Open Label Research Articles

A single-center, open label, randomized, controlled study of hydroxychloroquine sulfate in the treatment of low risk PLA2R-associated membranous nephropathy

ObjectiveTo evaluate the efficacy and safety of hydroxychloroquine sulfate (HCQ) in the treatment of low risk phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN).MethodsA total of 110 patients with low risk PLA2R-associated MN were included in the study. Patients who met the inclusion and exclusion criteria were assigned randomly to two groups: the HCQ treatment group and the control group. The control group received standard supportive treatment according to the guidelines, while the HCQ treatment group received HCQ in addition to the supportive treatment. The clinical data of the patients were analyzed, with comparisons made at baseline and during the six-month follow-up period. Any adverse reactions were recorded.ResultsThe baseline data were comparable between the HCQ treatment group and the control group. At the end of the six-month follow-up period, the reductions in urine protein excretion and serum PLA2R antibody titer were more notable in the HCQ treatment group than those in the control group, with these differences being statistically significant (p < 0.05). Compared to the control group, the HCQ treatment group had fewer patients who were converted from low risk to moderate-to-high risk (p = 0.084). There were also no severe adverse reactions in the HCQ treatment group.ConclusionIn patients with low risk PLA2R-associated MN, adequate supportive therapy combined with HCQ is superior to supportive therapy alone in controlling proteinuria and reducing serum PLA2R antibody titers. Additionally, our study demonstrated that the incidence of adverse reactions did not increase.Trial registrationThis study was registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757, Date of registration: 2019-03-08).

High flow nasal cannula oxygen therapy versus non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease with acute-moderate hypercapnic respiratory failure: a randomized controlled non-inferiority trial

BackgroundAlthough cumulative studies have demonstrated a beneficial effect of high-flow nasal cannula oxygen (HFNC) in acute hypercapnic respiratory failure, randomized trials to compare HFNC with non-invasive ventilation (NIV) as initial treatment in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients with acute-moderate hypercapnic respiratory failure are limited. The aim of this randomized, open label, non-inferiority trial was to compare treatment failure rates between HFNC and NIV in such patients.MethodsPatients diagnosed with AECOPD with a baseline arterial blood gas pH between 7.25 and 7.35 and PaCO2 ≥ 50 mmHg admitted to two intensive care units (ICUs) at a large tertiary academic teaching hospital between March 2018 and December 2022 were randomly assigned to HFNC or NIV. The primary endpoint was the rate of treatment failure, defined as endotracheal intubation or a switch to the other study treatment modality. Secondary endpoints were rates of intubation or treatment change, blood gas values, vital signs at one, 12, and 48 h, 28-day mortality, as well as ICU and hospital lengths of stay.Results225 total patients (113 in the HFNC group and 112 in the NIV group) were included in the intention-to-treat analysis. The failure rate of the HFNC group was 25.7%, while the NIV group was 14.3%. The failure rate risk difference between the two groups was 11.38% (95% CI 0.25–21.20, P = 0.033), which was higher than the non-inferiority cut-off of 9%. In the per-protocol analysis, treatment failure occurred in 28 of 110 patients (25.5%) in the HFNC group and 15 of 109 patients (13.8%) in the NIV group (risk difference, 11.69%; 95% CI 0.48–22.60). The intubation rate in the HFNC group was higher than in the NIV group (14.2% vs 5.4%, P = 0.026). The treatment switch rate, ICU and hospital length of stay or 28-day mortality in the HFNC group were not statistically different from the NIV group (all P > 0.05).ConclusionHFNC was not shown to be non-inferior to NIV and resulted in a higher incidence of treatment failure than NIV when used as the initial respiratory support for AECOPD patients with acute-moderate hypercapnic respiratory failure.Trial registration: chictr.org (ChiCTR1800014553). Registered 21 January 2018, http://www.chictr.org.cn

Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial

BackgroundMild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy.MethodsThe COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition.DiscussionThe COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds.Trial registration numberNCT05889507 June 5, 2023.

Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study

BackgroundIn the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.MethodsPatients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.ResultsOf 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).ConclusionIn SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

Twelve-month results from a randomized controlled trial comparing differential target multiplexed spinal cord stimulation and conventional spinal cord stimulation in subjects with chronic refractory axial low back pain not eligible for spine surgery

BackgroundSuccessful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). MethodsThis is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. ConclusionDTM SCS for chronic CLBP in non-surgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

Outpatient elective induction of labour at 39 weeks’ gestation (HOME INDUCTION): an open-label, randomised, controlled, phase III, non-inferiority trial

The increased demand for induction of labour (IOL) at 39 weeks' gestation in normal-risk nulliparous patients creates significant logistical challenges for busy maternity units. A potential innovation is commencing induction by means of outpatient cervical ripening, using either a vaginal prostaglandin preparation (Propess) or an osmotic cervical dilator (Dilapan-S). A Phase III, open label, single centre non-inferiority trial (EudraCT number 2019-004697-25) randomised healthy nulliparous women who chose elective IOL at 39 weeks to one of three methods of initial cervical ripening, specifically 12h of Dilapan-S(D12), 24h of Dilapan-S(D24), or 24h of Propess(P24) between November 2020 and July 2023. After initial administration of the IOL agent in the hospital, participants returned home for 12 or 24h, before readmission to complete delivery. The primary outcome was vaginal delivery achieved at any time, and this was compared in a non-inferiority analysis of Dilapan-S compared to Propess, within a 10% non-inferiority margin. Secondary outcomes included pairwise comparisons for each induction agent, and a range of logistical factors, such as time to delivery, the need for an additional cervical ripening agent, and length of hospital stay. Of the 327 women randomised at 38 weeks, 271 (83%) completed the induction intervention. The D24 and P24 groups showed similarly high rates of vaginal delivery, 75% and 76% respectively. D12 had a lower vaginal delivery rate of 64% and consequently the overall comparison of Dilapan-S to Propess did not demonstrate non-inferiority (difference=-6%, 95% CI=-17%, 5%) because the lower 95% CI exceeded the-10% threshold of non-inferiority. The majority of participants across all groups were delivered by any means within 72h of starting the induction process, inclusive of time spent at home (89% of the D24 group, 98% of the D12 group, 95% of the P24 group). There were no differences in rates of adverse events between groups. There were similarly high vaginal delivery rates for D24 and P24, with at least 75% of patients successfully delivering vaginally following outpatient cervical ripening, with no significant adverse maternal or neonatal outcomes. The Rotunda Foundation, Medicem Technology s.r.o.

Preoperative short-course radiotherapy followed by chemotherapy and PD-1 inhibitor administration for locally advanced rectal cancer: A study protocol of a randomized phase II/III trial (STELLAR II study).

For patients with locally advanced rectal cancer, previous STELLAR studies have shown that a new adjuvant treatment paradigm of short-course radiotherapy followed by neoadjuvant chemotherapy can achieve pathological complete response rates superior to those of standard care; however, the 3-year DFS is inferior to neoadjuvant concurrent radiotherapy. Recent studies have shown that immune checkpoint inhibitors may improve the prognosis of rectal cancer and have good synergy with radiotherapy. Therefore, neoadjuvant chemotherapy combined with immune checkpoint inhibitors after a short course of radiotherapy has the potential to further improve complete response rates and prognosis. The STELLAR II study is a multicentre, open label, two-arm randomized, phase II/III trial of short-course radiotherapy followed by neoadjuvant chemotherapy concurrent with immunotherapy for locally advanced rectal cancer. A total of 588 patients with locally advanced rectal cancer (LARC) will be randomly assigned to the experimental and control groups. The experimental group will receive short-course radiotherapy and neoadjuvant chemotherapy in combination with sindilizumab, while the control group will receive short-course radiotherapy and neoadjuvant chemotherapy. Both groups will subsequently receive either total rectal mesenteric resection or a watch & wait (W&W) strategy. The phase II primary endpoint is the complete remission rate, and the secondary endpoints include grade 3-4 adverse events, perioperative complications, R0 resection rate, overall survival, local recurrence rate, distant metastasis rate and quality of life score. A seamless phase II/III randomized controlled design will be used to investigate the effectiveness and safety of the TNT strategy with the addition of immunotherapy. The trial opened, and the first patient was recruited on 31 August 2022. Trial registration number and date of registration: ClinicalTrials.gov NCT05484024, 29 July 2022. The STELLAR II trial will prospectively evaluate the efficacy of TNT treatment strategies that incorporate immune checkpoint inhibitors. The trial will yield important information to guide routine management of patients with local advanced rectal cancer.

CLINICAL EVALUATION OF SUSHVIKADI VATI IN PURISHAJA KRIMI(PIN WORM) (A STUDY PROTOCOL)

The term "Krimi" in Ayurveda refers to all worms and microbes. The concept of krimi is not new; references to it date back to the Vedic era. The literature on Ayurveda describes the visible and invisible, or macro and micro, organisms that impact both living and non-living objects in the biosphere. In contemporary medical science, worms and bacteria are studied under different branches called helminthology and microbiology, respectively. However, in Ayurveda, the term "Krimi" refers to both types of worms and microbes. All acharyas in Ayurveda used the name "Krimi," and the majority of authors explained the term's classification, causes, symptoms, and treatments. Ayurvedic doctors have an understanding of Krimis and Krimi rogas ; they have identified as different varieties of Krimis.Thus, in the present study Purishaja Krimi(Pin worm) is taken as the subject of intervention with the drug ‘Sushvikadi Vati’ mentioned in a Arogya Raksha Kalpadrumah, krimi rog chikitsa adhyaya 10) MATERIALS AND METHODS : This prospective, open label, randomized clinical trial will be conducted at, School Of Ayurveda D.Y. Patil Deemed To Be University Navi Mumbai. A total of 60 children of aged 4-13 years irrespective of gender with classical symptoms of Purishaja Krimi (Pin worm )will be enrolled in the study. The outcome will be assessed according to the subjective and objective parameters established respective-ly for the study on each visit. Safety will be assessed based on the incidence of adverse events. DISCUSSION AND CONCLUSION: Krimi is the disease of GIT, and it has aaharaj and viharaja Nidana and its samprapti involves vitiation of Tridosha . Its samprapti involves agnimandya and mala dravata and the Ayurvedic formulation chosen for this study, “SUSHVIKADI VATI” usually have Krimighna property out-comes of this trial will suggest probable therapeutic options for the effective management of krimi of children.

Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study.

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-mo treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20mg/kg open label. Therefore, only results from the 2, 8, and 20mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular volumetric bone mineral density (vBMD) from baseline at month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro-finite element (microFE)-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12mo, there was a significant increase in mean (SE) failure load in the 20mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p>05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.

A phase 1 open label study to assess the human mass balance and metabolite profile of 14C-fosmanogepix, a novel Gwt-1 inhibitor in healthy male participants.

This study is registered with ClinicalTrials.gov as NCT04804059.

Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial.

Cervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB <37 weeks between each intervention in women who develop a short cervix in pregnancy. SuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring <25 mm between 14+0 and 23+6 weeks' gestation were eligible for randomisation (1:1:1) to receive either vaginal cervical cerclage (n = 128), cervical pessary (n = 126), or vaginal progesterone (n = 132). Minimisation variables were gestation at recruitment, body mass index (BMI), and risk factor for PTB. The primary outcome was PTB <37 weeks' gestation. Secondary outcomes included PTB <34 weeks', <30 weeks', and adverse perinatal outcome. Analysis was by intention to treat. A total of 386 pregnant women between 14+0 and 23+6 weeks' gestation with a cervical length <25 mm were randomised to one of the 3 interventions. Of these women, 67% were of white ethnicity, 18% black ethnicity, and 7.5% Asian ethnicity. Mean BMI was 25.6. Over 85% of women had prior risk factors for PTB; 39.1% had experienced a spontaneous PTB or midtrimester loss (>14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB <37 weeks (39/127 versus 38/122 versus 32/132, p = 0.4, cerclage versus pessary risk difference (RD) -0.7% [-12.1 to 10.7], cerclage versus progesterone RD 6.2% [-5.0 to 17.0], and progesterone versus pessary RD -6.9% [-17.9 to 4.1]). Similarly, no difference was seen for PTB <34 and 30 weeks, nor adverse perinatal outcome. There were some differences in the mild side effect profile between interventions (vaginal discharge and bleeding) and women randomised to progesterone reported more severe abdominal pain. A small proportion of women did not receive the intervention as per protocol; however, per-protocol and as-treated analyses showed similar results. The main study limitation was that the trial was underpowered for neonatal outcomes and was stopped early due to the COVID-19 pandemic. In this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix. EU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Jasminum grandiflorum oral gel as an add-on to standard of care in radiation induced grade 2 oral mucositis - an open label pilot clinical trial

BackgroundRadiation-induced oral mucositis is one of the most critical dose-limiting toxicities associated with radiation therapy for oral cancer which can result in treatment interruption and compromise the quality of the life of cancer patients. Jati (Jasminum grandiflorum) is used in Ayurveda to treat oral conditions like stomatitis and mouth ulcers. ObjectiveTo test the feasibility of Jati oral gel as an add on therapy in grade 2 radiation-induced oral mucositis. Materials and methodsA prospective, open-label, non-randomised pilot trial was conducted on 20 patients with grade 2 radiation-induced oral mucositis at a tertiary cancer hospital. The control group received sodium bicarbonate mouthwash 4–5 times daily as the standard of care, while the intervention arm also received Jati oral gel twice daily. We used the ImageJ software for objective assessment and the Visual Analogue Scale for subjective pain assessment. The study was continued for 15 days or until the mucositis progressed to grade 3 or resolved to grade 1. ResultThere was a significant reduction in the mean pain score and mean area of mucositis in the intervention group compared to the control group. ConclusionJati oral gel is a suitable medicament as an add-on therapy in managing grade 2 radiation-induced oral mucositis.

Cost-effectiveness of a two-layer compression bandage versus standard bandage following total knee arthroplasty.

To assess the cost-effectiveness of a two-layer compression bandage versus a standard wool and crepe bandage following total knee arthroplasty, using patient-level data from the Knee Replacement Bandage Study (KReBS). A cost-utility analysis was undertaken alongside KReBS, a pragmatic, two-arm, open label, parallel-group, randomized controlled trial, in terms of the cost per quality-adjusted life year (QALY). Overall, 2,330 participants scheduled for total knee arthroplasty (TKA) were randomized to either a two-layer compression bandage or a standard wool and crepe bandage. Costs were estimated over a 12-month period from the UK NHS perspective, and health outcomes were reported as QALYs based on participants' EuroQol five-dimesion five-level questionnaire responses. Multiple imputation was used to deal with missing data and sensitivity analyses included a complete case analysis and testing of costing assumptions, with a secondary analysis exploring the inclusion of productivity losses. The base case analysis found participants in the compression bandage group accrued marginally fewer QALYs, on average, compared with those in the standard bandage group (reduction of 0.0050 QALYs (95% confidence interval (CI) -0.0051 to -0.0049)), and accumulated additional mean costs (incremental cost of £52.68 per participant (95% CI 50.56 to 54.80)). Findings remained robust to assumptions tested in sensitivity analyses, although considerable uncertainty surrounded the outcome estimates. Use of a two-layer compression bandage is marginally less effective in terms of health-related quality of life, and more expensive when compared with a standard bandage following TKA, so therefore is unlikely to provide a cost-effective option.

FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN)

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

Stem cell therapy in diabetic men with erectile dysfunction: a 24-month follow-up of safety and efficacy of two intracavernous autologous bone marrow derived mesenchymal stem cells injections, an open label phase 2 clinical trial

BackgroundRecently we reported results of phase 1 pilot clinical trial of 2 consecutive intracavernous (IC) injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) for the first time in the treatment of diabetic patients with erectile dysfunction (DM-ED). In phase 2 of this study our aim is to evaluate long term safety and efficacy of IC injections of BM-MSC on additional eight patients with DM-ED.ResultsEach patient received 2 consecutive IC injections of BM-MSC and evaluated at 1, 3, 6, 12, and 24-month time points. Primary outcome was the tolerability and safety of stem cells therapy (SCT), while the secondary outcome was improvement of erectile function (EF) as assessed using the International Index of Erectile Function-5 (IIEF-5), Erection Hardness Score (EHS) questionnaires, and Color Duplex Doppler Ultrasound (CDDU). IC injections of BM-MSCs was safe and well-tolerated. Minor local and short-term adverse events related to the bone marrow aspiration and IC injections were observed and treated conservatively. There were significant improvement in mean IIEF-5, EHS, all over the follow-up time points in comparison to the baseline. At 24-month follow up there were significant decline in the mean IIEF-5, and EHS compared to the baseline. The mean basal and 20-min peak systolic velocity was significantly higher at 3-month after the IC injections compared to baseline.ConclusionsThis phase 2 clinical trial confirmed that IC injections of BM-MSC are safe and improve EF. The decline in EF over time suggests a need for assessing repeated injections.Clinical trial registrationNCT02945462

A Randomised Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1–10 Brain Metastases

AimsTo assess in patients with 1–10 brain metastases, each of which has been treated by neurosurgery or stereotactic radiosurgery, whether hippocampal sparing whole brain radiotherapy (HS-WBRT) better spares neurocognitive function (NCF) than standard WBRT. Further, to assess whether a phase III randomised trial of HS-WBRT would be feasible in the UK. Materials and methodsA multicentre, randomised, open label phase II trial was undertaken, randomising patients to 30Gy in 10 fractions of WBRT or HS-WBRT. The primary endpoint was decline in Total recall using Hopkins Verbal Learning Test Revised (HVLT-R) at 4 months post treatment. To assess this, we aimed to recruit 84 patients over 3 years. Secondary endpoints included further measures of NCF, quality of life, duration of functional independence, local control of treated metastases, development of new metastases, disease control within the hippocampal regions, overall survival, steroid and antiepileptic medication requirements, and toxicity. ResultsThe trial closed prematurely due to slower than anticipated recruitment. From April 2016 to January 2018, 23 patients were randomised. Follow up was a median of 25 months. Fifteen patients (6 WBRT, 9 HS-WBRT) were assessed for the primary endpoint; of these, 1 in each arm experienced significant decline in the 4-month HVLT-R Total recall score (p = 0.8). Patients in the HS-WBRT arm experienced less insomnia (p < 0.01) and drowsiness (p < 0.01). There were no differences in other secondary endpoints. ConclusionA phase III randomised trial of HS-WBRT was shown not to be feasible at this time in the UK. As most randomised trials of HS-WBRT reported to date share common endpoints, including NCF, an individual patient data meta-analysis should be undertaken.

Methylprednisolone alone or combined with cyclosporine or mycophenolate mofetil for the treatment of immune-mediated hemolytic anemia in dogs, a prospective study.

Benefit of adding a second-line immunosuppressive drug to glucocorticoids for the treatment of non-associative immune-mediated hemolytic anemia (naIMHA) in dogs has not been defined prospectively. Evaluate the effectiveness of different immunosuppressive protocols in naIMHA dogs. Forty-three client-owned dogs. Open label, randomized, clinical trial. Dogs were treated with methylprednisolone (M-group), methylprednisolone plus cyclosporine (MC-group) or methylprednisolone plus mycophenolate mofetil (MM-group). Dogs were defined as responders by disappearance of signs of immune-mediated destruction and hematocrit stabilization. Frequency of responders was compared between M-group and combined protocols (MC and MM-group evaluated together), and among the 3 different therapeutic groups at 14 (T14), 30 (T30), 60 (T60) days after admission. Frequency of complications, length of hospitalization and relapse were also compared. Death rate was evaluated at discharge, T60 and 365 (T365) days. Proportion of responders was not significantly different between M-group and combined protocols (MC and MM-groups), nor among the 3 therapeutic groups at T14, T30, and T60 (P > .17). Frequency of relapse, complications, and length of hospitalization were not significantly different between M-group and dogs treated with combined protocols, nor among the 3 treatment groups (P > .22). Death was significantly more common only for MM-group compared with MC-group at T60 (+42.8%; 95% CI: 11.5-67.4; P = .009), and at T365 (+50%; 95% CI: 17.5-73.2; P = .003). Combined immunosuppressive therapy did not improve hematological response in naIMHA.

P-631 Extended letrozole regimen versus routine letrozole regimen in women with polycystic ovary syndrome undergoing their first ovulation induction cycle

Abstract Study question Whether an extended letrozole regimen could result in a higher ovulatory rate than a routine regimen in PCOS women undergoing their first ovulation induction cycle. Summary answer PCOS women using the extended letrozole regimen failed to obtain a statistically higher rate of ovulation in comparison with the routine letrozole regimen. What is known already Letrozole has become the first-line agent for ovulation induction, however, nonresponsive cycles occurred in 10-58.8% of PCOS women during their ovulation induction therapy with letrozole alone. The extended letrozole regimen has been demonstrated to be a feasible method for inducing ovulation in those nonresponders. However, whether it could be applied to all the PCOS women as a first choice in the induction of ovulation remains to be explored. Study design, size, duration This is a prospective randomized controlled trial including 148 women with PCOS undergoing their first ovulation induction cycle with letrozole from January 2021 to October 2022. Participants/materials, setting, methods Participants were randomly assigned to receive an extended letrozole regimen (5 mg letrozole daily for 7 days) or a routine regimen(5 mg letrozole daily for 5 days) for one treatment cycle. Ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, the rate of multiple pregnancies. Main results and the role of chance The ovulation rate among women receiving a 7-day regimen was slightly higher than the rate with a 5-day regimen, but it did not reach a statistical significance in both the intention-to-treat analysis (90.54%[67/74]vs. 82.43%[59/74], P = 0.065) and per-protocol analysis (90.54%[67/74]vs. 84.29%[59/70], P = 0.257). The number of preovulatory follicles was nearly identical in the two groups (1.39±0.62 vs.1.37±0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. In the per-protocol analysis, the rates of clinical pregnancy (20.27%[15/74]vs.16.95%[10/70], P = 0.343) and live birth (13.51%[10/74]vs.11.43%[8/70], P = 0.976) did not differ significantly between treatment groups. Moreover, all the conceptions were singletons without neonatal defects. Limitations, reasons for caution The major concern of the current research is its single-centre and open label nature. Additionally, the limited number of lean PCOS women with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restrict the generalizability of our findings. Wider implications of the findings Letrozole 5-day regimen remains to be the first choice for PCOS women undergoing ovulation induction therapy. Additional prospective trials with a larger sample size and different subgroups of PCOS are needed to assess the ovulatory effects of different letrozole treatment duration. Trial registration number ChiCTR2100042082

The Effectiveness of High versus Low Dose Corticosteroid therapy in Pediatric Patients with Acute Respiratory Distress Syndrome

Abstract Background When the lungs fill with fluid as a result of an infection or injury, acute respiratory distress syndrome ensues. Inflamed and fluid-filled lungs occur. They become rigid as a result, making it difficult for them to breathe fully. Blood oxygen levels will fall, endangering the health of other organs. Patients will require a ventilator to help them breathe while their lungs mend. The aim of this study was: to evaluate safety and efficacy of high dose therapy in acute respiratory distress syndrome pediatric patients and to compare safety and efficacy of high dose versus low dose therapy in Acute respiratory distress syndrome patients. Patients and Methods A Prospective open label randomized trial included 15 patients as group1 received high dose corticosteroid therapy for 3 consequent days, high dose Methyl prednisone 30 mg/kg/day and 15 patients as group 2 received low dose corticosteroid therapy for 3 consequent days, low dose Methyl prednisone 2 mg/kg/day. Clinical and laboratory data chest ultrasound and bronchoalveolar lavage to measured pre collagen peptide were studied in each group before and after corticosteroid therapy. Results In the present study 15(50%) patients received high dose steroid and 15 (50%) patients received low dose steroid, male 23 (70%), female 7 (30%), age 7 (3.0-30.0), weight (9.55 ± 6.63), there was no significant difference in prognosis and total days in pediatric intensive care unit between high and low dose corticosteroid therapy as prognosis improving 17 patients (55%), death 13(45%) and As regards total days in pediatric intensive care unit median in high dose corticosteroid therapy 24.0 (15.50-33.0) and median in low dose corticosteroid therapy 18.50 (11.0-23.50) less days in pediatric intensive care unit in low dose steroid therapy group than high dose steroid therapy group but no significant difference between two groups as regarding decrease in chest ultrasound (BLUE Score) and increase in pre collagen peptide in bronchoalveolar lavage between study groups . Conclusion there was no significant difference in prognosis and total days in pediatric intensive care unit between high and low dose corticosteroid therapy as regarding change in chest ultrasound (BLUE Score) and change in pre collagen peptide in bronchoalveolar lavage between study groups.

P-747 Can patient self-scans using a home vaginal ultrasound device be used to monitor the ovarian stimulation in ART?

Abstract Study question Can patient self-scans with a home ultrasound device, with or without professional remote online guidance, be used for ovarian and endometrial monitoring during for ART? Summary answer Follicle number/size and endometrial thickness recorded from patients’ home ultrasound self-acquired scans, especially when guided online, corresponded with standard sonographies and aspirated oocyte yield. What is known already Follicle number and size are a key parameter for monitoring the ovarian stimulation and determining the time for triggering and OPU. The endometrial thickness (EMT) and pattern are important parameters associated with implantation and pregnancy. Both are measured repeatedly in serial sonographies during the ART cycles, imposing a significant burden of time, travel and cost on patients, while adding to the clinic’s workload. Patient self-scans with a home ultrasound device can potentially relief patient travel discomfort and the clinic’s patient congestion. Study design, size, duration Open label study performed during one IVF cycle. Participants were trained to visualize uterus and ovaries using the Pulsenmore FC device. After training the patients were randomized to two groups: independent use (IU-scans) or remote online guidance by a clinical sonographer (CG-scans). Before each in-clinic scan patients obtained and recorded their pelvic scan, which were read blindly and compared to the in-clinic scans for ovaries and uterus visualization, follicles number and size, and EMT. Participants/materials, setting, methods Patients without Mullerian or pelvic pathologies undergoing stimulation for IVF. Clinical decisions and triggering were based on individual considerations and the standard in-clinic ultrasound measurements. OPU was performed 36-38h after triggering. All ultrasound scans were analyzed for image quality, number and size of follicles and EMT and compared to the in-clinic scans as the gold standard (GS). Correlation was calculated based on the Spearman Correlation Factor (SCF). Patient satisfaction was measured using a questionnaire. Main results and the role of chance Twenty-four patients completed the study, 11-CG and 13-IU. Image quality score was&amp;gt;3 and adequate uterine visualization was achieved in 100% of the CG-scans and in 87% of the IU-scans. The right ovary was imaged in 100% of the CG-scans and 85.7% of the IU-scans. The left ovary in 97.4% of the CG-scans and 85.7% of the IU-scans. CG-scans AFC correlated better with the GS than IU-scans AFC (SCF 0.85vs.0.12). Correct identification of the first follicle&amp;gt;14mm was achieved in 100% of the CG-scans and in 92% of the IU-patients. Maximal EMT from CG-scans was better correlated with the GS than the IU-scans (SCF 0.64vs.0.46), with a clinically insignificant difference (0.4mm). The number of stimulated follicles obtained from CG-scans was better correlated with the GS than IU-scans (SCF 0.94 vs.0.43). The oocytes/stimulated follicles ratio was 1.19 for the GS and 1.28 for the self scans (1.06 for CG-scans, 1.9 for IU-scans). The MII/follicles&amp;gt;14mm ratio was 1.12 for the GS and 1.49 for the self scans (1.27 for CG-scans,1.69 for IU-scans). Patients’ questionnaire revealed that 89% of patients felt comfortable to self-scan themselfs, 86.5% were interested to use the device and 75% will recommend it to their friends. Limitations, reasons for caution Self vaginal ultrasound scanning is not suitable for all patients and online support by a sonographer is required. Inter-observer differences in scan measurements should be taken into consideration. Since participation in the study was limited to one cycle, no patient learning curve for IU-scans could be evaluated. Wider implications of the findings Reliable folliculometry and endometrial measurements can be obtained from patient self-use vaginal ultrasound scans. Online assistance enhances scanning accuracy. Together with near/home lab tests, safe remote management of ovarian stimulation can be realized, reducing costs, discomfort and travel time, ultimately reducing workload for fertility clinics, and improving workforce flexibility. Trial registration number NCT05485623