multi-center phase II double-blind, 2:1 randomized, parallel group comparison of the efficacy and safety of IV IFN beta-1a vs. placebo for the prevention of death after open surgery for an infra-renal RAAA. All study patients presented a confirmed infra-renal RAAA, survived the primary emergency surgery and were treated with IFN beta-1a (10 µg) or matching placebo for 6 days after surgery. Major exclusion criteria included fatal hemorrhagic shock, chronic renal replacement therapy, diagnosed liver cirrhosis, severe congestive heart failure, advanced malignant disease, primary attempt of endovascular aortic repair (EVAR), and per-operative suprarenal clamping over 30 min. Main outcome measure was all-cause mortality at day 30 (D30) from initial emergency aortic reconstruction. The study was pre-maturely stopped due to a reported drug-drug interaction and was left under-powered. Out of 40 randomized patients 38 were included in the outcome analyses (27 IFN beta-1a and 11 placebo). There was no statistically significant difference between treatment groups at baseline except more open-abdomen and intestinal ischemia was present in the IFN beta-1a arm. D30 all-cause mortality was 22.2% (6/27) in the IFN beta-1a arm and 18.2% (2/11) in the placebo arm (OR 1.30; 95% CI 0.21-8.19). The most common adverse event relating to the IFN beta-1a was pyrexia (20.7% in the IFN beta-1a arm vs. 9.1% in the placebo arm). Patients with high level of serum CD73 associated with survival (P = 0.001) whereas the use of glucocorticoids and the presence of IFN beta-1a neutralizing antibodies associated with a poor CD73 response and survival. The initial aim of the trial, if postoperative INF beta-1a treatment results on better RAAA survival, could not be demonstrated. Nonetheless the anticipated target mechanism up-regulation of CD73 was associated with 100% survival. According to present results the INF beta-1a induced up-regulation of serum CD73 was blocked with both use of glucocorticoids and serum IFN beta-1a neutralizing antibodies. The study was pre-maturely stopped due to interim analysis after a study concerning the use if IV IFN beta-1a in ARDS suggested that the concomitant use of glucocorticoids and IFN beta-1a block the CD73 induction. Trial registration: ClinicalTrials.gov NCT03119701. Registered 19/04/2017 (retrospectively registered).

Comparing the outcomes of treatment with INF-ß 1-a (interferon beta-1a) and IFN-ß 1-b (interferon beta-1b) among COVID-19 inpatients.

BACKGROUND: IFNßs are known as one of the most promising drugs used for COVID-19 treatment. This study aimed to investigate the effects of treatment with INF-ß 1-a (interferon beta-1a) and IFN-ß 1-b (interferon beta-1b) on COVID-19 inpatients. METHODS: In this study, we retrospectively evaluated the clinical treatment outcomes of 100 patients with COVID-19 who received IFN-ß 1-a and IFN-ß 1-b during their hospitalization period. The rate of discharge from the hospital was considered equal to the clinical improvement and then evaluated as a primary outcome. Moreover, mortality, ICU admission and length of ICU stay, frequency of intubation and use of mechanical ventilation, duration of hospitalization, laboratory factors, and medications were assessed as secondary outcomes. RESULTS: The median discharge time of IFN-ß 1a recipients was approximately equal to that of IFN-ß 1-b recipients as 9 (5-10) days and 7 (5-11) days, respectively (HR = 2.43, P = 0.75). Mortality rate was also estimated as 10% among IFN-ß 1-a recipients and 14% among IFN-ß 1-b recipients, which was not statistically significant (p = 0.190). ICU hospitalization rate for the IFN-ß 1-a recipients and IFN-ß 1-b recipients was 26% and 36%, respectively. In addition, no significant difference was found between these two intervention groups in terms of ICU length of stay (1 (0-2) vs. 1 (0-4.25(, respectively,) P = 0.357). There was no significant difference between the two study groups in terms of frequency of mechanical ventilation and length of hospital stay. CONCLUSION: There was no significant difference between the two groups in terms of shortening the disease time, clinical improvements and other outcomes.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN ß-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5-4-fold in response to sc IFN ß-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN ß-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN ß-1a treatment efficacy over 5 years.

Urokinase, CX3CL1, CCL2, TRAIL and IL-18 induced by interferon-ß treatment.

OBJECTIVE: To identify serum proteins associated with MS and affected by interferon beta treatment. METHODS: Plasma samples from 29 untreated relapsing-remitting MS patients and 15 healthy controls were investigated with a multiplexed panel containing 92 proteins related to inflammation. Follow-up samples were available from 13 patients at 1 and 3 months after initiation of treatment with interferon beta-1a. RESULTS: Ten proteins were differentially expressed in MS patients. Five of these were altered by treatment with IFN-ß 1a: uPA, CX3CL1, CCL2, TRAIL and IL18. CONCLUSION: CCL2 and TRAIL were confirmed to be modulated with interferon beta treatment in MS. As novel findings, we now report that uPA and CX3CL1 were differentially expressed in MS and increased after IFN-beta-1a treatment. Conflicting results have been reported on how interferon beta affects IL-18.

In inpatients with COVID-19, none of remdesivir, hydroxychloroquine, lopinavir, or interferon ß-1a differed from standard care for in-hospital mortality.

SOURCE CITATION: Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed antiviral drugs for Covid-19-interim WHO Solidarity Trial results. N Engl J Med. 2020. [Epub ahead of print.] 33264556.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a (the base therapeutic regimen) in moderate to severe COVID-19: A structured summary of a study protocol for a randomized controlled l trial.

OBJECTIVES: We will investigate the effectiveness of high dose Interferon Beta 1a, compared to low dose Interferon Beta 1a (the base therapeutic regimen) in COVID-19 Confirmed Cases (Either RT-PCR or CT Scan Confirmed) with moderate to severe disease TRIAL DESIGN: This is a single center, open label, randomized, controlled, 2-arm parallel group (1:1 ratio), clinical trial. PARTICIPANTS: The eligibility criteria in this study is: age ≥ 18 years, oxygen saturation (SPO2) ≤ 93% or respiratory rate ≥ 24, at least one of the following manifestation: radiation contactless body temperature ≥37.8, Cough, shortness of breath, nasal congestion/ discharge, myalgia/arthralgia, diarrhea/vomiting, headache or fatigue on admission. The onset of the symptoms should be acute (≤ 14 days). The exclusion criteria include refusal to participate, using drugs with potential interaction with lopinavir/ritonavir or interferon-ß 1a, blood ALT/AST levels > 5 times the upper limit of normal on laboratory results, pregnant or lactating women, history of alcohol or drug addiction in the past 5 years, the patients who be intubated less than one hours after admission to hospital. This study will be undertaken at the Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences. INTERVENTION AND COMPARATOR: COVID- 19 confirmed patients (using the RT-PCR test or CT scan) will be randomly assigned to one of two groups. The intervention group (Arms1) will be treated with lopinavir / ritonavir (Kaletra) + high dose Interferon-ß 1a (Recigen) and the control group will be treated with lopinavir / ritonavir (Kaletra) + low dose Interferon-ß 1a (Recigen) (the base therapeutic regimen). Both groups will receive standard care consisting of the necessary oxygen support, non-invasive, or invasive mechanical ventilation. MAIN OUTCOMES: Primary outcome: Time to clinical improvement is our primary outcome measure. This is an improvement of two points on a seven-category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization) or discharge from the hospital, whichever comes first. SECONDARY OUTCOMES: mortality from the date of randomization until the last day of the study which will be the day all of the patients have had at least one of the following outcomes: 1) Improvement of two points on a seven-category ordinal scale. 2) Discharge from the hospital 3) Death. Improvement of SPO2 during the hospitalization, duration of hospitalization from date of randomization until the date of hospital discharge or death, whichever comes first. The incidence of new mechanical ventilation uses from the date of randomization until the last day of the study and the duration of it will be extracted. Please note that we are trying to add further secondary outcomes and this section of the protocol is still evolving. RANDOMIZATION: Eligible patients with confirmed SARS-Cov-2 infections will be randomly assigned in a 1:1 ratio to two therapeutic arms using permuted, block-randomization to balance the number of patients allocated to each group. The permuted block (three or six patients per block) randomization sequence will be generated, using Package 'randomizeR' in R software version 3.6.1. and placed in individual sealed and opaque envelopes by the statistician. The investigator will enroll the patients and only then open envelopes to assign patients to the different treatment groups. This method of allocation concealment will result in minimum selection and confounding biases. BLINDING (MASKING): The present research is open-label (no masking) of patients and health care professionals who are undertaking outcome assessment of the primary outcome - time to clinical improvement. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Of the 100 patients randomised, 50 patients will be assigned to receive high dose Interferon beta-1a plus lopinavir/ritonavir (Kaletra), 50 patients will be assigned to receive low dose Interferon beta 1a plus lopinavir/ritonavir (Kaletra). TRIAL STATUS: Protocol version 1.2.1. Recruitment is finished, the start date of recruitment was on August 20th 2020, and the end date was on September 4th 2020. Last point of data collection will be the last day on which all of the 100 participants have had an outcome of clinical improvement or death, up to 14th days after hospitalization. TRIAL REGISTRATION: This study was registered with National Institutes of Health Clinical trials ( www.clinicaltrials.gov ; identification number NCT04521400, https://clinicaltrials.gov/ct2/show/NCT04521400 , registered August 18, 2020 and first available online August 20, 2020). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Cost-effectiveness of fingolimod versus interferon-ß1a for the treatment of pediatric-onset multiple sclerosis in Canada.

AIMS: To evaluate the cost-effectiveness of fingolimod versus interferon (IFN)-ß1a at a dose of 30 µg per week for the treatment of relapsing pediatric-onset multiple sclerosis (POMS) in Canada. MATERIAL AND METHODS: A discrete-time Markov model was developed to compare fingolimod with IFN ß-1a over a time horizon of two years representing patients followed up to mean age of 18 years from a Canadian health care system perspective. Twenty-one health states based on the Expanded Disability Status Scale (EDSS) were considered: EDSS 0‒9 for relapsing multiple sclerosis (MS), EDSS 0‒9 for secondary progressive MS, and "Death." Relative treatment efficacy for fingolimod versus IFN-ß1a was estimated from the PARADIGMS study. Costs and resource use were obtained from published literature and Canadian sources. Utilities were estimated by mapping the Pediatric Quality of Life inventory data onto the Child Health Utility Index-9 Dimension using a published mapping algorithm. Future costs and benefits were discounted at 1.5% per annum. RESULTS: Compared with IFN ß-1a, fingolimod led to an increase in quality-adjusted life-years (QALYs) (0.125) with incremental costs (Canadian dollars [CAD] 2,977) and to an incremental cost-effectiveness ratio (ICER) of CAD 23,886/QALY over a time horizon of two years representing patients followed up to mean age of 18 years. The monetary benefits of fingolimod treatment versus IFN ß-1a at a willingness-to-pay (WTP) threshold of CAD 50,000 per QALY gained were higher than the costs. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) both confirmed the robustness of the results. LIMITATIONS: The main limitations of this analysis primarily stem from the limited data availability in POMS. CONCLUSIONS: Fingolimod is cost effective compared with IFN ß-1a for the treatment of POMS over a time horizon of two years representing patients followed up to a mean age of 18 years in Canada.

Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults.

INTRODUCTION: To find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19. METHODS AND ANALYSIS: DisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-ß-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included. ETHICS AND DISSEMINATION: Inserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04315948 Eudra-CT 2020-000936-23.

A Randomized Clinical Trial of the Efficacy and Safety of Interferon ß-1a in Treatment of Severe COVID-19.

To the best of our knowledge, there is no published study on the use of interferon ß-1a (IFN ß-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN ß-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN ß-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir). Each 44-µg/ml (12 million IU/ml) dose of interferon ß-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted of 39 patients who received only the national protocol medications. The primary outcome of the study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of intensive care unit stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects, and complications during the hospitalization. Between 29 February and 3 April 2020, 92 patients were recruited, and a total of 42 patients in the IFN group and 39 patients in the control group completed the study. As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). On day 14, 66.7% versus 43.6% of patients in the IFN group and the control group, respectively, were discharged (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.05 to 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% versus 43.6%, respectively, P = 0.015). Early administration significantly reduced mortality (OR, 13.5; 95% CI, 1.5 to 118). Although IFN did not change the time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality. (This study is in the Iranian Registry of Clinical Trials under identifier IRCT20100228003449N28.).

Informe diário de evidências COVID-19: busca realizada em 22 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 22, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 20 artigos e 10 protocolos.

Informe diário de evidências COVID-19: busca realizada em 17 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 17, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.