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Introduction: de Quervain's syndrome is a painful condition commonly presented to hand therapists. Exercise is utilised as an intervention, but isometric exercise has not been investigated. We aimed to assess the feasibility and safety of isometric thumb extension exercise for de Quervain's syndrome and to explore differences between high-load and low-load isometric exercise. Method(s): This parallel-group randomised clinical feasibility trial included individuals with de Quervain's syndrome. All participants underwent a 2 week washout period where they received an orthosis, education, and range of motion exercises. Eligible participants were then randomised to receive high or low-load isometric thumb extension exercises, performed daily for 4 weeks. Feasibility and safety were assessed by recruitment and drop-out rates, adherence, adverse events, and participant feedback via semi-structured interviews. Secondary outcomes included patient-reported outcomes for pain and function, and blinded assessment of range of motion and strength. Result(s): Twenty-eight participants were randomised. There were no drop-outs after randomisation, and no serious adverse events. Adherence to exercise was 86.7%, with 84% of participants stating they would choose to participate again. There were clinically and statistically significant improvements in pain and function over time (p < 0.001) but not in range of motion or strength. There were no statistically significant between-group differences. Conclusion(s): Isometric thumb extension exercise within a multimodal approach appears a safe and feasible intervention for people with de Quervain's syndrome. A large multi-centre trial would be required to compare high- and low-load isometric exercises. Further research investigating exercise and multimodal interventions in this population is warranted.Copyright © The Author(s) 2023.
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Intro: GBP510 contains the self-assembling recombinant nanoparticle displaying SARS-CoV-2 Spike protein receptor binding domain and is adjuvanted with AS03. We report interim Phase 3 study (NCT05007951) results up to 4 weeks post-dose 2 (Data-cut: March-18-2022), where immunogenicity to the D614G ancestral strain and safety of 25mug GBP510/AS03 candidate was compared to ChAdOx1-S (Vaxzevria). Method(s): This Phase 3 randomized, active-controlled, observer-blind, parallel- group study in adults was conducted in 6 countries. Cohort1: 1,895 subjects (naive to COVID-19 vaccination and infection) randomized at 2:1 ratio (GBP510/AS03:ChAdOx1-S) to assess immunogenicity and safety;Cohort 2: 2,141 subjects at 5:1 ratio, regardless of their serostatus at screening for safety assessment. Subjects were vaccinated twice at a 4-week interval with 0.5 mL of the test vaccine (GBP510/AS03) or active control (ChAdOx1-S) in deltoid muscle. The primary objective was to demonstrate the superiority of geometric mean titer (GMT) and non-inferiority in seroconversion rate (SCR: >=4-fold rise from baseline) of neutralizing antibodies over ChAdOx1-S by live-virus neutralization assay (FRNT). Finding(s): At 2 weeks post-dose 2, GMT ratio of the two groups (Test vaccine/Active control) was 2.93 [95% CI: 2.63, 3.27], satisfying the hypothesis of superiority (95% CI lower limit> 1). The SCR difference (Test vaccine - Active control) was 10.76% [95% CI: 7.68, 14.32], satisfying the hypothesis of non- inferiority (95% CI lower limit> -5%). Good cell-mediated immune responses for Th1 cytokines were also observed with the test vaccine (FluoroSpot). The AE incidence rate for the test vaccine was higher than the active control for solicited local AEs (56.69% vs 49.20%), and comparable for solicited systemic AEs (51.21% vs 53.51%) and unsolicited AEs (13.34% vs 14.66%) after any vaccination. Conclusion(s): Higher immune responses were observed with GBP510/AS03 compared to ChAdOx1-S against D614G strain after 2 weeks post-dose 2. GBP510/AS03 showed a clinically acceptable safety profile;no safety concerns were identified during the study period.Copyright © 2023
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Purpose: Hand osteoarthritis (OA) is more common in women. Hand OA incidence increases further in females around the age of 50, the typical age of menopause. Estrogen-deficient states are associated with increased musculoskeletal pain and inflammation and with increased rates of symptomatic OA. Estrogen replacement and selective estrogen receptor modulators (SERMs) can improve pain and structure in some pre-clinical models of OA associated with estrogen loss, and in exploratory analysis from hormone replacement therapy (HRT) trials. However, no randomised clinical trials (RCTs) of HRT had been performed in symptomatic OA populations, specifically hand OA. By carrying out a RCT feasibility study of a form of HRT (conjugated estrogens (CE)-bazedoxifene) in post-menopausal women with painful hand OA, we set out to determine the feasibility and acceptability of this. We also aimed to generate proof-of concept data on likely outcomes, calculate a sample size and refine methods for a full trial. Method(s): We recruited females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and >=2 painful hand joints across three primary/secondary care sites and from the community. Medical exclusions included those typical for clinical HRT use. Design was parallel group, double-blind 1:1 randomisation of CE-bazedoxifene or placebo, taken orally once daily for 24 weeks, then tapering for 4 weeks before study end at Week 28. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Adverse events (AEs) were collected. Secondary clinical outcomes included the anticipated primary outcome in a full trial of mean hand pain over 14 days prior to each visit, scored on a 0-10 numerical rating scale (NRS) where 10 is worst pain possible, as well as hand function, appearance and menopause symptoms. Progression criteria to a full RCT were: (i) recruitment >=30 participants across all sites in 18 months (or proportionate to time open);(ii) a drop-out rate of <=30% of randomised individuals;and (iii) acceptability to the majority of participants, including acceptable AE rates. All clinical outcomes were analysed on an intention-to-treat basis. Though not powered to detect a treatment difference, change and treatment effects (the difference in the outcome between the two groups) were indicated with 95% CIs, with all models adjusted for clinical subtype of painful hand joint, study site, and baseline values. The sample size for a full trial was estimated using the standard deviation (SD) of week 24 mean hand pain. Result(s): Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. From May 2019 to December 2020, 434 enquiries/referrals were received. Of 96 telephone pre-screens, 35 individuals were potentially eligible and of these, 33 gave consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed, with the most common reason being not wanting to take HRT. 28/35 (80% (95%CI 63%,92%)) eligible participants were randomised to study medication. All 28 participants completed all follow-ups with high compliance (100% active, 13/14[93%] placebo) and outcome measure completeness (100%, mean hand pain). All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs occurred. Participants/investigators were well blinded (participant blinding index 0.50[95%CI 0.25 to 0.75]). All three prespecified progression criteria were therefore met for a full trial. The treatment effect difference over 24 weeks in mean hand pain between active and placebo was -0.71 (95% CI -2.20 to 0.78) (Fig 1A). During tapering/stopping medication, mean hand pain increased by 1.31 points in the active arm compared with 0.17 in the placebo arm, indicating a possible effect of cessation of medication (Fig 1A). Furthermore, 6/13 (46%) participants in the active group reported worsening pain at week 28 compared with week 24, but only 2/12 (17%) were worse on withdrawing placebo (Fig 1B). The sample size for a full trial was estimated as 296 (based on MCID 0.8 on NRS, SD 2.0, 90% power, 10% drop-out, alpha 5%). Conclusion(s): This first study of a RCT of HRT for painful hand OA met its progression criteria, indicating that a full trial of an HRT in this population is feasible and acceptable. Although not powered to detect an effect, there was a trend towards improvement in hand pain on treatment and worsening of hand pain on tapering in the active arm only. This adds to proof-of-concept data in this area, justifying more work.ISRCTN12196200. Funded by Research for Patient Benefit programme, National Institute for Health Research (UK) PB-PG-0416-20023 [Formula presented]Copyright © 2023
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Background: Anticoagulation with fondaparinux (FPX) has shown benefit to improve clinical outcomes in hospitalized patients with COVID-19. However, optimal thromboprophylaxis dosing in critically ill patients remains unknown. Purpose(s): To evaluate the effects of D-dimer-driven (DDD) FPX compared with standard prophylactic-dose (SPD) FPX in critically ill patients with COVID-19 and associated coagulopathy. Method(s): This was a single-center, open-label, two-arms, parallel-group, randomized controlled trial conducted between April 1, 2021 and Feb 28, 2022. The eligible COVID-19 patients who were critically ill (defined as a presence of critical care-level organ support at enrollment) and presented with coagulopathy were randomly assigned (1:1 ratio) to receive pragmatically defined regimens of either DDD FPX or SPD FPX throughout hospitalization. The primary efficacy outcome was a composite of all-cause mortality (ACM), acute myocardial infarction (MI), confirmed arterial (ATE) or venous thromboembolisms (VTE), assessed up to 30 days. The secondary efficacy outcomes were 30-day ACM, composite thrombotic events, progression to invasive mechanical ventilation (IMV) or ARDS, and acute kidney injury (AKI). The safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB). Outcomes were blindly adjudicated and analysed on a 30-day intention-to-treat basis. Result(s): During allocated period, 270 (58%) of 465 patients were eligible and were equally assigned to DDD and SPD groups. The baseline characteristics were well-matched between groups (all p>0.05). At 30 days, the primary efficacy outcome was met in 49 of 135 patients (36.3%) with DDD FPX versus 47 of 135 patients (34.8%) with SPD FPX (hazard ratio [HR], 1.32;95% CI, 0.89-1.98;p=0.17). DDD group compared with SPD group revealed no significant difference in 30-day ACM (22.9% vs 31.8%;HR, 0.73;p=0.17). At 30 days, DDD group demonstrated no significant reduction in thromboembolism, i.e. acute MI (14.1% vs 11.8%;HR, 1.53;p=0.21);ATE (3.0% vs 3.0%;HR, 1.27;p=0.74);and VTE (2.2% vs 4.4%;HR, 0.69;p=0.59) when compared with SPD group. Among those not on IMV at randomization, DDD group showed no significant reduction in the proportion of patients meeting the need for IMV (18.5% vs 32.6%;HR, 0.72;p=0.18) or progression to ARDS (17.8% vs 27.4%;HR, 0.81;p=0.43). Allocation to DDD FPX had no significant effect on the proportion of patients experiencing AKI within 30 days (17.8% vs 14.8%;HR, 1.36;p=0.39). There was no significant difference between DDD and SPD groups in terms of major bleeding (2.2% vs 0%;HR, 8.35;p=0.35) or CRNMB (3.0% vs 2.2%;HR, 1.70;p=0.48) at 30 days. Conclusion(s): In critically ill patients with COVID-19 and coagulopathy, D-dimer-driven anticoagulation with fondaparinux did not significantly improve clinical outcomes at 30 days as compared to standard prophylacticdose. The risk of bleeding was not significantly increased in this trial. (Table Presented).
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Background: Today, various drugs have been investigated as the primary or complementary treatment for coronavirus disease 2019 (COVID-19). N-acetylcysteine (NAC) has been used as a mucolytic in pulmonary diseases. This drug apparently contributes to the retrieval of the intracellular antioxidant system. Objective(s): This study aimed to determine the efficacy of NAC in severe COVID-19 patients admitted to the intensive care unit (ICU). Method(s): This single-blinded randomized controlled phase III clinical trial included 40 patients with confirmed COVID-19 (based on polymerase chain reaction) admitted to the Shahid Mohammadi Hospital's ICU, Bandar Abbas, Iran, in 2020. All cases had severe COVID-19. They were allocated randomly to two equal groups. Patients in the control group received standard drug therapy based on the treatment protocol of the national COVID-19 committee, while those in the NAC group received a single dose of intravenous NAC (300 mg/kg) upon admission to the ICU in addition to standard drug treatment. Clinical status and laboratory tests were done on admission to the ICU and then 14 days later or at discharge without knowing the patient grouping. Result(s): The two groups were comparable regarding age, gender, and other baseline laboratory and clinical parameters. At the final evaluation, respiratory rate (21.25 +/- 4.67 vs. 27.37 +/- 6.99 /min) and D-dimer (186.37 +/- 410.23 vs. 1339.04 +/- 2183.87 ng/mL) were significantly lower in the NAC group (P = 0.004 and P = 0.030, respectively). Also, a lower percentage of patients in the NAC group had lactate dehydrogenase (LDH) <= 245 U/L (0% vs. 25%, P = 0.047). Although the length of ward and ICU stay was shorter in the NAC group than in controls, the difference was statistically insignificant (P = 0.598 and P = 0.629, respectively). Mortality, on the other hand, was 75% in the control group and 50% in the NAC group, with no statistically significant difference (P = 0.102). Concerning the change in the study parameters, only the decrease in diastolic blood pressure (DBP) was significantly higher with NAC (P = 0.042). The intubation and mechanical ventilation rates were higher, while oxygen with mask and nasal oxygen rates were lower with NAC, but the difference was statistically insignificant. Conclusion(s): Based on the current research, NAC is related to a significant decrease in RR, D-dimer, and DBP in severe COVID-19. Also, LDH was significantly lower in the NAC group than in the controls. More research with larger sample sizes is needed to validate the current study results.Copyright © 2023, Author(s).
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Importance: Women with interstitial cystitis/bladder pain syndrome (ICBPS) face isolation and treatment challenges. Group medical visits using Centering models have successfully treated other conditions but have not been explored in ICBPS. Objective(s): This study aimed to describe ICBPS pain and symptom control comparing standard treatment alone versus standard treatment augmented with Centering visits. Study Design: This prospective cohort study recruited women with ICBPS receiving standard care (control) or standard care augmented with group Centering. We administered validated questionnaires at baseline and monthly for 12 months. The primary outcome was change in the pain numerical rating scale, with Patient-Reported Outcomes Measurement Information System Pain Interference Scale and Bladder Pain/Interstitial Cystitis Symptom Score change as secondary measures. Result(s): We enrolled 45 women (20 Centering, 25 controls). Centering had significantly better numerical rating scale pain scores at 1 month (mean difference [diff], -3.45) and 2 months (mean diff, -3.58), better Patient-Reported Outcomes Measurement Information System Pain Interference Scale scores at 1 month (mean diff, -10.62) and 2 months (mean diff, -9.63), and better Bladder Pain/Interstitial Cystitis Symptom Score scores at 2 months (mean diff, -13.19), and 3 months (mean diff, -12.3) compared with controls. In modeling, treatment group (Centering or control) and educational levels were both associated with all the outcomes of interest. Beyond 6 months, there were too few participants for meaningful analyses. Conclusion(s): Women with ICBPS participating in a Centering group have, in the short term, less pain, pain interference, and ICBPS-specific symptoms than patients with usual care alone. Larger studies with more follow-up are needed to determine if this treatment effect extends over time.Copyright © 2022 American Urogynecologic Society. All rights reserved.
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Background: Platelets (plt) may contribute to the inflammatory thrombosis in Cov-ARDS. Glenzocimab a humanized monoclonal antibody fragment against plt glycoprotein VI, inhibiting plt binding to the thrombus does affect physiological hemostasis, is assessed in Stroke (ph.II/II) and thrombotic diseases. Method(s): GARDEN (NCT04659109) was a randomized, double -blind, multicenter, parallel group, ph.IIb trial. Patients (pts) randomized 1/1 to Glenzocimab (1000 mg/day/3days)-placebo. All had confirmed SARS-CoV2, moderate respiratory clinical signs and a prothrombotic status. Primary endpoint: day 4 severe progression. Result(s): 60 pts enrolled in Brazil & France, aged median 56yrs;75% male Caucasians with >= 1 comorbidity. All had thromboprophylaxis and steroids. Safety analysis confirmed good tolerance of Glenzocimab. No deaths, serious drug-related adverse event nor major bleeding. 31 SAEs in 15 pts mainly related to Cov-ARDS or infection. No difference for the primary endpoint. Insufficient power, imbalance of risk factors (within Glenzocimab group), or lesser role of GPVI in Cov-ARDS pathophysiology are possible reasons. Conclusion(s): The GARDEN study was set up to tackle a global Public Health emergency. Glenzocimab was safe in doses three times higher than used in stroke. Albeit efficacy was not shown, overall, GARDEN provides insights into Cov-ARDS.
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Aims: ENO Breathe is an online breathing and wellbeing programme for people with Long COVID focusing on breathing re-training using singing techniques. Aim(s): to assess whether ENO Breathe improves health related quality-of-life (HRQoL) in people with persistent breathlessness following COVID-19. Method(s): A parallel-group, single-blind, RCT, comparing ENO Breathe(6 weeks) with usual care in adults, with persisting breathlessness +/- anxiety, following assessment at an NHS Long COVID clinic. Primary Outcome: change in HRQoL using the RAND SF-36 Mental(MHC) and Physical(PHC) Health Composite Scores. Secondary Outcomes: CAT, VAS for breathlessness (rest, walking, stairs, and running), Dysp-12, GAD-7. Participant experience was assessed using focus groups and free-text responses. Result(s): 150 participants (mean(SD) 49(12)years, 81% female, 320(127) days symptomatic;ENO Breathe(n=74), Control(n=76). ENO Breathe was associated with improvement in MHC of 2.42 points (95%CI 0.03 to 4.80, p=0.045), but not PHC 0.6 (-1.33 to 2.52, p=0.541). VAS breathlessness (running) favoured ENO Breathe -10.48(-17.23 to -3.73, p=0.003). Three participant experience themes were identified 1) improvements in symptoms;2) feeling that the programme was complementary to standard care;3) the particular suitability of singing and music to address their needs. Conclusion(s): An online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind-body and music-based approaches, including practical, enjoyable symptom-management techniques may have a role supporting recovery.
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Availability of well-tolerated novel agents that can slow or stop disease progression and improve quality of life remain an unmet medical need in IPF management. GB0139, a novel inhaled galectin-3 inhibitor, has shown good tolerability and antifibrotic potential via changes in biomarkers associated with IPF progression in an animal model (Delaine, T. et al. Chembiochem 2016;17:1759-70) and a Phase I study (Hirani, N. et al. Eur Respir J 2021;57(5):2002559) in healthy participants and IPF patients. We report the design of a Phase IIb study of GB0139 in IPF. This randomised, double-blind, placebo-controlled, parallel-group, multicentre study (NCT03832946) was initiated in April 2019. The primary endpoint is rate of decline in forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are proportion of participants with an absolute decline from baseline in FVC % predicted of <=10%, change from baseline in St. George's Respiratory Questionnaire total score, time to first respiratory-related hospitalisation, and time to death (all-causes). Systemic GB0139 pharmacokinetics are included as an exploratory endpoint. Despite the COVID-19 pandemic, study recruitment has continued in ~100 centres across 15 countries, with over 400 participants randomised as of February 2022. Initially, participants treated with or without standard of care (SOC) were included. Following a protocol amendment in 2021, the current target is to randomise 141 participants who are not treated with SOC, with study completion in mid-2023.
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BACKGROUND: Sotrovimab, a dual-action Fc-engineered human immunoglobulin G (IgG1) mAb, binds to a conserved epitope on the SARS-CoV- 2 receptor binding domain and was developed to treat mild to moderate COVID-19. A high concentration formulation is being evaluated to offer the potential for IM administration at lower volumes and at different injection sites. METHOD(S): COSMIC (NCT05280717) is a phase 1, open-label healthy volunteer study comprising three parts. Part A is an ongoing randomized, parallel group study investigating the relative bioavailability, safety, and tolerability of two concentrations of sotrovimab administered at different injection sites. A total of 215 subjects were randomized in a 2:2:1:1 ratio into 4 treatment arms: dorsogluteal injection (62.5 mg/mL), or 100 mg/mL administered as dorsogluteal, thigh, or deltoid injection(s). PK will be evaluated for 24 weeks post-dose. RESULT(S): Preliminary PK is available from 50 participants who received a 500 mg IM dose of sotrovimab of the higher concentration (100 mg/mL). Administration into thigh or deltoid resulted in higher geometric mean Cmax and AUCD1-15 and lower inter-subject variability compared to 100 mg/mL dorsogluteal. Following gluteal, thigh, or deltoid injections, the geometric mean (%CV) Cmax was 44.8 mug/mL (63.3), 70.9 mug/mL (35.5), and 65.1 mug/mL (27.1), respectively, and the geometric mean (%CV) AUCD1-15 was 534 day*mug/mL (67.5), 814 day*mug/mL (39.7), and 782 day*mug/mL (26.3), respectively. Median Tmax was earlier following thigh (4 days) and deltoid (5.5 days) injection than gluteal (7 days) injection. CONCLUSION(S): Administration of sotrovimab into thigh or deltoid muscles may improve exposure and reduce inter-subject variability compared to gluteal IM administration. These data may inform IM injection site selection for mAbs.
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Aim: To evaluate the potential use of ivermectin with standard therapy among mild to moderate covid-19 illness. Methods: This is a single-centered, prospective observational, randomized, parallel group (1:1 ratio), standard versus controlled ivermectin study recruited 210 confirmed COVID-19 positive patients who were admitted in COVID treatment center of Dr Ruth Kum Pafu Civil hospital Karachi, Pakistan from 1st November 2020 to 30th May 2021. Data were analyzed using SPSS version Results: Total of 210 patients were enrolled in the study and aged matched patients were divided in two groups 105 patients received ivermectin 6 mg twice a day for five days along with standard therapy while remaining 105 patients received standard therapy as per local and international guidelines. Male were 140(66.7%) and female 70(33.3%);age ranges between 26 to 77 years and majority 140( 66.7%) were more than 50 years of age. Fever, dry cough and dyspnea were the major symptoms seen;112(53.3%) patients had DM as a comorbid illness . Total of 21(20%) of 105 patients of ivermectin group had negative PCR for COVID 19 on day seven while the other group had positive covid test in all of 105 patients . On day 10 total of 49 more patients from ivermectin group found COVID negative along with 21 previously negative had second PCR was found negative in this way total of 70( 66.7%) of ivermectin group had negative PCR for COVID 19 while 21(20%) patients from non ivermectin got negative PCR for COVID 19 on day 10 . Conclusion: Use of ivermectin with standard therapy clear the virus earlier than standard therapy in mild to moderate COVID-19 infected patients admitted in COVID treatment center of Dr Ruth Kum Pafu Civil Hospital Karachi.
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BACKGROUND: A novel therapeutic approach using molecularly targeted radiation is currently in development for patients with recurrent GBM. Many tumor types, including GBM, overexpress the L-type amino transporter 1 (LAT-1)4, which is able to internalize the small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine (131I-IPA). In preclinical research, combining 131I-IPA with external radiation therapy (XRT) yielded addi- tive cytotoxic effects. Tumoral accumulation of 131I-IPA was confirmed in a proof-of-principle study using single doses of 2-7 GBq 131I-IPA as a monotherapy or in combination with XRT in patients with recurrent GBM. The objective of the IPAX-1 study was to evaluate the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-IPA in combination with secondline radiotherapy in patients with recurrent GBM. METHOD(S): IPAX-1 is a multi-center, open-label, single-arm, dose-finding phase 1/2 study. Key inclusion criteria: 1. Confirmed histological diagnosis of GBM with evidence of first recurrence 2. History of GBM standard therapy 3. >= 6 months since end of first-line XRT 4. Pathologically increased amino acid tumor uptake shown by molecular imaging 5. Current indication for repeat radiation 6. Gross tumour volume of up to 4.8 cm diameter. Treatment: In phase 1 of the study patients received intravenous 131I-IPA at a dose level of 2 GBq administered in one of three different dosing regimens: single dose group with 2 GBq before radiation, 3 (f)-fractionated-parallel group: 3 x 0.67 GBq during XRT and 3 (f)-fractionated-sequential group: 0.67 GBq x 1 -> XRT -> 0.67 GBq x 2. XRT is delivered in 18 fractions of 2 Gy each. RESULT(S): 10 patients were randomized;one patient with Covid related death was withdrawn from analysis. Survival from start of TLX101 therapy showed mPFS2 of 4.33 M (95% -CI 4.18 - 4.48), PFS-6: 18 % and mOS2 of 15.97 M (95% -CI 2.9 - 29.1) at data lock 09/2021. Updated results will be presented at the meeting. CONCLUSION(S): There were no clinically relevant laboratory changes over time. Urinalysis, vital signs, and ECG did not show any clinically relevant changes from baseline. There were no notable differences in safety and tolerability between groups. Injections of single or fractionated doses of 131I-IPA containing a total activity of 2 GBq in combination with XRT in patients with recurrent GBM were safe and well tolerated. Survival data look promising;extension cohort will be treated in a phase II study in Linz;phase 1/2 study in first line setting is planned.
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Purpose : Dry age-related macular degeneration (AMD) is a leading contributor to visual impairment across the globe. No current treatment exists to improve visual function or reduce disease progression outside of vitamin supplementation and lifestyle changes. LIGHTSITE III is evaluating multiwavelength photobiomodulation (PBM) therapy using the LumiThera Valeda® Light Delivery System in dry AMD Methods : LIGHTSITE III (NCT04065490) is a prospective, double-masked, randomized, sham-controlled, parallel group, multi-center study to assess the safety and efficacy of PBM in dry AMD. Target enrollment was approximately 96 subjects (144 eyes). Subjects are treated with six series of PBM/Sham treatments (3x per week for 3 weeks) delivered over a 24-month period with a 13-month efficacy analysis of data. PBM therapy consists of low-level light exposure to selected tissues resulting in positive effects on mitochondrial output and improvement in cellular activity. Valeda is used to deliver multiwavelength PBM treatment using 590, 660 and 850 nm of light. Subjects are assessed for clinical and safety outcomes (i.e., best-corrected visual acuity (BCVA), low- luminance BCVA, contrast sensitivity, reading speed, color vision, VFQ-25 and perimetry). Independent OCT, FAF and color fundus imaging outcomes at selected timepoints are analyzed by a masked imaging reading center Results : A total of 148 eyes from 100 subjects with dry AMD have been enrolled and randomized in a 2:1 design (PBM:Sham). The majority of subjects are female (68%) and Caucasian (99%). The average age at enrollment was 75 years and mean time since dry AMD diagnosis is 4.9 years. COVID-19 interference has been minimal and not significantly impacted subject enrollment or retention. Clinical and anatomical outcome data from the interim analysis conducted at Month 13 is presented. Results from the 21-month time point are expected at end of 2022 Conclusions : LIGHTSITE III provides the largest, randomized controlled trial evaluating the effects of PBM in dry AMD subjects. PBM therapy may offer a new treatment strategy with a unique mechanism and modality for patients with dry AMD.
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Background High-flow nasal cannulae (HFNC) deliver high flows of blended humidified air and oxygen via wide-bore nasal cannulae and may be useful in providing respiratory support for adults experiencing acute respiratory failure, or at risk of acute respiratory failure, in the intensive care unit (ICU). This is an update of an earlier version of the review. Objectives To assess the effectiveness of HFNC compared to standard oxygen therapy, or non-invasive ventilation (NIV) or non-invasive positive pressure ventilation (NIPPV), for respiratory support in adults in the ICU. Search methods We searched CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane COVID-19 Register (17 April 2020), clinical trial registers (6 April 2020) and conducted forward and backward citation searches. Selection criteria We included randomized controlled studies (RCTs) with a parallel-group or cross-over design comparing HFNC use versus other types of non-invasive respiratory support (standard oxygen therapy via nasal cannulae or mask;or NIV or NIPPV which included continuous positive airway pressure and bilevel positive airway pressure) in adults admitted to the ICU. Data collection and analysis We used standard methodological procedures as expected by Cochrane.
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Background: There is an unmet need for new treatments for hand osteoarthri-tis (OA). Symptomatic hand OA is more common in women and its incidence increases round the age of menopause. Pre-clinical, epidemiological and post hoc studies in Hormone Replacement Therapy (HRT) trials implicate estrogen defciency as of likely importance in OA aetiopathogenesis. No clinical trials of HRT have been carried out in hand OA to date. The licensed HRT Duavive (conjugated estrogens + SERM bazedoxifene) was selected on its potential for efficacy and tolerability. Objectives: We set out to determine the feasibility and acceptability of this form of HRT in post-menopausal women with hand OA, to generate proof of concept data and refne methods for a full study. Methods: ISRCTN12196200. Females aged 40-65 yrs and 1-10yrs after fnal menstrual period with hand OA fulflling ACR criteria and 2+ painful hand joints were recruited. Eligibility incorporated best practice for HRT prescription but did not require menopausal symptoms. Recruitment was at 3 sites in primary/secondary care, including directly from the community. Design was parallel group, double-blind 1:1 randomisation of Duavive or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before stopping. Routes and rates of recruitment and the acceptability of randomisation, medication (compliance, retention), and proposed outcomes were measured, and the likelihood of unblinding. Measures related to hand pain and function, menopause symptoms and joint appearance. Patient and Public Involvement actively informed study rationale, design and materials. An end of study questionnaire and 2 participant focus groups provided further acceptability data. Results: Recruitment was for 12/possible 18 months, interrupted due to COVID-19. Some study procedures were modifed to allow reopening whilst collecting all primary outcomes. 434 enquiries/referrals were received, leading to 96 telephone pre-screens, of which 33 gave written informed consent and attended face to face screening. 28/33 screened (85%) were eligible and randomised. The highest number of randomisations was from study web presence (n=7) followed by SMS text from GP surgeries (n=5). Of 401 not proceeding, 250 (62%) were ineligible, most commonly due to contraindicated medication, followed by medical contraindication, whilst 55 (14%) decided not to take part, for reasons including not wanting to take a hormone-based drug or difficulty attending study visits. Retention and compliance were excellent. All 28 participants completed all study follow ups, with only 3 withdrawals from treatment due to AEs, 2 of these at week 24 and all in the placebo arm. There were no serious AEs. High levels of completeness of all study outcome measures were achieved. Bang's blinding index suggested that participants/investigators were well blinded. There were overall high/good levels of satisfaction with taking part in the study. 26/28 (92%) would recommend taking part to others with hand OA (irrespective of study arm). Many found the fexibility offered by a combination of remote and face to face visits (due to the pandemic) attractive. Additional insights from focus groups were to include hand stiffness as well as pain measures but to reduce the overall number of questions. Conclusion: Despite COVID-19 and a reduced recruitment period, this study recruited sufficient numbers to assess feasibility outcomes. Randomisation of eligible people and retention rates were high. A mixture of remote and face to face visits due to COVID-19 probably improved recruitment and retention and was supported by participants, who were generally satisfed with the study design and medication. The study provided useful insight and improvements that would be incorporated into a future study. Overall, this feasibility study showed that with clear messaging on eligibility and a defned recruitment strategy, recruitment and retention to a study testing this treatment is possible.
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Background: SB5, an adalimumab (ADL) biosimilar, was developed in a low-concentration (40 mg/0.8 mL, SB5-LC) aligned with the reference ADL product. Pharmacokinetics (PK) equivalence of SB5 and reference ADL was demonstrated in a Phase I study conducted in healthy subjects1. Equivalent efficacy and comparable safety between 40 mg/0.8 mL SB5 and 40 mg/0.8 mL reference ADL were demonstrated in a Phase III study conducted in patients with rheumatoid arthritis2. High-concentration, low-volume, citrate-free SB5 (40 mg/0.4 mL, SB5-HC) has been developed as a part of life cycle management in line with the reference ADL formulation. Objectives: To compare the PK, safety, and tolerability of the newly developed SB5-HC (40 mg/0.4 mL) to prior SB5-LC (40 mg/0.8 mL) in healthy male subjects. Methods: This study was a randomised, single-blind, two-arm, parallel group, single-dose study in healthy male subjects. Subjects were randomised in a ratio of 1:1 to receive a single dose of either SB5-HC or SB5-LC by subcutaneous injection on Day 1 and then observed for 57 days during which the PK, safety, and immunogenicity were evaluated. The serum concentration of ADL was measured using an enzyme-linked immunosorbent assay. The primary PK parameters were area under the concentration-time curve from time zero to infnity (AUCinf) and maximum serum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confdence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatment groups compared were completely contained within the pre-defned equivalence margin of 0.80 to 1.25 using an analysis of variance. Results: Of 188 randomised subjects, 187 subjects were analysed as PK Analysis Set (PKS) (n=93 in SB5-HC and n=94 in SB5-LC). One subject was excluded from the PKS in SB5-HC group (major protocol deviation for not being withdrawn in the event of confrmed COVID-19). The geometric LSMeans ratios for the comparison of SB5-HC and SB5-LC for AUCinf and Cmax were 0.920 and 0.984, respectively, and the corresponding 90% CIs were within the pre-defned equivalence margin of 0.80 to 1.25 (Table 1), indicating the two treatment groups are bioequivalent. There were no deaths, serious adverse events or discontinuation of the study due to treatment-emergent adverse events (TEAEs) during the study. The proportions of subjects who experienced TEAEs were comparable between the two treatment groups (44.7% in SB5-HC vs 51.1% in SB5-LC). The most frequent TEAEs were headache (10.6% in SB5-HC vs 12.8% in SB5-LC). Conclusion: This study demonstrated PK equivalence between SB5-HC and SB5-LC in healthy subjects. Both SB5-HC and SB5-LC were generally well tolerated with similar safety profiles.
ABSTRACT
Background: Studies of mobile diabetes applications (apps) have demonstrated improvements in glycemia, and patient-reported outcomes (PROs). In addition, shift to shorter pen needles (PN) and guidance on proper injection techniques have shown the potential for reduced glycemic variability. The purpose is to determine the impact of using a diabetes mobile app plus a novel 4 mm PN on PROs and glycemic outcomes in type 2 diabetes mellitus (T2DM) for multiple daily injection (MDI) insulin users. Materials and methods: In this 8-week prospective, parallel-group, randomized controlled trial, subjects either received (1:1) intervention (BD Diabetes Care [DC] App + BD Nano TM 2nd Gen PN) or control therapy. Controls used their current PN and did not use diabetes apps. Results: Fifty-eight subjects were randomized. Fifty-seven completed the study (intervention n = 27, control n = 30). At study end, there were no significant differences in PROs between groups, except improved medication adherence (ARMS-D) in controls. From flash glucose monitoring (fGM) data, there were no significant differences in most glycemic measures between groups except for a trend for improved glycemic variability [mean amplitude of the glycemic excursions (MAGE)] in the Intervention (p = 0.06). Controls had significantly reduced time spent in hypoglycemia but had 2 to 3-fold higher incidence at baseline. In general, Intervention subjects reported satisfaction with both the app and PN. Conclusions: This is the first BD DC App study, in combination with BD Nano TM 2nd Gen PN, to assess glycemic outcomes. This combination intervention shows promising results for reduced glycemic variability and the potential to positively impact self-management.
ABSTRACT
To evaluate the efficacy and safety of synthesized drug OUTBREAK, an Ayurvedic formulation for fever of viral origin in mild and moderate COVID19 positive patients. This is the prospective, randomized, multicentre, open label, parallel group interventional clinical endpoint study. Patients coming for the general outpatient department, were screened for viral fever by using the hematological, Biochemical and microbiological antibody assays. One Hundred patients who satisfied the selection criteria were enrolled in the study. Participants were randomized into 2 groups with 50 patients in each group. Patients were given standard treatment. In addition, Tab. OUTBREAK of Bageo Pharmaceuticals Pvt. Ltd., was administered to test groups. There is a highly significant improvement (P<0.001) in the subjects temperature, fever score, headache and SpO2 suggesting a good Analgesic and antipyretic activity of OUTBREAK. There is asignificant improvement in platelet count in the OUTBREAK treated group (P<0.01) when compared to the control group, proving its efficacy intreating thrombocytopenia. The improvement (P<0.01) in the random Sugar level in the OUTBREAK treated group depicts the anti-diabetic property of OUTBREAK.The improvement (P<0.01) in the WBC count in the OUTBREAK treated group depicts the antiviral property of OUTBREAK. The overall quality of life was better in OUTBREAK treated group compared to the control group. There were no serious adverse events reported. OUTBREAK is safe and efficacious in reversing thrombocytopenia and thus normalizing the platelet counts and relieving the clinical signs and symptoms (fever, headache and SpO2) of viral fever associated with thrombocytopenia and other cases of viral fever without thrombocytopenia. OUTBREAK is having good anti-viral, anti-pyretic and immuno-modulatory property.
ABSTRACT
SARS-CoV-2 is a coronavirus that infects epithelial cells in the naso- and oropharynx before infecting epithelial cells of the lower airways and alveoli and in severe COVID-19 spreading systemically and inducing a systemic inflammatory response. SARS-CoV-2 is spread mainly by virus particles in droplets and aerosols. This suggests that inhaled therapies may be useful in the treatment of early COVID-19 disease before severe respiratory systemic features develop and potentially in reducing transmission of the virus in the community. To be effective any inhaled therapy must be rapidly acting to prevent viral replication in respiratory epithelial cells to prevent the disease spreading down the respiratory tract and into the systemic circulation. It also needs to be safe and available for early prescription in order to prevent severe disease and hospitalisation. The development of inhaled therapies for COVID-19 may involved repurposing of existing inhaled therapies or developing inhaled formulations of new drugs with antiviral effects. Patients with asthma and COPD were reported to be less likely to be hospitalised with SARS-CoV-2 infection despite the concern that this coronavirus would have severe consequences for these patients as coronaviruses are known to trigger severe exacerbations. One possibility was that this may be due to the widespread treatment with inhaled corticosteroids (ICS), which are known to suppress ACE2 and TMPRSS2 on epithelial cells that are key entry receptors for the virus and also reduce virus replication in vitro. A community based open label parallel group phase 2 study of the ICS budesonide (800 lg bid until recovery) in people with early symptoms (within 7 days of onset) of COVID-19 and confirmed by PCR testing (STOIC) showed that only 1/69 people in the ICS group developed severe disease compared with 10/70 in the usual care group.1 Clinical recovery was also shorter in the ICS group. This finding was confirmed in an open label study of inhaled budesonide in individuals over the age of 65 years at risk from severe COVID-19 (PRINCIPLE), which showed a reduction in time to recovery and a trend towards reduced hospitalisation and death.2 Several other trials, including double-blind studies, of ICS in early COVID-19 are currently underway with different corticosteroids, including ciclesonide, which appears to be the most effective against SARS-CoV-2 in vitro.3 However, a recent double-blind study of nasal and inhaled ciclesonide failed to show any benefit in early COVID-19, although the population was mainly young adults who have a low risk of disease progression.4 The mechanism of action of ICS in COVID- 19 has not yet been established, but may involve reduced viral entry due to suppression of ACE2 and TMPRSS2 in airway epithelial cells, reduced viral proliferation or reduced inflammatory mediators secreted by airway epithelial cells that may promote viral spreading. Interferon b1 is currently approve for treating multiple sclerosis. Nebulised IFN-b1a (SNG001) gave a greater degree of clinical improvement in hospitalised COVID-19 patients and a reduction on symptoms (mainly dyspnoea) compared to with placebo and was well tolerated.5 However, studies in early disease are underway but have not yet been reported, although there are logistical problems in the need for a nebuliser to deliver the drug. Inhaled PUL-42 is a combination of a TLR2/6 and a TLR9 inhibitors which is effective in a single inhaled dose against SARS-CoV and MERS-CoV infection in mice and reduces the lung viral load.6 This drug is now in clinical trials for COVID-19. Other inhaled drugs, including antivirals such as remdesivir and niclosamide, are also in development.
ABSTRACT
Background: A strategy for maintaining and/or improving cardiorespiratory fitness (CRF) in the growing population of cancer survivors is of major clinical importance in the COVID-19 era. With the aim of increasing CRF, recent studies have focused on the use of high-intensity interval training (HIIT) in supervised experimental settings, which appeared to be more beneficial than usual care in cancer survivors at all stages of treatment and aftercare. However, the effect of unsupervised HIIT on increasing CRF in breast cancer survivors is not known. Purpose: To determine whether the newly developed habit-B program, which involves home-based smartphone-supported HIIT using body-weight exercises, improves CRF in early-stage breast cancer survivors. We hypothesized that the habit-B program would improve VO2peak compared with a control group. Methods: This single-center, 12-week, parallel-group, single-blind, randomized controlled trial involved 50 women with stage I-IIa breast cancer, aged 20 to 59 years, who had completed initial treatment except for hormone therapy. Participants wore a smartwatch and were randomized to either the exercise or control group from May 27, 2019 through November 30, 2020. The planned sample size was 60 Spatients to detect the increase of 2.0 ml/kg/min change in VO2peak with a standard deviation of 2.6 ml/kg/min, one-sided significance level of 2.5% and 80% power. The exercise group underwent home-based HIIT using a smartphone and a Fitbit Versa thrice weekly for 12 weeks (three times per week). The primary outcome was the 12-week change in peak oxygen uptake (VO2peak;mL/kg/min) between the groups. Other outcomes included muscle strength, 6-min walk test, resting heart rate, physical activity, fatigue, safety, and quality of life. Results: Of the 50 participants, 44 (exercise group, n=23;control group, n=21) completed the CRF assessment and 6 did not because of issues related to the COVID-19 pandemic. The change in VO2peak increased significantly in the exercise group (0.9 [95%CI, 0.1 to 1.7]) compared with the control group (-0.8 [95%CI,-1.5 to-0.1]) (mean difference, 1.7 [95% CI, 0.7 to 2.7], p <.01). Leg strength also increased significantly in the exercise group compared with the control group (mean difference, 13.5 [95% CI, 2.9 to 24.1], p <.01). Changes in other outcomes were not significantly different between the groups. Conclusion: A home-based HIIT intervention can lead to improved cardiorespiratory fitness and muscle strength in early-stage breast cancer survivors;however, a multicenter pragmatic clinical trial is required to confirm the benefits of the habit-B program.