Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes

IntroductionType 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12–45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups.Methods and analysisMinimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5–25 years diagnosed with T1D within 3–9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12–15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements.Ethics and disseminationMELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu).Trial registration numberNCT03936634; Pre-results.

Research on the Impact of Environmental Regulations on Industrial Green Total Factor Productivity: Perspectives on the Changes in the Allocation Ratio of Factors among Different Industries

This paper constructs a two-sector manufacturer model of endogenous technological progress. We analyze the impact of environmental regulations on the factor input and output of different industries. Then, we reveal the intermediary role of inter-industry factor allocation in the impact of environmental regulations on industrial green total factor productivity (GTFP). Finally, the paper uses panel data from 30 provinces in China’s industry from 2000 to 2017 to conduct empirical tests. We can draw the following conclusions: (1) The relative magnitude of the output compensation of the production department and the innovation compensation of the R&D department could change the impact of environmental regulations on the input and output of inter-industry factors, and the comprehensive effects of both input and output will affect the level of GTFP. (2) The curve of the direct impact of environmental regulations on GTFP is in an inverted “U” shape. However, the production factor allocation ratio can “reverse” the inhibitory effect of high-intensity regulations on GTFP. (3) The capital factor has a greater impact on the regulatory effect, but the labor factor has a more lasting impact on the regulatory effect. High-strength environmental regulations can enhance manufacturers’ preference for human capital. Therefore, formulating environmental regulatory policies oriented to improve the ratio of factor allocation, mixing different types of regulatory policies, and increasing investment in human capital are all conducive to accelerating the transformation and upgrading of China’s industrial structure and achieving high-quality development of the industrial economy.

Adaptive group sequential survival comparisons based on log-rank and pointwise test statistics

Whereas the theory of confirmatory adaptive designs is well understood for uncensored data, implementation of adaptive designs in the context of survival trials remains challenging. Commonly used adaptive survival tests are based on the independent increments structure of the log-rank statistic. This implies some relevant limitations: On the one hand, essentially only the interim log-rank statistic may be used for design modifications (such as data-dependent sample size recalculation). Furthermore, the treatment arm allocation ratio in these classical methods is assumed to be constant throughout the trial period. Here, we propose an extension of the independent increments approach to adaptive survival tests that addresses some of these limitations. We present a confirmatory adaptive two-sample log-rank test that allows rejection regions and sample size recalculation rules to be based not only on the interim log-rank statistic, but also on point-wise survival rate estimates, simultaneously. In addition, the possibility is opened to adapt the treatment arm allocation ratio after each interim analysis in a data-dependent way. The ability to include point-wise survival rate estimators in the rejection region of a test for comparing survival curves might be attractive, e.g., for seamless phase II/III designs. Data-dependent adaptation of the allocation ratio could be helpful in multi-arm trials in order to successively steer recruitment into the study arms with the greatest chances of success. The methodology is motivated by the LOGGIC Europe Trial from pediatric oncology. Distributional properties are derived using martingale techniques in the large sample limit. Small sample properties are studied by simulation.

Epidural morphine in COVID ARDS patients with high respiratory drive: a structured summary of a study protocol for a randomised controlled trial

Objectives We aim to study the effect of epidural morphine as a means to reduce high respiratory drive in COVID 19 patients on non-invasive ventilation (NIV)—primary end point—and to study its effect on respiratory parameters, subjective patient comfort, rates of endotracheal intubation, duration of mechanical ventilation and mortality. Trial design Parallel group, randomised, double blind, single centre placebo control trial. Allocation ratio 1:1, superiority trial Participants Trial site and population—COVID ICU patients in the All India Institute of Medical Sciences (AIIMS) Bhubaneswar, Odisha, India Inclusion and exclusion criteria Inclusion criteria Adult patients on NIV with COVID-19 Exclusion criteria Metabolic acidosis HCO3-< 16 and pH < 7.2. Severe hypoxemia warranting cessation of NIV and intubation, non-acceptance of NIV and proven sepsis. Technical difficulty for epidural catheterization, coagulation abnormalities, low respiratory drive and EOL orders. Sources or methods of recruitment—daily discussion at 8 am of new admissions to COVID ICU on NIV—consenting adult patients with COVID19 on NIV and high respiratory drive; not meeting exclusion criteria will be recruited for the trial and randomised. Intervention and comparator Patients of both groups will be turned to a lateral or sitting position (as comfortable), and an injection of local anaesthetic be given at lumbar 2–3/3–4 space. In the intervention group, an epidural catheter will be inserted using aseptic technique and fixed to the skin. The control group will have a sham catheter fixed exactly like in the intervention group, but not entering the epidural space. The intervention group will be administered injection morphine sulphate once every 18–24 h into the epidural space. The doses will be escalated daily (5–10 mg), titrated to effect: escalation limited by hypoventilation resulting in respiratory acidosis (pH < 7.2). The intervention will continue for a minimum of 2 doses and a maximum of 5 doses (96 h) of morphine. It will be stopped if the epidural catheter gets dislodged before the second dose or the patient is weaned off non-invasive ventilation to high flow mask for a continuous period of 24 h or requires endotracheal intubation. The patient will be followed up till death or 28 days after ICU discharge. Main outcomes Primary outcome—diaphragm thickening index fraction (average of minimum 3 readings) Secondary outcomes—ventilator parameters, sedation and pain scores, subjective comfort and dyspnoea scores, time to intubation, length of stay on NIV and 28-day mortality Timing of outcome assessment—every 8th hour assessment for 24 h after the last dose of epidural morphine or 120 h whichever is greater Randomisation A central random number list will be kept with the study research assistant. She will randomise according to the numbers available in the list using an allocation ratio of 1:1. An opaque sealed envelope concealing the allotted randomisation code will be dispatched to the ICU team. Blinding (masking) The assessor, patient, nurses and physicians will be blind to group allocation. One member of the team not involved in research will administer the intervention. Numbers to be randomised (sample size) Twenty-five patients per group; 50 patients total Trial status Protocol version 1. Not recruiting yet. Recruitment to begin by 24 July 2021 and end by 31 August 2022 Trial registration Central Trials Registry India CTRI CTRI/2021/07/035093. Registered on 23 July 2021. Prospectively registered Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Prophylactic potential of honey and Nigella sativa L. against hospital and community-based SARS-CoV-2 spread: a structured summary of a study protocol for a randomised controlled trial

Objectives Considering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019 (COVID-19) patients, the objective of the study is defined to evaluate the prophylactic role of HNS. Trial design The study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial. Participants All asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study High-risk exposure (<6 feet distance for >10min without face protection) Moderate exposure (<6 feet distance for >10min with face protection) Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study. Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Intervention and comparator In this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan. Main outcomes Primary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization. Randomisation Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure. Blinding (masking) Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking. Numbers to be randomised (sample size) 1000 participants will be enrolled in the study with 1:1 allocation. Trial Status The final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022. Trial registration Clinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Honey and Nigella Sativa in the Prophylaxis of COVID-19; A Randomized Controlled Trial

ObjectivesConsidering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019 (COVID-19) patients, the objective of the study is defined to evaluate the prophylactic role of HNS. Trial designThe study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial.ParticipantsAll asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study● High-risk exposure (<6 feet distance for >10min without face protection) ● Moderate exposure (<6 feet distance for >10min with face protection)Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study.Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Intervention and comparatorIn this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan.Main outcomesPrimary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization. RandomisationParticipants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure. Blinding (masking)Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking.Numbers to be randomised (sample size)1000 participants will be enrolled in the study with 1:1 allocation.Trial StatusThe final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022. Trial registrationClinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087.

Homogenization of Japanese Industrial Technology From the Perspective of R&D Expenses

The aim of this paper is to discuss the reasons for the decline in the profitability of Japanese R&D from the perspective of in-house R&D efforts. Focusing on changes in the allocation ratio of in-house R&D expenses by industry from 1972 to 2017, technological structure changes in the Japanese industry during that period are empirically analyzed. Based on the analysis, the technological structure of the Japanese industry has been consistently moving toward homogenization since 1972. Homogenization is mainly directed toward the related technical fields of automobiles and information and communication machinery/equipment/electronic parts, which are the main industries that currently lead the Japanese economy. While the types of technical knowledge possessed by the Japanese industry are decreasing, there is a lack of R&D activities that will create new products and markets and increase the pie of the Japanese industry or greatly promote the metabolism of technology of the entire industry.

Efektivitas Penyaluran Dana Zakat Infak dan Sedekah pada Badan Amil Zakat Nasional (Periode Tahun 2016-2018)

Zakah, infaq and Shodaqa are instrument of Islamic social economics having a role in improving the welfare of ummah. The success of this is largely determined by the management of ZIS fund by thr Badan Amil Zakat Nasional. The purpose of this paper is to measure the effectiveness of ZIS fund disbursement by BAZNAS in the period 2016 to 2018. Using quantitative methods with secondary data, namely the financial statements of the audit results of BAZNAS's financial statements during that period, by adopting the calculation of the activity ratio from Puskas BAZNAS. The activity ratio is a measure of the effectiveness of the distribution of zakat, infaq and shodaqa funds. The results showed that BAZNAS during the 2016-2018 period was effective in distributing Zakat funds and was very effective in distributing Infaq shodaqa funds with the Allocation Ratio Zakat and Infaq and Shodaqa ratio of 93% and 106%. The activeness in collecting and distributing ZIS funds is still below 1, it means that the ZIS funds that are collected are not fully channeled during that period or have settled for more than 12 months, so that the ZIS turnover in the BAZNAS institution is said to be still not effective in distributing ZIS funds. Thus the performance of BAZNAS is important to improve so effective in the welfare of the people.

INFLUENCE OF GOVERNMENT CREDIT RISK ON PPP PROJECTS IN OPERATION STAGE

In PPP projects, insufficient risk management may lead to the breakdown of partnerships and even project failures. Among them, the government credit risk is regarded as unbearable risk and a key risk affecting PPP projects because of its high frequency and impact. Therefore, based on the contractual relationship between both sides, a principal-agent model for the optimal choice of investors and the government under the government default probability is constructed. This paper explored the quantity relationship of the government credit risk and the project utility through analysing the effect of government default probability perceived by both parties on the investor’s optimal effort level and government allocation ratio. The results demonstrate that the government credit risk will decrease the effort level of investors and have a negative impact on the utility of the project. Furthermore, the government’s modification of the contract allocation ratio based on its own credit rating can offset the negative impact of its credit risk on the effectiveness of the project. But this regulatory effect is limited. The findings effectively provide some insights and theoretical basis for solving the negative effects of government credit risk.

A quadruple blinded placebo controlled randomised trial to evaluate the effectiveness of an Iodine complex for patients with mild to moderate COVID-19 in Pakistan (I-COVID-PK): A structured summary of a study protocol for a randomised controlled trial

Objectives The objective of the study is to measure the efficacy of ionic-iodine polymer complex [1] for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients. Trial design The trial will be closed label, randomized and placebo-controlled with a 1:1:1:1 allocation ratio and superiority framework. Participants All PCR confirmed COVID-19 adult patients including non-pregnant females, with mild to moderate disease, will be enrolled from Shaikh Zayed Post-Graduate Medical Complex, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Patients with any pre-existing chronic illness will be excluded from the study. Intervention and comparator In this multi-armed study ionic-iodine polymer complex with 200 mg of elemental iodine will be given using three formulations to evaluate efficacy. Patients will be receiving either encapsulated iodine complex of 200 mg (arm A), iodine complex syrup form 40 ml (arm B), iodine complex throat spray of 2 puffs (arm C) or empty capsule (arm D) as placebo; all three times a day. All the 4 arms will be receiving standard care as per version 3.0 of the clinical management guidelines for COVID-19 established by the Ministry of National Health Services of Pakistan. Main outcomes Primary outcomes will be viral clearance with radiological and clinical improvement. SARS-CoV-2 RT-PCR and HRCT chest scans will be done on the admission day and then after every fourth day for 12 days or till the symptoms are resolved. RT-PCR will only be shown as positive or negative while HRCT chest scoring will be done depending on the area and severity of lung involvement [2]. Time taken for the alleviation of symptoms will be calculated by the number of days the patient remained symptomatic. 30-day mortality will be considered as a secondary outcome. Randomisation Stratification for initial COVID-19 status (or days from initial symptoms as a proxy), age groups, gender, baseline severity of symptoms and co-morbidities will be used to ensure that the study arms remain balanced in size for the 1:1:1:1 allocation ratio. Randomization will be done using the lottery method. As patients are being admitted at different times, they will be recruited after obtaining their voluntary written informed consent following all standard protocols of the infection, control and disinfection. Blinding (masking) This is a quadruple (participants, care providers, investigators and outcomes assessors) blinded study where only the study’s Primary Investigator will have information about the arms and their interventions. Numbers to be randomised (sample size) 200 patients will be randomized into four groups with three experimental and one placebo arm. Trial Status Protocol Version Number is 2.3 and it is approved from IRB Shaikh Zayed Hospital with ID SZMC/IRB/Internal0056/2020 on July 14th, 2020. The recruitment is in progress. It was started on July 30, 2020, and the estimated end date for the trial is August 15, 2021. Trial registration Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04473261 dated July 16, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.