Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial.

BACKGROUND AND PURPOSE: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. METHODS: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. RESULTS: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33). CONCLUSIONS: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

A composite outcome for mild traumatic brain injury in trials of hyperbaric oxygen.

INTRODUCTION: Global outcomes can strengthen inferences from clinical trials. We evaluate global outcomes for persistent post-concussive symptoms (PCS) after mild traumatic brain injury (mTBI) in two clinical trials of hyperbaric oxygen (HBO2) in United States service members. METHODS: During study design, outcomes of symptom, cognitive, and functional impairments planned for a trial of HBO2 for PCS (HOPPS) were weighted and grouped into different domains to formulate the composite outcome total score. The composite outcome was compared between the intervention groups in HOPPS and those in a subsequent HBO2 trial (BIMA) for validation. Additionally, two post hoc global outcome measures were explored, including one composed of components that demonstrated favorable characteristics in both studies and another via components used in another TBI randomized trial (COBRIT). RESULTS: In total, 143 active-duty or veteran military personnel were randomized across the two studies. Composite total scores improved from baseline for HBO2 (mean ± SD -2.9±9.0) and sham (-2.9±6.6) groups in HOPPS but did not differ significantly between groups (p=0.33). In BIMA, 13-week changes from baseline favored the HBO2 group (-3.6±6.4) versus sham (-0.3±5.2; p=0.02). No between-group differences were found when COBRIT composite scoring was applied to BIMA. Overall, HBO2 effects were maximized when the post hoc global measure derived from both studies was applied to the data. CONCLUSIONS: Composite total scores in HOPPS and BIMA were consistent with primary study results. The global measures considered may offer utility as endpoints to achieve maximal HBO2 effect in future trials of the mTBI population. IDS: clinicaltrials.gov Identifiers NCT01611194 (BIMA) and NCT01306968 (HOPPS).

Eye tracker outcomes in a randomized trial of 40 sessions of hyperbaric oxygen or sham in participants with persistent post concussive symptoms.

PURPOSE: Eye movements may offer a sensitive method to measure response to intervention in mild traumatic brain injury (mTBI). METHODS: The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) randomized 71 participants to 40 sessions of hyperbaric oxygen or sham. A companion normative study (Normal) enrolled 75 participants. An eye tracking system measured left and right eye movements for saccadic and smooth pursuit. At baseline two smooth pursuit tasks, circular and horizontal ramp, and four saccadic tasks, horizontal and vertical step, reading, and memory guided-on tasks differentiated BIMA from Normal participants. The change from baseline in these tasks were measured and compared between interventions and against Normal participants at 13 weeks and six-month follow-up using the two-sample t-test. The Holm-Bonferroni procedure was used to adjust for multiple testing. RESULTS: Change from baseline in eyetracker measures for participants assigned to the hyperbaric oxygen arm did not significantly differ from those assigned to the sham arm at post-randomization time points 13 weeks and six months. Consistent shifts of BIMA participant values toward Normal values at 13 weeks and six months were observed for overall fixation duration, forward saccadic duration, and number of lines read for the reading task, number of misses on the memory guided-on task, and absolute intersaccadic interval velocity and absolute saccadic amplitude on the circular task. The distributions between Normal and BIMA participants were no longer statistically significantly different at 13 weeks and six months post enrollment for these measures. CONCLUSION: The baseline differences between BIMA and Normal suggest potential vulnerability of the smooth pursuit system and the saccadic system. During the six-month follow-up period, improvement toward Normal was seen on some measures in both the hyperbaric oxygen and sham intervention arms without difference between intervention groups. IDS: clinicaltrials.gov Identifiers NCT01611194 and NCT01925963.

Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms.

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

Extended follow-up in a randomized trial of hyperbaric oxygen for persistent post-concussive symptoms.

To date, several Department of Defense (DoD) and civilian studies have evaluated hyperbaric oxygen for mild forms of traumatic brain injury. Prior to the DoD-sponsored "Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA)" trial, none included post-intervention follow-up beyond three to six months. Post-hoc attempts at long-term follow-up were complicated by low participation and potential self-selection bias. BIMA planned for follow-up through 12 months but was amended to add post-concussive and post-traumatic stress disorder, quality of life, pain, depression, anxiety, and alcohol use assessments at 24 and 36 months. A total of 42 of 71 BIMA participants consented to extendedfollow-up, and 40 and 14 completed a 24- or 36-month visit, respectively, representing an overall response rate of 59% and 20%. Participants who completed extended follow-up were similar to the study group that did not in terms of demographics, perceived intervention allocation, and initial response to intervention. There were no significant differences at 24 or 36 months between intervention groups, and group mean scores were near pre-intervention values. This return to baseline could be due to waning treatment effect, selection bias, or participant or perception effects. Though BIMA implemented several participant retention strategies, more frequent participant contact and increased compensation might improve long-term retention in future studies. clinicaltrials.gov Identifier NCT01611194.

Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial.

BACKGROUND: In prior military randomized trials, participants with persistent symptoms after mild traumatic brain injury (TBI) reported improvement regardless of receiving hyperbaric oxygen (HBO2) or sham intervention. This study's objectives were to identify outcomes for future efficacy trials and describe changes by intervention. METHODS: This Phase II, randomized, double-blind, sham-controlled trial enrolled military personnel with mild TBI and persistent post-concussive symptoms. Participants were randomized to receive 40 HBO2 (1.5 atmospheres absolute (ATA), ⟩99% oxygen, 60 minutes) or sham chamber sessions (1.2 ATA, room air, 60 minutes) over 12 weeks. Participants and evaluators were blinded to allocation. Outcomes assessed at baseline, 13 weeks and six months included symptoms, quality of life, neuropsychological, neurological, electroencephalography, sleep, auditory, vestibular, autonomic, visual, neuroimaging, and laboratory testing. Participants completed 12-month questionnaires. Intention-to-treat results are reported. RESULTS: From 9/11/2012 to 5/19/2014, 71 randomized participants received HBO2 (n=36) or sham (n=35). At baseline, 35 participants (49%) met post-traumatic stress disorder (PTSD) criteria. By the Neurobehavioral Symptom Inventory, the HBO2 group had improved 13-week scores (mean change -3.6 points, P=0.03) compared to sham (+3.9 points). In participants with PTSD, change with HBO2 was more pronounced (-8.6 vs. +4.8 points with sham, P=0.02). PTSD symptoms also improved in the HBO2 group, and more so in the subgroup with PTSD. Improvements regressed at six and 12 months. Hyperbaric oxygen improved some cognitive processing speed and sleep measures. Participants with PTSD receiving HBO2 had improved functional balance and reduced vestibular complaints at 13 weeks. CONCLUSIONS: By 13 weeks, HBO2 improved post-concussive and PTSD symptoms, cognitive processing speed, sleep quality, and balance function, most dramatically in those with PTSD. Changes did not persist beyond six months. Several outcomes appeared sensitive to change; additional studies are warranted.

Neuropsychological assessments in a hyperbaric trial of post-concussive symptoms.

Results of studies addressing the effect of mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) on symptoms and neuropsychological assessments are mixed regarding cognitive deficits in these populations. Neuropsychological assessments were compared between U.S. military service members with mTBI only (n=36) vs. those with mTBI÷ PTSD (n=35) from a randomized interventional study of mTBI participants with persistent post-concussive symptoms (PCS). The mTBI group endorsed worse symptoms than published norms on PCS, PTSD and pain scales (⟩50% abnormal on Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Civilian, McGill Pain Questionnaire-Short Form) and some quality of life domains. Worse symptom reporting was found in the mTBI÷ PTSD group compared to mTBI (e.g., mean NSI total score in mTBI 27.5 (SD=12.7), mTBI÷ PTSD 39.9 (SD=13.6), p⟨0.001). The mTBI÷PTSD group performed worse than mTBI on the Weschler Adult Intelligence Scale digit span (mean difference -1.5, 95% CI[-2.9,-0.1], p=0.04) and symbol search (mean difference -1.5, 95% CI[-2.7,-0.2], p=0.03) and Grooved Pegboard (dominant hand mean difference -7.0, 95% CI[-11.5,-2.4], p=0.003; non-dominant mean difference -9.8, 95% CI[-14.9,-4.7], p⟨0.001). Differences were detected in ANAM simple reaction time (p=0.04) and mathematical processing (p=0.03) but not verbal fluency or visuospatial memory assessments. Results indicate increased symptom severity and some cognitive deficits in mTBI÷ PTSD compared to mTBI alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Hyperbaric oxygen for mild traumatic brain injury: Design and baseline summary.

The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense, is a randomized double-blind, sham-controlled clinical trial that has a longer duration of follow-up and more comprehensive assessment battery compared to recent HBO2 studies. BIMA randomized 71 participants from September 2012 to May 2014. Primary results are expected in 2017. Randomized military personnel received hyperbaric oxygen (HBO2) at 1.5 atmospheres absolute (ATA) or sham chamber sessions at 1.2 ATA, air, for 60 minutes daily for 40 sessions. Outcomes include neuropsychological, neuroimaging, neurological, vestibular, autonomic function, electroencephalography, and visual systems evaluated at baseline, immediately following intervention at 13 weeks and six months with self-report symptom and quality of life questionnaires at 12 months, 24 months and 36 months. Characteristics include: median age 33 years (range 21-53); 99% male; 82% Caucasian; 49% diagnosed post-traumatic stress disorder; 28% with most recent injury three months to one year prior to enrollment; 32% blast injuries; and 73% multiple injuries. This manuscript describes the study design, outcome assessment battery, and baseline characteristics. Independent of a therapeutic role of HBO2, results of BIMA will aid understanding of mTBI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Review of recent non-hyperbaric oxygen interventions for mild traumatic brain injury.

Traumatic brain injury (TBI) affects 3.2 to 5.3 million persons in the United States (U.S.), and the impact in the U.S. military is proportionally higher. Consensus is lacking regarding an accepted outcome to measure the effectiveness of interventions to improve the symptoms associated with TBI, and no standard-of-care treatment exists for mild TBI (mTBI). A recent literature review evaluated hyperbaric oxygen therapy (HBO2) interventions, and findings were mixed. We conducted a systematic review of non-HBO2 mTBI interventional trials published in 2005-2015 in military and civilian populations. A total of 154 abstracts, seven randomized controlled trials (RCTs) and five pilot studies were reviewed. RCTs were evaluated using Consolidated Standards of Reporting Trials criteria. Results indicated that studies published within the period of review were small pilot studies for rehabilitation therapy and motion capture or virtual reality gaming interventions. Neuropsychological assessments were commonly specified outcomes, and most studies included a combination of symptom and neuropsychological assessments. Findings indicated a lack of large-scale, well-controlled trials to address the symptoms and sequelae of this condition, but results of small exploratory studies show evidence of potentially promising interventions.

Executive summary: The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) Study.

The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense and held under an investigational new drug application by the Office of the Army Surgeon General, is one of the largest and most complex clinical trials of hyperbaric oxygen (HBO2) for post-concussive symptoms (PCS) in U.S. military service members.

Baseline neurological evaluations in a hyperbaric trial of post-concussive syndrome.

Standard neurologic examinations may not detect abnormalities in U.S. military service members with persistent post-concussive symptoms following mild traumatic brain injury. The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) enrolled 71 participants September 2012-May 2014. Participants received: comprehensive neurological and oculomotor exam; balance testing (Berg Balance Scale-BBS; Romberg Test-RT, Sharpened Romberg Test-SRT); olfactory function (Brief Smell Identification Test-BSIT). Two trained neurologists conducted the examinations at a central facility in Colorado Springs. Median age was 32 years (range 21-53), 99% male, 82% Caucasian, 49% PTSD, 28% most recent qualifying injury three months to one year prior to enrollment, 32% blast injuries only, and 73% multiple injuries. Some participants presented with abnormal facial sensation (15%), abnormal tandem gait (13%), and tremor (11%). 54% had abnormal near point of convergence (abnormal range 13-80 cm). 86% scored ≥ 55 on the BBS, with no participant scoring ⟨ 50. 49% scored ⟨ 30 seconds on the best trial of the SRT. RT was abnormal in 10%. 15% of participants scored ≤ 9 (out of 12) on BSIT, about twice what is expected in a normal population. The neurological examination found abnormalities across a range of testing, with convergence insufficiency and SRT having the most sensitivity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study.

The Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), sponsored by the Department of Defense, is a randomized, double-blind, sham-controlled trial of hyperbaric oxygen (HBO2) in service members with persistent post-concussive symptoms following mild TBI, undergoing comprehensive assessments. The clinical EEG was assessed by neurologists for slow wave activity, ictal/interictal epileptiform abnormalities, and background periodic discharges. There is scant literature about EEG findings in this population, so we report baseline clinical EEG results and explore associations with other evaluations, including demographics, medication, neurological assessments, and clinical MRI outcomes. Seventy-one participants were enrolled: median age 32 years, 99% male, 49% comorbid PTSD, 28% with mTBI in the previous year, 32% blast injuries only, and 73% multiple injuries. All participants reported medication use (mean medications = 8, SD = 5). Slowing was present in 39%: generalized 37%, localized 8%, both 6%. No other abnormalities were identified. Slowing was not significantly associated with demographics, medication or neurological evaluation. Participants without EEG abnormalities paradoxically had significantly higher number of white matter hyperintensities as identified on MRI (p = 0.003). EEG slowing is present in more than one-third of participants in this study without evidence of associations with demographics, medications or neurological findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Linear analysis of heart rate variability in post-concussive syndrome.

Heart rate variability (HRV) represents measurable output of coordinated structural and functional systems within the body and brain. Both mild traumatic brain injury (mTBI) and HRV are modulated by changes in autonomic nervous system function. We present baseline HRV results from an ongoing mTBI clinical trial. HRV was assessed via 24-hour ambulatory electrocardiography; recordings were segmented by physiological state (sleep, wakefulness, exercise, standing still). Time, frequency, and spatial domain measures were summarized and compared with symptoms, sleep quality, and neurological examination. Median low frequency/high frequency (LF/HF) ratio exceeded 1.0 across segments, indicating prevalence of sympathetic modulation. Abnormal Sharpened Romberg Test was associated with 29% LF/HF decrease (95% CI [2.1, 47.7], p=0.04); pathological nystagmus associated with decreased standard deviation of electrocardiogram R-R interval (SDNN) index (25% decrease, 95% CI [0.8, 43.4], p=0.04). Increased sympathetic modulation was associated with increased anger scores (19% LF/HF increase with 5-point State Trait Anger Expression Inventory-2 trait anger increase (95% CI [1.2, 39.1], p=0.04)). A 13% HF increase (95% CI [2.1, 25.7], p=0.02) was observed with increased Pittsburgh Sleep Quality Index scores. These results support autonomic nervous system dysfunction in service members after mTBI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Central site monitoring: results from a test of accuracy in identifying trials and sites failing Food and Drug Administration inspection.

BACKGROUND: Site monitoring and source document verification account for 15%-30% of clinical trial costs. An alternative is to streamline site monitoring to focus on correcting trial-specific risks identified by central data monitoring. This risk-based approach could preserve or even improve the quality of clinical trial data and human subject protection compared to site monitoring focused primarily on source document verification. PURPOSE: To determine whether a central review by statisticians using data submitted to the Food and Drug Administration (FDA) by clinical trial sponsors can identify problem sites and trials that failed FDA site inspections. METHODS: An independent Analysis Center (AC) analyzed data from four anonymous new drug applications (NDAs) where FDA had performed site inspections overseen by FDA's Office of Scientific Investigations (OSI). FDA team members in the OSI chose the four NDAs from among all NDAs with data in Study Data Tabulation Model (SDTM) format. Two of the NDAs had data that OSI had deemed unreliable in support of the application after FDA site inspections identified serious data integrity problems. The other two NDAs had clinical data that OSI deemed reliable after site inspections. At the outset, the AC knew only that the experimental design specified two NDAs with significant problems. FDA gave the AC no information about which NDAs had problems, how many sites were inspected, or how many were found to have problems until after the AC analysis was complete. The AC evaluated randomization balance, enrollment patterns, study visit scheduling, variability of reported data, and last digit reference. The AC classified sites as 'High Concern', 'Moderate Concern', 'Mild Concern', or 'No Concern'. RESULTS: The AC correctly identified the two NDAs with data deemed unreliable by OSI. In addition, central data analysis correctly identified 5 of 6 (83%) sites for which FDA recommended rejection of data and 13 of 15 sites (87%) for which any regulatory deviations were identified during inspection. Of the six sites for which OSI reviewed inspections and found no deviations, the central process flagged four at the lowest level of concern, one at a moderate level, and one was not flagged. LIMITATIONS: Central data monitoring during the conduct of a trial while data checking was in progress was not evaluated. CONCLUSION: Systematic central monitoring of clinical trial data can identify problems at the same trials and sites identified during FDA site inspections. Central data monitoring in conjunction with an overall monitoring process that adapts to identify risks as a trial progresses has the potential to reduce the frequency of site visits while increasing data integrity and decreasing trial costs compared to processes that are dependent primarily on source documentation.

Progression of geographic atrophy and genotype in age-related macular degeneration.

PURPOSE: We sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Prospective analysis of participants in a randomized controlled clinical trial. PARTICIPANTS: We included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). METHODS: Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. MAIN OUTCOME MEASURES: Genotype frequencies and change in cumulative area of GA. RESULTS: The mean growth rate of GA for the 114 eyes was 1.79 mm(2)/year (range, 0.17-4.76). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value = 0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. CONCLUSIONS: Growth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association.