Unblinded Data Research Articles

Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation

Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate® tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time 188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data. Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190

LEADER and the new ‘cardiovascular’ glucose‐lowering agents

<scp>LEADER</scp> and the new ‘cardiovascular’ glucose‐lowering agents

Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies

Study objective:We evaluated thromboembolic events after vitamin K antagonist reversal in post hoc analyses of pooled data from 2 randomized trials comparing 4-factor prothrombin complex concentrate (4F-PCC) (Beriplex/Kcentra) with plasma.Methods:Unblinded investigators identified thromboembolic events, using standardized terms (such as “myocardial infarction,” “deep vein thrombosis,” “pulmonary embolism,” and “ischemic stroke”). A blinded safety adjudication board reviewed serious thromboembolic events, as well as those referred by an independent unblinded data and safety monitoring board. We descriptively compared thromboembolic event and patient characteristics between treatment groups and included detailed patient-level outcome descriptions. We did not power the trials to assess safety.Results:We enrolled 388 patients (4F-PCC: n=191; plasma: n=197) in the trials. Thromboembolic events occurred in 14 of 191 patients (7.3%) in the 4F-PCC group and 14 of 197 (7.1%) in the plasma group (risk difference 0.2%; 95% confidence interval −5.5% to 6.0%). Investigators reported serious thromboembolic events in 16 patients (4F-PCC: n=8; plasma: n=8); the data and safety monitoring board referred 2 additional myocardial ischemia events (plasma group) to the safety adjudication board for review. The safety adjudication board judged serious thromboembolic events in 10 patients (4F-PCC: n=4; plasma: n=6) as possibly treatment related. There were 8 vascular thromboembolic events in the 4F-PCC group versus 4 in the plasma group, and 1 versus 6 cardiac events, respectively. Among patients with thromboembolic events, 3 deaths occurred in each treatment group. All-cause mortality for the pooled population was 13 per group. We observed no relationship between thromboembolic event occurrence and factor levels transiently above the upper limit of normal; there were no notable differences in median factor or proteins C and S levels up to 24 hours postinfusion start in patients with and without thromboembolic events.Conclusion:The incidence of thromboembolic events after vitamin K antagonist reversal with 4F-PCC or plasma was similar and independent of coagulation factor levels; small differences in the number of thromboembolic event subtypes were observed between treatment groups. [Ann Emerg Med. 2016;67:96-105.]

Phase II Upgrade of the GERDA Experiment for the Search of Neutrinoless Double Beta Decay

Observation of neutrinoless double beta decay could answer the question regarding the Majorana or Dirac nature of neutrinos. The GERDA experiment utilizes HPGe detectors enriched with the isotope 76Ge to search for this process. Recently the GERDA collaboration has unblinded data of Phase I of the experiment. In order to further improve the sensitivity of the experiment, additionally to the coaxial detectors used, 30 BEGe detectors made from germanium enriched in 76Ge will be deployed in GERDA Phase II.BEGe detectors have superior PSD capability, thus the background can be further reduced. The liquid argon surrounding the detector array will be instrumented in order to reject background by detecting scintillation light induced in the liquid argon by radiation. After a short introduction the hardware preparations for GERDA Phase II as well as the processing and characterization of the 30 BEGe detectors are discussed.

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

Adaptive graph-based multiple testing procedures.

Multiple testing procedures defined by directed, weighted graphs have recently been proposed as an intuitive visual tool for constructing multiple testing strategies that reflect the often complex contextual relations between hypotheses in clinical trials. Many well-known sequentially rejective tests, such as (parallel) gatekeeping tests or hierarchical testing procedures are special cases of the graph based tests. We generalize these graph-based multiple testing procedures to adaptive trial designs with an interim analysis. These designs permit mid-trial design modifications based on unblinded interim data as well as external information, while providing strong family wise error rate control. To maintain the familywise error rate, it is not required to prespecify the adaption rule in detail. Because the adaptive test does not require knowledge of the multivariate distribution of test statistics, it is applicable in a wide range of scenarios including trials with multiple treatment comparisons, endpoints or subgroups, or combinations thereof. Examples of adaptations are dropping of treatment arms, selection of subpopulations, and sample size reassessment. If, in the interim analysis, it is decided to continue the trial as planned, the adaptive test reduces to the originally planned multiple testing procedure. Only if adaptations are actually implemented, an adjusted test needs to be applied. The procedure is illustrated with a case study and its operating characteristics are investigated by simulations.

Litigation seeking access to data from ongoing clinical trials: a threat to clinical research.

Researchers conducting randomized clinical trials may find themselves subject to legal subpoenas for interim data. When a subpoena demands premature disclosure of unblinded data, there is potential for damage to the scientific integrity and reputation of the on-going trial. We describe herein general issues raised by subpoenas for trial data and the particular case of a 2012 subpoena served on investigators from Yale University who were successful in winning reprieve from Connecticut Superior Court.

When is a seamless study desirable? Case studies from different pharmaceutical sponsors

Inferentially seamless studies are one of the best-known adaptive trial designs. Statistical inference for these studies is a well-studied problem. Regulatory guidance suggests that statistical issues associated with study conduct are not as well understood. Some of these issues are caused by the need for early pre-specification of the phase III design and the absence of sponsor access to unblinded data. Before statisticians decide to choose a seamless IIb/III design for their programme, they should consider whether these pitfalls will be an issue for their programme. We consider four case studies. Each design met with varying degrees of success. We explore the reasons for this variation to identify characteristics of drug development programmes that lend themselves well to inferentially seamless trials and other characteristics that warn of difficulties. Seamless studies require increased upfront investment and planning to enable the phase III design to be specified at the outset of phase II. Pivotal, inferentially seamless studies are unlikely to allow meaningful sponsor access to unblinded data before study completion. This limits a sponsor's ability to reflect new information in the phase III portion. When few clinical data have been gathered about a drug, phase II data will answer many unresolved questions. Committing to phase III plans and study designs before phase II begins introduces extra risk to drug development. However, seamless pivotal studies may be an attractive option when the clinical setting and development programme allow, for example, when revisiting dose selection.

Wartime toxicology: evaluation of a military medical toxicology telemedicine consults service to assist physicians serving overseas and in combat (2005-2012).

Those medical providers deployed to remote countries and tasked with caring for military personnel must diagnose and treat diseases and nonbattle injuries that result from exposures rarely seen in developed countries. Military providers must also function with limited resources and a lack of access to physician specialists, to include medical toxicologists. There have been limited published approaches to addressing this clinical gap for medical toxicology. To address this void, the US Army Medical Department deployed an electronic mail telemedicine system to provide teleconsultations for remote health-care providers worldwide, including Iraq and Afghanistan. This study aimed to describe the types and the frequency of toxicology teleconsultation and consultant responses using electronic mail to assist physicians serving in resource-limited locations. This was a retrospective observational study in which an unblinded data extractor independently reviewed all medical toxicology email consultations. Using a previously developed data collection worksheet, the extractor recorded the type of question asked by the consultant (overdose case, envenomation, occupational exposure, etc.) and the duration of time from when the teleconsultation was placed until the consultant replied. The extractor also recorded if the patient was adult or pediatric and if the patient was US military, US contractor, or local national. The extractor also recorded how often the toxicologist provided the consulting physician with information, resources, or protocols to aid in the management of future cases. In addition, for clinical teleconsultations, the extractor documented the frequency that the consulted toxicologist (i) provided a differential diagnosis or specific diagnosis, (ii) provided specific management guidelines for a patient, and (iii) recommended to evacuate or not evacuate a patient. The results were analyzed using descriptive statistics. Of the 99 consultations evaluated, the most common consultation was for snake envenomation and antivenom recommendations (n = 23, 23%) followed by accidental chemical exposures (n = 14, 14%), drug testing (n = 13, 13%), and substance abuse (n = 10, 10%). In 41% of consults, the toxicologist provided a differential diagnosis or specific diagnosis, and in 60% of cases, the toxicologist provided specific management or evaluation guidelines. In 11% of cases, the toxicologist recommended for or against evacuation of the patient. In 25% of consults, the toxicologist provided the consulting physician with information, resources, or protocols to aid in the management of future cases. The most frequent consultations for the military telemedicine consultation service were for direct patient cases, specifically snake envenomation management and accidental chemical exposures. Our results may be used to educate physicians prior to military deployment or international humanitarian efforts and to create toxicology clinical guidelines for remote locations. Expansion of the current military teleconsultation program capabilities to include video teleconsultation may improve the effectiveness of military medical toxicology teleconsultation.

Blinded versus Unblinded Covariate Selection in Confirmatory Survival Trials

Adjustment for covariates and specification of the correct covariate set are important issues in the analysis of clinical trials. Edwards (1999) proposes a model selection approach where the model is chosen on the final data set, which remains blinded for treatment group allocation. We investigate this method for time-to-event endpoints and compare its performance to variable selection within an adaptive design. This adaptive design integrates the methods of Schäfer and Müller (2001) and Keiding et al. (1987) and allows variable selection on the unblinded data during an interim analysis. Monte Carlo simulation shows that Edwards’ method—though blinded—outperforms the adaptive method in terms of ability to select the survival relevant covariates and power. The application of the methods is illustrated by a clinical trial example.

Comparing Two Deep Brain Stimulation Leads to One in Refractory Tremor

A sizable proportion of medication refractory tremor patients may not respond satisfactorily to deep brain stimulation (DBS) to the ventralis intermedialis nucleus of the thalamus (Vim). Implanting a second DBS lead ipsilaterally to the first one is thought to be beneficial based on scarce and unblinded data. This article aims to report a double-blind assessment of five patients with a second DBS lead for refractory tremor. Tremor was assessed by two blinded movement disorder specialists using a videotaped tremor rating scale (TRS) evaluation of each patient in four conditions: both leads OFF, Vim ON/2nd lead OFF, Vim OFF/2nd lead ON, and both leads ON. Paired t-test was used to determine if double stimulation was different than stimulation of Vim alone or than stimulation of the 2nd lead alone. Each hypothesis was tested with the total TRS as well as the contralateral upper limb score and the contralateral hemibody score. Tremor was secondary to multiple sclerosis in two patients and to essential tremor in three. The second lead was in the ventralis oralis anterior nucleus of the thalamus in three patients and in the prelemniscal radiations in two patients. There was improvement with the 2nd lead or double ON in four patients compared to stimulating the Vim alone. However, when taken as a group, the results were not statistically significant. These results were constant with the three different ratings used. The lack of overall statistically significant improvement might be secondary to the small size and the heterogeneity of our sample. However, four patients had 17 to 60 % tremor improvement after the implant of the 2nd lead on double-blinded evaluation. We report objective improvement after addition of a second DBS lead in patients with tremor refractory to Vim DBS. Larger studies are needed to confirm these results.

Statistical analysis plans (SAPS) for academic clinical trials at the edinburgh clinical trials unit: what should they contain?

Once a study is final, the creation of the Statistical Analysis Plan (SAP) can commence. Accordingly to ICH E9 a SAP contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol but the level of detail is not specified. This topic is currently being discussed between UK-CRC registered Trials Units, and there is as yet no agreement on the amount of detail that should be covered in the SAP. Within the Edinburgh Clinical Trials Unit (ECTU), we created a consensus document outlining what we thought the essential aspects of a SAP should be. Briefly, we set out the essential aspects of a SAP as follows. It should be written by someone who has not seen unblinded data from the trial, and should describe analyses unambiguously and in sufficient detail for another statistician to be able to repeat them. It should include a brief description of the trial design, and the statistical methods section from the protocol. Analysis populations, e.g. ITT, per protocol, should be defined in an unambiguous fashion. The SAP should state overall level of significance, and any other relevant information that will be used in the majority of analyses (e.g. treatment of missing data, adjustment for covariates, adjustment for multiplicity, adjustment of p-value due to interim analyses). A list of analyses should describe each precise outcome, the analysis method to be used, any sensitivity analyses, any deviations from the methods listed in ‘Overall Statistical Principles', and any subgroup analyses.

A randomized controlled Alzheimer's disease prevention trial's evolution into an exposure trial: The preadvise trial

To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. PREADViSE was designed as a double blind randomized controlled trial (RCT). SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2×2 factorial structure. In the RCT, participants completed the Memory Impairment Screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II): statistical analysis plan.

BackgroundPrevious studies had suggested that the outcome for patients with spontaneous lobar intracerebral haemorrhage (ICH) and no intraventricular haemorrhage (IVH) might be improved with early evacuation of the haematoma. The Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) set out to establish whether a policy of earlier surgical evacuation of the haematoma in selected patients with spontaneous lobar ICH would improve outcome compared to a policy of initial conservative treatment. It is an international, multi-centre, prospective randomised parallel group trial of early surgery in patients with spontaneous lobar ICH. Outcome is measured at six months via a postal questionnaire.ResultsRecruitment to the study began on 27 November 2006 and closed on 15 August 2012 by which time 601 patients had been recruited. The protocol was published in Trials (http://www.trialsjournal.com/content/12/1/124/). This update presents the analysis plan for the study without reference to the unblinded data. The trial data will not be unblinded until after follow-up is completed in early 2013. The main trial results will be presented in spring 2013 with the aim to publish in a peer-reviewed journal at the same time.ConclusionThe data from the trial will provide evidence on the benefits and risks of early surgery in patients with lobar ICH.Trial registrationISRCTN: ISRCTN22153967

518O - Maintenance Treatment with Immunomodulator MGN1703 Following Induction with Standard 1ST Line Therapy Prolongs Progression-Free Survival in Patients with Metastatic Colorectal (MCRC): Results of the Phase II/III Impact Trial

ABSTRACT Introduction Standard chemotherapy is increasingly discontinued after successful “induction” in patients (pts) undergoing 1st line treatment for mCRC. MGN1703 is a synthetic DNA-based immunomodulator acting as an agonist of TLR-9 that has shown preclinical activity in mCRC. This study has been conducted to assess clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance vs. placebo. Methods The IMPACT study is an international, multicenter, randomized double-blind placebo-controlled phase II/III study. Pts with mCRC showing disease control (CR, PR or SD) after 4.5 to 6 months of 1st-line standard therapy with FOLFOX/XELOX or FOLFIRI +/- bevacizumab (investigatoŕs choice) were included. Results Interim analysis of the unblinded data revealed a strong therapeutic effect compared to anticipated PFS. Therefore, patients were withheld from further randomization, according to a decision of the steering committee. In the ITT population (N = 55 pts), hazard ratio (HR) was 0.53 in favor of MGN1703 (p = 0.062). In the per-protocol population (excluding screening failures; N = 50), HR was 0.43 (p = 0.015). In the pre-defined target population (2 out of 3 factors: CEA Conclusions Maintenance therapy with MGN1703 after standard chemotherapy with or without bevacizumab, is associated with significantly improved progression-free survival compared to placebo and is accompanied by low toxicity. A confirmatory clinical study in patients with metastatic CRC is currently being planned. Disclosure M. Tschaika: Employment, stock ownership. M. Schmidt: Employment. B. Wittig: Stock ownership. All other authors have declared no conflicts of interest.

A randomized controlled Alzheimer’s disease Prevention trial’s evolution into an exposure trial: The Preadvise trial

To summarize the ongoing prevention of Alzheimer's disease (AD) by vitamin E and selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. PREADViSE was designed as a double blind randomized controlled trial (RCT). SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2x2 factorial structure. In the RCT, participants completed the memory impairment screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a modified telephone interview of cognitive status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) to predict response to preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer: Translational breast cancer research consortium (TBCRC008).

10509 Background: PST allows for improved surgical outcomes and response assessment without compromising long term outcomes. PST is an attractive model for assessing surrogate markers of response to therapy. We hypothesized that changes in tumor standardized uptake values corrected for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of therapy would predict pathological complete response (pCR) to PST in women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: TBCRC008 is a multicenter placebo-controlled trial that investigates pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat. FDG-PET followed by tumor biopsies were performed at baseline and C1D15. We correlated % reduction in SULmax on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no invasive cancer in breast/axilla). We compared % reduction in SULmax between responders (pCR) and non responders (no pCR) using nonparametric Wilcoxon rank sum test. We explored association of % reduction in SULmax at pre-specified cutoff with response using Fisher’s exact test and logistic regression. We correlated baseline, C1D15, and % change in Ki67 at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled (10/2009-11/2011), 40 have completed study PST and surgery (median age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an intent to treat analysis (n=39), we observed a significant difference in median % reduction in SULmax between responders vs not (66.6% vs 32.4%, p &lt;0.001). We observed a higher proportion of reduction in SULmax ≥ 60% in responders vs not (80% vs 3.5%, p &lt;0.001). The differences in baseline, C1D15 and % change in Ki67 were not significant between responders and non-responders. Conclusions: Change in SULmax on FDG-PET 15 days after initiating PST was significantly greater in patients with pCR versus no pCR. Future studies will determine whether altering therapy based on early changes in SULmax will improve pCR. Unblinded data from all participants will be presented at the meeting.

Independent Data and Safety Monitoring in Psychiatric Intervention Research

A data and safety monitoring board (DSMB) is a multidisciplinary group of scientists that monitors a randomized clinical trial. Although DSMBs have been used for clinical trials in cardiology, oncology, and infectious disease for decades, it was not until the late 1990s that the National Institute of Mental Health (NIMH) initially required a DSMB for some of its larger trials. The NIMH mandate expanded during the succeeding decade to require DSMBs for many of the clinical trials in psychiatry. In turn, the need for board members has grown quickly. The objective of this commentary is to consider the purpose of a DSMB and to describe its roles, responsibilities, composition, and implementation. The rationale for a DSMB is to ensure the integrity and validity of the trial and, most importantly, to protect the safety of trial participants. A board conducts comprehensive reviews of accumulating unblinded data for safety and, in some trials, for efficacy. Reviewers examine adverse events and serious adverse events at regular intervals during the course of the trial. In addition, a DSMB monitors recruitment, randomization, retention, adherence, and follow-up in an effort to evaluate the validity of a trial. Because it is unethical to expose a participant to the risks of an experiment that will be unable to answer the scientific question that was postulated, a board should also evaluate the study protocol prior to trial commencement. Ultimately, a DSMB's responsibilities are broader than that of the trial being monitored. It will protect potential study participants and eventually could affect patients seeking clinical treatment for the disorder being studied.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

BackgroundIntravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.ResultsThe initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.ConclusionThe data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registrationISRCTN25765518

Complete Molecular Response (CMR) Rate with Nilotinib in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) without CMR After ≥ 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial of Nilotinib 400 Mg Twice Daily (BID) Vs Imatinib

Abstract 606 Background: Recent studies have demonstrated that about 40% of very highly selected CML-CP pts treated with imatinib achieve durable CMR and may be able to cease therapy without disease recurrence. However, most CML pts don9t achieve CMR on imatinib even with long-term therapy. Results from ENESTnd demonstrated that significantly more patients achieved MMR (≤ 0.1%IS), CMR4 (≤ 0.01%IS), and CMR4.5 (≤ 0.0032%IS) with nilotinib vs imatinib by 12, 18, and 24 months (mo). No pt in ENESTnd who achieved CMR4.5 has progressed to AP/BC. In this study we asked whether pts on long-term imatinib would be more likely to achieve undetectable BCR-ABL levels if they switched to nilotinib, allowing for participation in potential cessation studies in the future. Methods: This open label, 1:1 randomized, prospective, multi-center, phase 3 study enrolled 207 pts with CML-CP who had achieved a complete cytogenetic response (CCyR) but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib. CMR (primary endpoint) was defined as undetectable BCR-ABL by RQ-PCR where there was no detectable BCR-ABL with a sample sensitivity of ≥ 4.5-logs. CMR4 and CMR4.5 were defined as BCR-ABL levels of ≤ 0.01% and ≤ 0.0032% expressed on the International Scale (IS), respectively and included patients with undetectable BCR-ABL levels with high sample sensitivity (4 or 4.5 logs). Patients were randomized to nilotinib 400 mg BID vs continuing imatinib 400 or 600 mg daily (same dose as at study entry.) The randomization was stratified by prior use of IFN (none, ≤ 12 mo, > 12 mo) and prior duration of imatinib therapy (> 36 mo or ≤ 36 mo). The primary endpoint was the rate of confirmed best cumulative CMR by 12 mo of study therapy with nilotinib or imatinib. Secondary objectives included the kinetics of CMR at different timepoints, duration of CMR, progression-free survival, and overall survival in both arms. During the study, RQ-PCR for BCR-ABL was performed at baseline (BL) and every 3 mo and expressed on the IS in national reference laboratories in Australia, Brazil, and Canada. For this report: BL, 6 mo, and 12 mo results were analyzed in a central laboratory in Australia. Assessment of the primary efficacy endpoint has not been completed for 2% of the randomized pts; unblinded data will be available for all pts and will be presented by treatment arm. Results: BL results were available for 205/207 randomized pts. Overall, 56% of pts had no prior IFN exposure, while 21% and 23% had IFN exposure of ≤ 12 mo or > 12 mo, respectively; 81% of pts had been on imatinib > 36 mos. At BL, 153 pts (74%) were known to be in MMR and 54 pts (26%) had Disclosures: Hughes:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Leber:Novartis Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Spector:Novartis: Membership on an entity9s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; BMS: Speakers Bureau. Pasquini:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Schwarer:Novartis: Honoraria; BMS: Honoraria. Mahon:Novartis: Honoraria, Research Funding. Rea:BMS: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Kamel-Reid:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Reynolds:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Branford:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.