Cytomegalovirus immunoglobulin serology prevalence in patients with newly diagnosed multiple myeloma treated within the GMMG-MM5 phase III trial.

OBJECTIVES: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown. METHODS: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months. RESULTS: CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS. DISCUSSION: Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.

Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial.

BACKGROUND: Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma. METHODS: This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731. FINDINGS: Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related. INTERPRETATION: Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma. FUNDING: Sanofi and Bristol Myers Squibb (Celgene).

Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)-study protocol for a randomized, controlled, interventional, open-label, multicenter trial.

BACKGROUND: Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. METHODS: The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient's quality of life is expected. DISCUSSION: The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. TRIAL REGISTRATIONS: DRKS-ID DRKS00022782 . Registered on August 25, 2020 ClinicalTrials.gov NCT04571801 . Registered October 1, 2020.

Prognostic Impact of Serum Free Light Chain Ratio Normalization in Patients with Multiple Myeloma Treated within the GMMG-MM5 Trial.

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47-0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48-0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60-0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41-0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.

Next-generation sequencing diagnostics of bacteremia in pediatric sepsis.

INTRODUCTION: Sepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting. METHODS: The Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1-d28, n = 50), infants (d29 to <1 yr, n = 50), and toddlers (1 yr to <5 yr, n = 50) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definition) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard of care (culture-based) microbiological diagnostics. Potential changes in anti-infective treatment regimens based on these NGS results will be estimated retrospectively by a panel of 3 independent clinical specialists. DISCUSSION: Neonates, infants, and young children are significantly affected by sepsis. Fast and more sensitive diagnostic approaches are urgently needed. This prospective, observational, non-interventional, multicenter study seeks to evaluate an NGS-based approach in critically ill children suffering from sepsis. TRIAL REGISTRATION: DRKS-ID: DRKS00015705 (registered October 24, 2018). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015705.

Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma.

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with

Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age.

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61-65 years (S2, n = 107) and 66-70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray's p = 0.83) and non-relapse mortality (Gray's p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

Protocol of a randomised controlled phase II clinical trial investigating PREoperative endoscopic injection of BOTulinum toxin into the sphincter of Oddi to reduce postoperative pancreatic fistula after distal pancreatectomy: the PREBOTPilot trial.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is still the most frequently occurring and clinically relevant complication after distal pancreatectomy (DP). Preoperative endoscopic injection of botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent POPF. The aim of this project (PREBOTPilot) is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent clinically relevant POPF following DP. METHODS AND ANALYSIS: PREBOTPilot is an investigator-initiated, single-centre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups and an exploratory study design. 60 patients scheduled for DP will be randomised to intervention and control group. In the intervention group, patients will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi, whereas in the control group no preoperative endoscopy will be performed. The combined primary endpoint is the occurrence of clinically relevant POPF and/or death within 30 days after DP. The secondary endpoints comprise further postoperative outcome parameters and quality of life up to 3 months after DP as well as safety and feasibility of the procedure. Statistical analysis is based on the modified intention-to-treat population, excluding patients without status post DP. For safety analysis, rates of adverse events (AEs) and serious AEs will be calculated with 95% CIs for group comparisons. ETHICS, FUNDING AND DISSEMINATION: PREBOTPilot has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4043654) and the Ethics Committee of Heidelberg University (reference number AFmo-523/2019). This trial is supported by the German Federal Ministry of Education and Research (BMBF). The results of the trial will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00020401.

Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study).

INTRODUCTION: Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only. METHODS AND DESIGN: The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment. ETHICS AND DISSEMINATION: Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal. TRIAL REGISTRATION NUMBER: DRKS0006547; EudraCT2014-001991-76; Pre-result. DATE OF REGISTRATION: 30 October 2014; 24 February 2017.

Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol.

RATIONALE: Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth. AIM: To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device). SAMPLE SIZE: We aim to randomize 776 patients 1:1 to the intervention arm or care as usual. DESIGN: Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment. OUTCOMES: The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by ≥ 1 mm) on repeated MR or CT angiography within 36 ± 6 months after randomization. DISCUSSION: The Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

BACKGROUND: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. METHODS/DESIGN: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. DISCUSSION: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. TRIAL REGISTRATION: ISRCTN16345835 (date of registration 2010-08-24).

Clinical Research in Vulnerable Populations: Variability and Focus of Institutional Review Boards' Responses.

BACKGROUND: Children and patients with cognitive deficits may find it difficult to understand the implication of research. In the European Union (EU), clinical studies outside the EU directives concerning medicinal products or medical devices, i.e., "miscellaneous clinical studies", have no legally mandated timelines for institutional review boards' (IRB) decisions. GOAL: To evaluate the review process of IRBs for two different "miscellaneous" multicenter clinical research protocols involving vulnerable subjects (children and adult stroke patients). METHODS: Descriptive and comparative statistics. Protocol 1 is a prospective, multicenter, cross-sectional screening study of a symptomatic pediatric population at risk for Fabry disease involving genetic testing (NCT02152189). Protocol 2 is a prospective, multicenter, randomized, controlled, open-label, blinded endpoint post-market study to evaluate the effectiveness of stent retrievers (NCT02135926). After having obtained positive initial IRB votes at the main study site, both protocols were subsequently submitted to the remaining IRBs. RESULTS: Protocol 1 was submitted to 19 IRBs. No IRB objected to the study. Median time-to-final vote was 34 (IQR 10-65; range 0 to 130) days. Two IRBs accepted the coordinating center's IRB votes without re-evaluation. Changes to the informed consent documents were asked by 7/19 IRBs, amendments to the protocol by 2. Protocol 2 was submitted to 16 IRBs. Fifteen decisions were made. No IRB objected to the study. Median time-to final vote was 59 (IQR 10 to 65; range 0 to 128) days, which was not statistically significantly different compared with protocol 1 (Wilcoxon test). Two IRBs accepted a previous IRB decision and did not conduct an independent review. Eight/16 IRBs required changes to the informed consent documents; two IRBs recommended an amendment of the protocol. CONCLUSION: Both clinical research protocols involving vulnerable populations were well accepted. IRB workflows and decision times varied substantially. Some IRBs accepted a previous IRB decision without the necessity of another reevaluation process. Requested changes were focused on the informed consent documents. A more standardized approach across jurisdictions is desirable.

Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke.

BACKGROUND: Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain. METHODS: We randomly assigned 112 patients 61 years of age or older (median, 70 years; range, 61 to 82) with malignant middle-cerebral-artery infarction to either conservative treatment in the intensive care unit (the control group) or hemicraniectomy (the hemicraniectomy group); assignments were made within 48 hours after the onset of symptoms. The primary end point was survival without severe disability (defined by a score of 0 to 4 on the modified Rankin scale, which ranges from 0 [no symptoms] to 6 [death]) 6 months after randomization. RESULTS: Hemicraniectomy improved the primary outcome; the proportion of patients who survived without severe disability was 38% in the hemicraniectomy group, as compared with 18% in the control group (odds ratio, 2.91; 95% confidence interval, 1.06 to 7.49; P=0.04). This difference resulted from lower mortality in the surgery group (33% vs. 70%). No patients had a modified Rankin scale score of 0 to 2 (survival with no disability or slight disability); 7% of patients in the surgery group and 3% of patients in the control group had a score of 3 (moderate disability); 32% and 15%, respectively, had a score of 4 (moderately severe disability [requirement for assistance with most bodily needs]); and 28% and 13%, respectively, had a score of 5 (severe disability). Infections were more frequent in the hemicraniectomy group, and herniation was more frequent in the control group. CONCLUSIONS: Hemicraniectomy increased survival without severe disability among patients 61 years of age or older with a malignant middle-cerebral-artery infarction. The majority of survivors required assistance with most bodily needs. (Funded by the Deutsche Forschungsgemeinschaft; DESTINY II Current Controlled Trials number, ISRCTN21702227.).

HAnd Suture Versus STApling for Closure of Loop Ileostomy (HASTA Trial): results of a multicenter randomized trial (DRKS00000040).

OBJECTIVES: The objective of the HASTA trial was to compare hand suture versus stapling loop ileostomy closure in a randomized controlled trial. BACKGROUND: Bowel obstruction is one of the main and the clinically and economically most relevant complication following closure of loop ileostomy after low anterior resection. The best surgical technique for closure of loop ileostomy has not been defined yet. METHODS: HASTA trial is a multicenter pragmatic randomized controlled surgical trial with 2 parallel groups to compare hand suture versus stapling for closure of loop ileostomy. The primary endpoint was the rate of bowel obstruction within 30 days after ileostomy closure. RESULTS: A total of 337 randomized patients undergoing closure of loop ileostomy after low anterior resection because of rectal cancer in 27 centers were included. The overall rate of postoperative ileus after ileostomy closure was 13.4%. Seventeen of 165 (10.3%) patients in the stapler group and 27 of 163 (16.6%) in the hand suture group developed bowel obstruction within 30 days postoperatively [odds ratio (OR) = 1.72; 95% confidence interval (CI): 0.89-3.31 = 0.10]. Duration of surgical intervention was significantly shorter in the stapler group (15 minutes; P < 0.001). Multivariable analysis of potential risk factors did not reveal any significant correlation with development of postoperative ileus. Rate of anastomotic leakage (stapler: 3.0%, hand suture: 1.8%, P = 0.48) did not differ significantly as well as all other secondary endpoints. CONCLUSIONS: Hand-sewn anastomosis versus stapler ileo-ileostomy for ileostomy closure are equally effective in terms of postoperative bowel obstruction, with stapler anastomosis leading to a shorter operation time. Postoperative ileus after ileostomy reversal remains a relevant complication.