ICH-GCP Guidelines Research Articles

A CASE STUDY ON THE ROLE OF NIMBA KALKA LEPA IN THE MANAGEMENT OF DUSHTA VRANA

Acharya Sushruta mentioned various types of Vrana (wound) and their management, which is vital in any surgical practice/ procedure. There has been progress in surgery in various fields, which reduces the incidence of wound infection by decreasing impediments associated with wound healing to certain limits. Still, wound management continues to be a matter of speculation. Healing of Vrana is a natural process, but due to interference with causatives becoming dushta (non-healing) and the normal healing process delayed, the prime motto of the surgeon is effective wound healing with a minimum scar and control of pain effectively. Treatment methods for Vrana are mentioned in Ayurvedic treaties. Dushta Vrana is an issue that is frequently seen in surgical practice. The presence of Dushta Vrana (non-healing ulcer) can harm the patient's state, causing various complications. Wound management of any post-surgical lesion should follow the principle of moist wound therapy and avoid agents that may impede the normal healing process. The aim of the present study is that when diagnosed early, the majority are readily treated with office-based therapy, which is curative with regard to treatment. In the present study, Vrana lepa (topical application) is the therapy for Vrana shodhana action (wound cleansing). This study reports a 60-year-old female patient with Dusta Vrana who presented with a blackish lesion (non-healing ulcer) behind the right ear for two years. The treatment protocol was sthanika (topical). The patient had significant results with this treatment, which is presented here. The study is carried out as per ICH-GCP Guidelines.

Pregnancies and Childbirth Following Advanced-Stage Hodgkin Lymphoma Treatment with Brecadd or Beacopp in the Randomized Phase III GHSG HD21 Trial

INTRODUCTION The GHSG-HD21 trial in adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) compares BrECADD (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Superior treatment-related morbidity (TRMB) and at least non-inferior efficacy of BrECADD with high progression-free survival (PFS) rates after three years were presented previously. Fertility following chemotherapy is a major concern for these mostly young AS-HL patients. Therefore, we analyzed pregnancies and childbirth rates reported in HD21. METHODS This international open-label phase III trial included adult patients aged ≤ 60 yrs with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. Frequency of pregnancies among patients or their partners were analyzed in all female patients below 40 years and male patients below 50 years included in the ITT cohort for the safety endpoint TRMB. Descriptive statistics were used to report pregnancy rates. Childbirth rates per year were compared to German population data for women between 18-40 years in the years 2016-2020, obtained from the German Federal Statistical Office (Destatis). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. RESULTS Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries and 233 trial sites. The final cohort for this analysis comprised 1200 patients (496 women and 704 men; 80.1% of ITT). Baseline characteristics were well balanced between treatment arms and median follow-up for this analysis was 40 months. 55.6% of the patients had cryocpreservation prior to chemotherapy (46.1% women, 76.4% men). At time of this analysis, there were 126 reported pregnancies during follow-up. Data was incomplete in 25 cases, and these were excluded from analysis. Overall, 97 (9.1%) patients had at least one documented pregnancy; 38 (7.2%) and 53 (9.8%) in eBEACOPP and BrECADD arm, respectively. Nine patients had more than one pregnancy. Compared to eBEACOPP, pregnancy rates following BrECADD were higher in males (5.7% vs. 2.5%) and females (13.2% vs. 11.8%). 8.2% of patients with reported pregnancy made use of cryopreservation. 82.2% of all pregnancies resulted in childbirth and 17.9% ended early (4% due to induced abortion; 13.9% due to abortion). Among patients with reported childbirth, there was a greater proportion of female patients vs. partners of male patients (63.9% vs. 36.1%); otherwise there were no notable differences between baseline characteristics or total cycles of chemotherapy in patients with reported pregnancy compared to the rest of the cohort. Median time from last day of chemotherapy until date of birth was 32 months (range 4-57). In women between 18 and 40 years, the childbirth rate per year increased during the first two years after treatment (first year: 0.6% [CI95: -0.1-1.3]; second year: 4.4% [CI95: 2.4-6.3]) and were numerically above the population reference (6.51%) starting from the third year (third year: 8.8% [CI95: 5.9-11.7]; fourth year: 8.0% [CI95: 4.5-11.4]; fifth year: 7.8% [CI95: 2.9-12.8]). CONCLUSION We report high rates of pregnancy following chemotherapy in the HD21 trial; approximately one tenth of patients below age 40 (female) or 50 (male) in the HD21 trial have reported a pregnancy during follow-up. Compared to eBEACOPP, pregnancy rates were twofold higher in partners of men who received BrECADD and slightly higher in women. Notably, childbirth rates in women after the second year of follow-up were comparable to the German population. Together with unparalleled primary cure rates achieved with BrECADD, our data supports its use in young patients with a desire to have children.

Comprehensive Analysis of Treatment Related Morbidity and Progression -Free Survival in the GHSG Phase III HD21 Trial

INTRODUCTION The GHSG-HD21 trial for newly diagnosed adult patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) compares the BrECADD regimen (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in a PET adapted approach. Separate analyses of the co-primary endpoints for tolerability and efficacy demonstrated a significant and relevant reduction in treatment-related morbidity (TRMB) and non-inferiority of PFS, respectively. Here, we report the first combined comprehensive analysis of the primary endpoints of the HD21 trial. METHODS This international open-label phase III trial included adult patients aged ≤ 60 yrs with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 21-day cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. At a planned interim analysis at 36 months follow-up, the efficacy endpoint PFS was determined in the ITT cohort comprising 1,482 patients (eBEACOPP n=740, and BrECADD n=742) while the safety endpoint TRMB was determined in 1,470 patients (BEACOPP n=732, and BrECADD n=738). Subgroup analyses were calculated with 95% confidence intervals (Cis). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. RESULTS Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries across 233 trial sites. Actual median follow-up for this analysis was 40 months. Baseline characteristics were well balanced between treatment arms, median age was 34 yrs (range 18-61), and 47% were high-risk (international prognostic index IPS ≥ 3). Overall, the relative risk for a TRMB event was 0.72 (95% CI, 0.65-0.79) in favor of BrECADD. Subgroup analyses confirmed a consistent, highly significant TRMB benefit in all relevant subgroups. Dose reductions were required less frequently with BrECADD than with eBEACOPP (figure 1); full dose treatment at cycle 4 was administered in 58.5% of patients in the eBEACOPP group compared to 77.8% in the BrECADD group. In PET2-positive patients at cycle 6, full dose treatment was received by 42.5% in the eBEACOPP group versus 67.3% in the BrECADD group. Most frequent reasons for dose reductions were leukopenia for eBEACOPP (in 33.7% of patients) and thrombocytopenia for BrECADD (in 23.1 % of patients). 59% of patients achieved a PET2-negative response and were treated with a total of 4 cycles in each group; conversely, 41% of patients were PET2-positive and received 6 cycles. At the end of treatment with either 4 or 6 cycles, a complete metabolic response was seen in 80% and 82% of patients in the eBEACOPP and BrECADD cohorts, respectively. The 3-yr PFS was 94.9% for BrECADD (95% CI 93.5% - 96.7%), and 92.3% for eBEACOPP (95% CI 90.3% - 94.3%), with a corresponding HR of 0.63 (95% CI 0.42-0.94). A HR favoring BrECADD was consistently observed across all relevant subgroups (figure 2). Notably, HRs favoring BrECADD were generally lower in lower-risk cohorts including IPS (0, 1; 2, 3; 4-7: HR 0.45, 0.59, 0.87, respectively), stage (Ann-Arbor stage II, III, IV: HR 0.35, 0.6, 0.78, respectively), or PET-2 response (negative versus positive, HR 0.4, 95% CI 0.21-0.76 vs 0.78, 95% CI 0.44-1.38). Corresponding 3-yr PFS rates for BrECADD versus eBEACOPP were 97.1% (95% CI 95.5% - 98.7%) versus 93.6% (95% CI 91.3% - 95.9%) for PET2-negative patients and 93.5% (95% CI 90.6% - 96.5%) versus 90.6% (95% CI 87.1% - 94.1%) for PET2-positive patients, respectively. CONCLUSION With the novel BrECADD regimen, we observed the highest 3-yr PFS rates reported to date in a randomized clinical trial in advanced-stage cHL. Our analyses suggest that the unexpectedly high and improved efficacy of the new BrECADD regimen compared to eBEACOPP is a direct consequence of its improved tolerability and deliverability. Importantly, while the larger patient cohort of PET2-negative patients achieves a very high 3-yr PFS of 97% with a very short and safe 12-week treatment, this benefit was also observed for PET2-positive patients. In conclusion, the optimized risk-benefit ratio of the BrECADD regimen combined with the individualized PET2-guided treatment duration sets a new benchmark for the treatment of adult patients with newly diagnosed advanced stage cHL

Toxicities at one year follow‐up in patients with advanced stage classical Hodgkin Lymphoma: results from the randomized phase III HD21 trial by the German Hodgkin Study Group

Introduction: The HD21 trial compares BrECADD with eBEACOPP for the first-line treatment of advanced stage classical Hodgkin Lymphoma (AS-cHL). We previously reported a superior acute tolerability profile for BrECADD. However, persisting treatment sequelae as peripheral neuropathy or gonadal dysfunction are a major concern for survivors of AS-cHL. Accordingly, resolution of organ toxicities is highly relevant from the patient´s perspective. Therefore, we report treatment-related toxicities at twelve months follow-up (FU12) after treatment in HD21. Methods: Adult patients ≤60 years of age with AS-cHL were included in this ongoing international open label randomized phase III trial and randomized in a 1:1 ratio to receive PET2-guided 4–6 cycles of either standard eBEACOPP or experimental BrECADD treatment. For detection of treatment sequelae at FU12, non-hematological adverse events and serum levels of FSH levels are reported. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries. Baseline characteristics were well balanced between treatment arms. Documented FU12 was available in 1395/1470 (94.9%) patients in the ITT cohort. 557 (80.8%) and 566 (80.2%) patients had no documented toxicity following eBEACOPP and BrECADD, respectively. At FU12, grade 2 or higher PNP was reported for 17 (2.7%) patients following eBEACOPP and for 12 (1.9%) patients following BrECADD; however, no or only grade 1 PNP was reported for most patients in both treatment groups with 97.3% for eBEACOPP and 98.1% for BrECADD. Rate of PNP was numerically higher in patients receiving 6 cycles of chemotherapy (3.0%) compared to 4 cycles (1.9%). FSH levels at FU12 were available for 597 patients and were higher for patients who received eBEACOPP (mean FSH 29.4 and 31.8 after 4 and 6 cycles, respectively) compared to BrECADD (mean FSH 18.3 and 20.5 after 4 and 6 cycles, respectively. Other than PNP, most frequent organ toxicities at FU12 were classified as respiratory, thoracic or mediastinal disorders (4.4%), and cardiac disorders (2.9%). All other organ toxicities were rare and equally distributed between trial arms. Conclusions: Complete resolution of acute adverse events is frequent following either regimen in the GHSG HD21 study. However, less patients report higher grade PNP or impaired gonadal function at FU12 after treatment with BrECADD than after eBEACOPP. Accordingly, persisting toxicities were reported in only few patients after BrECADD. Although these results are indicate good overall tolerability, they still need to be complemented by patient-reported outcomes for which analyses are ongoing. The non-inferiority of the experimental BrECADD regimen also remains to be demonstrated to draw definitive conclusions. The research was funded by: Takeda Keywords: Hodgkin lymphoma, Molecular Targeted Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. P. Borchmann Consultant or advisory role: Takeda Oncology, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Amgen, Miltenyi Biotech Honoraria: Takeda Oncology, Novartis, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Miltenyi Biotech, Incyte, Abbvie Research funding: Takeda Oncology, Roche, Novartis, Merck Sharp & Dohme, Amgen

Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis – study protocol for a randomised controlled trial

IntroductionThe chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role....

Good Clinical Practices

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. It also serves to protect the rights, integrity and confidentiality of trial subjects. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so. In this paper, we address the historical background and the events that led up to the formation of these guidelines. Today, the ICH-GCP guidelines are used in clinical trials throughout the globe with the main aim of protecting and preserving human rights.

Immediate postoperative parenteral anticoagulant therapy in patients with mesenteric ischemia after intestinal resection: a retrospective cohort study at a single institute

BackgroundBowel gangrene represents a major fatal event in acute mesenteric ischemia. Intestinal resection is inevitable in patients with peritonitis and bowel gangrene. This retrospective study aimed to elucidate the benefit of postoperative parenteral anticoagulation in patients with intestinal resection.MethodsPatients with acute mesenteric ischemia and bowel gangrene were recruited retrospectively between January 2007 and December 2019. All patients underwent bowel resection. They were categorized into two groups: patients without immediate parenteral anticoagulant therapy (Group A) and those with immediate parenteral anticoagulant therapy (Group B). Thirty-day mortality and survival were analyzed.ResultsA total of 85 patients were included, with 29 patients in Group A and 56 patients in Group B. Patients in Group B had lower 30-day mortality (16.1%) and a higher 2-year survival rate (45.4%) than patients in Group A (30-day mortality: 51.7%, p = 0.001; 2-year survival rate: 19.0%, p = 0.001). In the 30-day mortality multivariate analysis, patients in Group B had a better outcome (odds ratio = 0.080, 95% confidence interval between 0.011 and 0.605, p = 0.014). Patients in Group B also had a better outcome in the survival multivariate analysis (hazard ratio: 0.435, 95% confidence interval between 0.213 and 0.887, p = 0.022).ConclusionsImmediate postoperative parenteral anticoagulant therapy improves prognosis in patients with acute mesenteric ischemia treated by intestinal resection.Trial registration This research was retrospectively approved by the Institutional Review Board (IRB) I&II of Taichung Veterans General Hospital (TCVGH-IRB No.CE21256B) on July 28th, 2021. The informed consent waiver was also approved by IRB I&II of Taichung Veterans General Hospital. The Declaration of Helsinki and ICH-GCP guidelines were followed during this study.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Assent, parental consent and reconsent for health research in Africa: thematic analysis of national guidelines and lessons from the SickleInAfrica registry.

The enrolment of children and adolescents in health research requires that attention to be paid to specific assent and consent requirements such as the age range for seeking assent; conditions for parental consent (and waivers); the age group required to provide written assent; content of assent forms; if separate assent and parental consent forms should be used, consent from emancipated young adults; reconsent at the age of adulthood when a waiver of assent requirements may be appropriate and the conditions for waiving assent requirements. There is however very little available information for researchers and ethics committees on how to navigate these different issues. To provide guidance to research initiatives, the SickleInAfrica consortium conducted a thematic analysis of a sample of research ethics guidelines and procedures in African countries, to identify guidance for assent requirements in health research. The thematic analysis revealed that 12 of 24 African countries specified the age group for which assent is required. The minimum age for written assent varied across the countries. Five countries, Algeria, Botswana, Cameroon, Nigeria and The Democratic Republic of Congo require consent from both parents/family council in certain circumstances. Botswana, Nigeria, South Africa and Uganda have specific assent/consent requirements for research with emancipated minors. South Africa and Algeriarequires re-consent at onset of adulthood. Five countries (Botswana, Cameroon, Nigeria, South Africa and Tanzania) specified conditions for waiving assent requirements. The CIOMS and the ICH-GCP guidelines had the most comprehensive information on assent requirements compared to other international guidelines. An interactive map with assent requirements for different African countries is provided. The results show a major gap in national regulations for the inclusion of minors in health research. The SickleInAfrica experience in setting up a multi-country SCD registry in Africa highlights the need for developing and harmonising national and international guidelines on assent and consent requirements for research involving minors. Harmonisation of assent requirements will help facilitate collaborative research across countries.

Treatment Related Morbidity in Patients with Classical Hodgkin Lymphoma: Results of the Ongoing, Randomized Phase III HD21 Trial By the German Hodgkin Study Group

INTRODUCTION Interim PET (PET2)-guided intensive upfront treatment of newly diagnosed advanced stage (AS) classical Hodgkin Lymphoma (cHL) patients with eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). CD30-targeted therapy with the antibody-drug conjugate brentuximab vedotin (BV) has proven high efficacy and favorable tolerability in cHL. For the German Hodgkin Study Group (GHSG) HD21 study we thus hypothesized that using BV to remodel the eBEACOPP regimen could further decrease TRMB while maintaining the high efficacy of PET2-guided eBEACOPP. Here, we report the final analysis of the TRMB endpoint from the HD21 study. Methods This international open label randomized phase III trial included adult patients ≤ 60 years of age with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either standard eBEACOPP or experimental BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) treatment. PET2 was assessed by blinded panel review (PP-2). Reduction of TRMB was the first part of the co-primary endpoint, whereas non-inferiority of efficacy as determined by progression-free survival was the second part. TRMB was determined using the Cochran-Mantel-Haenszel method. Stratification factors included sex, age, International Prognostic Score (IPS), and location of trial site. TRMB was defined as any CTCAE grade 3 or 4 organ toxicity or grade 4 hematological toxicity (defined as anemia, thrombocytopenia, infection) during study treatment. Categorical variables were compared using fisher´s exact test. Exploratory analyses were performed for further safety outcome parameters. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries and more than 250 trial centers. The intention-to-treat (ITT) population comprised 1,470 patients. Baseline characteristics such as sex (56 % male), age (79% ≤45 years), IPS (54% 0-2), location (92% Europe), performance status (70% ECOG 0), B symptoms (68%), and Ann-Arbor stage III/IV (84%) were well balanced between the treatment arms. As recommended by PP-2, 59% of patients (n=861, eBEACOPP n=430, BrECADD n=431) received 4 cycles and 41% (n=609, eBEACOPP n=302, BrECADD n=307) received 6 cycles of therapy. TRMB was analyzed in the ITT cohort comprising 732 patients in the eBEACOPP and 738 patients in the BrECADD group. Overall, TRMB was documented in 59% and 42 % of patients in the eBEACOPP and BrECADD groups, respectively (relative risk for eBEACOPP 1.41; 95% CI, 1.27 - 1.56, p<0.001, relative risk for BrECADD 0.72; 95% Confidence interval [CI], 0.65 - 0.79, p<0.001). The relative risk estimates remained stable among the stratification factors (sex, age, IPS, location). In the eBEACOPP group 52% of patients had hematological TRMB events compared to 31% in the BrECADD group (p<0.001). The significant difference for hematological TRMB was reflected in the reduction in red cell and platelet transfusions. At least one red cell transfusion was given in 22% of patients in the eBEACOPP group and in 8% in the BrECADD group, and at least one platelet transfusion in 13% and 6%, respectively. Leukopenia grade 4 was observed in 94% and 87%, respectively. TRMB organ toxicity was documented in 17% of patients in the eBEACOPP group and 19% in the BrECADD group (p = 0.455). Peripheral sensory neuropathy all grades was documented in 49% and 38% in the eBEACOPP and BrECADD group, respectively, which was mainly grade 1 (33% and 31%), whereas grade 2 occurred in 14% and 6%, and grade 3 in 2% and 1%, respectively. Peripheral motor neuropathy all grades was documented in 4% in both treatment groups, which was grade 1 in 3%, and grade 2 in 1% in each group, respectively. CONCLUSION This analysis of the GHSG HD21 for patients with newly diagnosed AS-cHL shows a significant and clinically relevant reduction in treatment-related morbidities with BrECADD as compared to eBEACOPP.

T002: Treatment related morbidity in patients with classical Hodgkin Lymphoma: results of the ongoing, randomized phase III HD21 Trial by The German Hodgkin Study Group

Introduction: PET-guided treatment of newly diagnosed advanced stage (AS) classical Hodgkin Lymphoma (cHL) patients with eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procar-bazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). CD30-targeted therapy with brentuximab vedotin (BV) has proven high efficacy and favorable tolerability in patients with cHL. In the HD21 study, we hypothesized that using BV to remodel the eBEACOPP regimen could further decrease TRMB while maintaining its high efficacy. Here, we report the final analysis of the TRMB endpoint. Methods: Adult patients ≤ 60 years of age with AS-cHL were included in this international randomized phase III trial. Patients were randomized in a 1:1 ratio to PET2-guided 4–6 cycles of either standard eBEACOPP or experimental BrECADD treatment (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone). PET2 was assessed by blinded panel review (PP-2). Reduction of TRMB was the first part of the co-primary endpoint, whereas non-inferiority of progression-free survival (PFS) was the second part. TRMB was defined as any CTCAE grade 3 or 4 organ toxicity or grade 4 hematological toxicity (anemia, thrombocytopenia, infection) during treatment. TRMB was determined using the Cochran-Mantel-Haenszel method. Stratification factors included sex, age, IPS, and location of trial site. Categorical variables were compared using fisher’ s exact test. Exploratory analyses were performed for further safety outcome parameters. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries. 1,470 patients are in the intention-to-treat (ITT) population (eBEACOPP n=732, BrECADD n=738). Baseline characteristics such as sex (male=56%), age (≤45 years=79%), IPS (0–2=54%), location (Europe=92%) and stage (III/IV=84%) were well balanced between treatment arms. As recommended by PP2, 59% of patients had 4 cycles and 41% received 6 cycles of therapy, without differences between treatment groups. TRMB was documented in 59% of patients in the eBEACOPP group (rel-risk, 1.41; 95% CI, 1.27–1.56, p<0.001) and 42% in the BrECADD group (rel-risk, 0.72; 95% CI, 0.65–0.79, p<0.001). The relative risk estimates remained stable among stratification factors. In the eBEACOPP group 52% of patients had hematological TRMB events compared to 31% in the BrECADD group (p<0.001). At least one red cell transfusion was given in 22% of patients in the eBEACOPP group and in 8% in the BrECADD group and at least one platelet transfusion in 13% and 6%, respectively. Severe leukopenia was observed in 94% and 87%, respectively. TRMB organ toxicity was documented in 17% of patients in the eBEACOPP group and 19% in the BrECADD group (p=0.455). Conclusion: The BrECADD regimen shows a significant and clinically relevant reduction of treatment-related morbidities compared to eBEACOPP in patients with newly diagnosed AS-cHL.

Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial

IntroductionType 2 diabetes (T2D) is characterised by elevated plasma glucose, free fatty acid (FFA) and insulin concentrations, and this metabolic profile is linked to diabetic cardiomyopathy, a diastolic dysfunction at...

Clinical Trial Agreement – Eliminate legal problems when conducting clinical trials in Germany

The possibilities of structuring clinical trial agreement are far reaching. Especially regarding the question, who the contract partner will be, an initial, also liability-related, positioning is possible; by either including or not including the respective examining physician in the agreement. The agreement has in large parts a clarifying function regarding the contractual obligations of both parties, as the AMG, the ICH-GCP guideline and various european regulations and directives stipulate a wide range of requirements for the performance of clinical trials. Inclusion in the agreement allows for a clear division of responsibilities and liability in the event of non-compliance with the requirements. It is also necessary that the sponsor is obligated to carry out quality assurance measures and the modalities of their implementation, including the remuneration of the time spent for this purpose.&#x0D; A central question is also, who is entitled to the results of the clinical trial or to inventions based on them, whereby the ArbnErfG also must be taken into account. Whether there are at least rights of use for non-commercial purposes for the other party, should also be regulated. Also relevant is the agreement of confidentiality agreements and the answer to the question, when and to which extent publications on the results of the tests in question are permissible, in order to ensure an appropriate balance of the parties' interests.&#x0D; In terms of data protection law, special attention must be paid to the question which party is the controller within the meaning of the GDPR - depending on the answer to this question, complicated and extensive regulations must be made. In addition to the regulation of the remuneration and its payment modalities, regulations regarding the liability, at least within the legal ramifications are possible and necessary. Conclusively – as always - general cancellation rights and other possibilities of terminating the agreement can be added.&#x0D; The preceding explanations show how complex and comprehensive the aspects to be taken into account are. Numerous possibilities have been highlighted above, in order to provide an overview and to simplify the drafting, in hope that the contribution may aid as an orientation.

Selinexor in Combination with Daratumumab-Bortezomib and Dexamethasone for the Treatment of Relapse or Refractory Multiple Myeloma: Initial Results of the Phase 2, Open-Label, Multicenter GEM-Selibordara Study

Selinexor in Combination with Daratumumab-Bortezomib and Dexamethasone for the Treatment of Relapse or Refractory Multiple Myeloma: Initial Results of the Phase 2, Open-Label, Multicenter GEM-Selibordara Study

Evaluation of knowledge, attitude and practices of postgraduate medical students towards clinical research in a tertiary care teaching hospital

Background: Clinical research is a component of medical and health research that facilitates valuable knowledge regarding diagnosis, prevention as well as treatment of a disease. Nowadays, the practise of medicine is evidence-based and combining medical education with clinical research provides a channel for translating scientifically advanced knowledge into better public health. The aim of the study was to assess knowledge (K), attitude (A), and practices (P) about clinical research among post graduate medical students.Methods: After obtaining institutional ethics committee approval, a cross-sectional and questionnaire-based study was conducted. A pre-structured and validated KAP questionnaire comprising of 25 questions (knowledge-15, attitude-5 and practices-5) was shared online through google forms with post graduate students. The responses to the questions were later marked correct or incorrect. The data was collected and compiled using Microsoft excel and expressed in percentage (%). Data analysis was performed using SPSS version 25.0.Results: 102 students responded to the questionnaire completely. Out of which males (55.9%) pre-dominated and majority of the PG students belonged to I year accounting for 40.2%. About 61.76% PG students were aware about a clinical research unit in the college. Majority of the students acknowledged the necessity of conducting clinical research and exhibited good knowledge about key concepts of clinical trials. Even responses to questions pertaining to attitude towards clinical research were also majorly positive. On the contrary, more than 90% students had neither attended any workshop on ICH-GCP guidelines nor registered their academic study under clinical trial registry of India. However, 73.5% of them expressed their willingness to participate in a clinical trial in future.Conclusions: Although, assessment of knowledge and attitudes about clinical research among post graduate students showed positive results but discrepancies were observed in its practise. As such, this necessitates incorporation of clinical research activities into existing medical education system.

Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0\u20132-month-old low birth weight infants in India\u2014the \u201cProSPoNS\u201d Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial

BackgroundProgress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising.MethodsA phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites.DiscussionThis adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low–middle-income countries.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019

Ethical Considerations for safeguarding human participants in pandemic research: a rapid review protocol.

COVID-19 is a respiratory disease caused by a coronavirus, designated SARS-CoV-2, which is responsible for a global pandemic in 2020. Public interest in this disease has led to the publication of thousands of articles in the medical literature in a very short timeframe. It is imperative that medical research into COVID-19 is conducted quickly and safely, and that due reference is given to the ethical considerations enshrined in the ICH GCP guidelines, according to the Declaration of Helsinki. In order to review the reporting of ethical considerations in these papers, we hereby propose a protocol for a systematic review of COVID-19 papers up to April 14 th 2020. The search criteria proposed for the review are based upon what would be a reasonable search conducted by a lay member of the public with access to PubMed.gov. Institutional Research Ethics Committees (RECs) face significant challenges in providing thorough and timely ethical review during the COVID-19 pandemic. It is proposed to publish the findings of this rapid review along with a summary of an institutional REC response to the challenges of reviewing and approving clinical research proposals in the time of a pandemic.

Ethical Considerations for safeguarding human participants in pandemic research: a rapid review protocol

COVID-19 is a respiratory disease caused by a coronavirus, designated SARS-CoV-2, which is responsible for a global pandemic in 2020. Public interest in this disease has led to the publication of thousands of articles in the medical literature in a very short timeframe. It is imperative that medical research into COVID-19 is conducted quickly and safely, and that due reference is given to the ethical considerations enshrined in the ICH GCP guidelines, according to the Declaration of Helsinki. In order to review the reporting of ethical considerations in these papers, we hereby propose a protocol for a systematic review of COVID-19 papers up to April 14 th 2020. The search criteria proposed for the review are based upon what would be a reasonable search conducted by a lay member of the public with access to PubMed.gov. Institutional Research Ethics Committees (RECs) face significant challenges in providing thorough and timely ethical review during the COVID-19 pandemic. It is proposed to publish the findings of this rapid review along with a summary of an institutional REC response to the challenges of reviewing and approving clinical research proposals in the time of a pandemic.

Protocol for systematic review of ethical declarations made in clinical publications concerning COVID-19

COVID-19 is a respiratory disease caused by a coronavirus, designated SARS-CoV-2, which is responsible for a global pandemic in 2020. Public interest in this disease has led to the publication of thousands of articles in the medical literature in a very short timeframe. It is imperative that medical research into COVID-19 is conducted quickly and safely, and that due reference is given to the ethical considerations enshrined in the ICH GCP guidelines, according to the Declaration of Helsinki. In order to review the reporting of ethical considerations in these papers, we hereby propose a protocol for a systematic review of COVID-19 papers up to April 14 th 2020. The search criteria proposed for the review are based upon what would be a reasonable search conducted by a lay member of the public with access to PubMed.gov. It is proposed to publish the findings of the review with a summary of the institutional Research Ethics Committee response to the challenges of reviewing and approving clinical research proposals in the time of a pandemic.

Regulatory requirements for conducting Clinical Trials in India

Clinical trial is mandatory for approval of drug to assure safety and efficacy of drug. To safeguard the safety of patient and ethical conduction of clinical trial, India has laid down CT regulations. Compliance with ICH-GCP guideline is mandatory which describes quality assurance and safety of subjects. Clinical trial is regulated under Drug and Cosmetic act 1940 and Rules 1945 which has given Rules to conduct the clinical trial. On March 19, 2019, the Union Ministry for Health and Family Welfare notified New drugs and Clinical Trials Rules, 2019 for promoting clinical research in the country. Central Government notified final rules in Gazette of India vide G.S.R.227(E). The objective of this study is to provide an overview on regulatory requirements to conduct the clinical trials in India and challenges involved in that.