Explore Treatment Effects Research Articles

Bayesian evidence synthesis for exploring generalizability of treatment effects: a case study of combining randomized and non-randomized results in diabetes.

In this paper, we present a unified modeling framework to combine aggregated data from randomized controlled trials (RCTs) with individual participant data (IPD) from observational studies. Rather than simply pooling the available evidence into an overall treatment effect, adjusted for potential confounding, the intention of this work is to explore treatment effects in specific patient populations reflected by the IPD. In this way, by collecting IPD, we can potentially gain new insights from RCTs' results, which cannot be seen using only a meta-analysis of RCTs. We present a new Bayesian hierarchical meta-regression model, which combines submodels, representing different types of data into a coherent analysis. Predictors of baseline risk are estimated from the individual data. Simultaneously, a bivariate random effects distribution of baseline risk and treatment effects is estimated from the combined individual and aggregate data. Therefore, given a subgroup of interest, the estimated treatment effect can be calculated through its correlation with baseline risk. We highlight different types of model parameters: those that are the focus of inference (e.g., treatment effect in a subgroup of patients) and those that are used to adjust for biases introduced by data collection processes (e.g., internal or external validity). The model is applied to a case study where RCTs' results, investigating efficacy in the treatment of diabetic foot problems, are extrapolated to groups of patients treated in medical routine and who were enrolled in a prospective cohort study.

Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation.

Feasibility, acceptability and validity of SMS text messaging for measuring change in depression during a randomised controlled trial.

BackgroundDespite widespread popularity, text messaging has rarely been used for data collection in clinical research. This paper reports on the development, feasibility, acceptability, validity, and discriminant utility of a single item depression rating scale, delivered weekly via an automated SMS system, as part of a large randomised controlled trial.Methods755 depressed patients (BDI-II score ≥20) were recruited from primary care into a randomised trial of acupuncture versus counselling or usual care, and invited to opt into a repeated-measures text messaging sub-study. Two weeks following random allocation, trial participants were sent a weekly text message for 15 weeks. Texts were a single question asking, on a scale from 1 to 9, the extent to which they felt depressed. Feasibility and acceptability of the automated SMS system were evaluated according to cost, ease of implementation, proportion consenting, response rates, and qualitative feedback. Concurrent validity was estimated by correlating SMS responses with the Patient Health Questionnaire (PHQ-9). SMS responses were compared between groups over time to explore treatment effects.Results527 (69.8%) trial participants consented to the texting sub-study, of whom 498 (94.5%) responded to at least one message. Participants provided a valid response to an average of 12.5 messages. Invalid responses accounted for 1.1% of texts. The automated SMS system was quick to set-up, inexpensive, and well received. Comparison of PHQ-9 and SMS responses at 3 months demonstrated a moderate to high degree of agreement (Kendall’s tau-b = 0.57, p < 0.0001, n = 220). SMS depression scores over the 15 weeks differed significantly between trial arms (p = 0.007), with participants allocated to the acupuncture and counselling arms reporting improved depression outcomes compared to usual GP care alone, which reached statistical significance ten weeks after randomisation. Overall, the single item SMS scale also appeared more responsive to changes in depression, resulting from treatment, than the PHQ-9.ConclusionsAutomated SMS systems offer a feasible and acceptable means of monitoring depression within clinical research. This study provides clear evidence to support the regular use of a simple SMS scale as a sensitive and valid outcome measure of depression within future randomised controlled trials.Trial registrationCurrent Controlled Trials - ISRCTN63787732 http://www.controlled-trials.com/ISRCTN63787732/ACUDEP Date of registration: 15/12/2009

The superior ⁃ ilioinguinal approach: a new approach beyond the classical ilioinguinal or modified Stoppa approach

Objective To explore treatment effects,image results and preoperative complications of the acetabular fractures managed by the superior ilioinguinal approach.Methods Clinical and follow-up data of 22 patients with acetabular fracture involving the quadrilateral plate managed operatively by superior ilioinguinal approach from October 2010 to November 2012 were retrospectively analyzed.Among them 12 cases were male and 10 cases were female,with an average age of 35.2 years old (range,16-62 years old).According to the fracture classification of Letournel and Judet,there were 6 cases associated with two column fractures,12 anterior column fractures,2 anterior column fractures with posterior hemitransverse,1 transverse and 1 Tshaped.We classificated image results by Matta standard and assessed the results of acetabular function after surgery by modified Merle D'Aubigne score.Results The 22 patients were with followed up for at least 9 months.Average time of the 22 patients from injury to operation was 5 days.Average blood loss was 750 ml,and average operative time was 186 min.According to the criteria described by Matta,68％ of the reductions were graded excellent,23％ were graded good,and 9％ poor.Clinical outcomes (Merle D'Aubigne) at 9 months were 73％ excellent,18％ good,and 9％ poor.No inguinal or abdominal wall hernias occurred.The lateral femoral cutaneous nerve was injured in two patients,due to the trauma or traction during surgery.One patient (4.5％) had a vascular injury.One patient had a fatty fluidization.All patients had 9 to 28 months follow-up (mean,13.5 months).In the last follow-up anatomic reduction were achieved in 15 cases,a satisfactory reduction in 5 and poor reduction in 2.Hip functional results were excellent in 16 cases,good in 4,poor in 2,on the basis of Matta standard and Modified Merle D'Aubigne score.The lateral femoral cutaneous nerve injuries were found in 2 cases,vascular injury and fatty fluidization in 1 case respectively.Conclusion The superior ilioinguinal approach,including the pararectus approach belongs to a new way and has advantages over classic ilioinguinal approach and modified Stoppa approach,which could overcome disadvantages of lack direct vision to quadrilateral surface and Corona Mortis artery. Key words: Acetabulum; Fractures, bone; Fracture fixation, internal; Internal fixators

Cumulative Benefits of Extended-Release Memantine (28 mg, Once Daily) Across Clinical Domains in Patients With Moderate to Severe Alzheimer's Disease: An Area Under the Curve Analysis

The efficacy and safety of the extended-release formulation of memantine (MemER; 28 mg, once daily) in patients with moderate to severe Alzheimer's disease (AD) have been demonstrated in a 24-week, randomized, double-blinded, placebo-controlled trial of 677 patients (placebo, n=335; MemER, n=342) concurrently receiving background therapy with a cholinesterase inhibitor (ChEI) (Grossberg et al, 2013). The protocol-specified analyses in Grossberg et al. focused on changes from baseline (Week 0) to endpoint (Week 24), and revealed significant benefits of adding MemER to the ongoing ChEI therapy in the domains of cognition (Severe Impairment Battery [SIB]), global clinical status (Clinician's Impression of Change Plus Caregiver Input [CIBIC-Plus]), behavior (Neuropsychiatric Inventory [NPI]), and semantic processing ability (Verbal Fluency Test [VFT]); no significant benefits were observed in the domain of daily function (the 19-item Alzheimer Disease Cooperative Study - Activities of Daily Living scale [ADCS-ADL19]). Instead of limiting analysis of treatment benefits to score changes between baseline (Week 0) and the Week-24 endpoint, which provides little information about variation among trial participants in their cumulative responses over time, this study aimed to explore treatment effects during the entire course of the trial. For each patient (observed cases; N=540), the area under the curve (AUC) for changes from baseline on the SIB, CIBIC-Plus, NPI, VFT, and ADCS-ADL19 was calculated for all available time intervals (Weeks 0-24, 4-24, etc), using the trapezoidal rule. For each treatment interval, patient-level data were combined and treatment groups were compared by means of an analysis of covariance (ANCOVA) model with treatment group, center, and baseline value in the model (α=0.05, two-sided). Over the entire study period (Weeks 0-24), the group treated with add-on MemER (MemER-ChEI) displayed AUCs for the SIB, CIBIC-Plus, and NPI that reflected mean improvements of 88% (71.2 ± 11.1 vs 37.9 ± 10.8, P=0.014), 133% (-5.3 ± 1.1 vs -2.3 ± 1.0, P=0.019), and 109% (-91.1 ± 11.9 vs -42.9 ± 11.5, P<0.001), respectively, over the AUC improvements observed in the placebo-ChEI group. (For CIBIC-Plus and NPI, negative score changes indicate improvement.) For the VFT, an AUC indicating cumulative improvement in the MemER-ChEI group was significantly different than the AUC for the placebo-ChEI group that indicated cumulative worsening (P=0.014); the cumulative worsening in the placebo-ChEI group was 139% greater in magnitude than the improvement observed in the MemER-ChEI group (2.5 ± 2.9 vs -6.0 ± 2.8). For the ADCS-ADL19, the mean AUC improvement in the MemER-ChEI group was 117% greater in magnitude than the AUC worsening observed in the placebo-ChEI group, but the difference was not statistically significant (3.9 ± 7.4 vs -1.8 ± 7.2, P=0.528). Other time intervals yielded similar results, i.e., significant AUC improvements for the MemER-ChEI group for the SIB, CIBIC-Plus, NPI, and VFT. In this post-hoc AUC analysis of a randomized placebo-controlled trial, cumulative benefits were observed across multiple clinical domains for the treatment of patients with moderate to severe AD with memantine ER added to background ChEI therapy. The AUC approach provides a more complete representation of longitudinal therapeutic effect than the change score analyses often used in clinical trials: it is more ecologically valid, robust, and dynamic; does not rely on simple two-point change scores; and is not limited by an assumption of linear changes with time in making inferences and interpreting results. The significant cumulative improvements in cognition, global clinical status, behavior, and semantic processing abilities provide support to the view that add-on therapy with memantine ER yielded meaningful therapeutic benefits across the 24-week trial period.

Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: Subgroup analysis of demographic and clinical characteristics

Our objective was to explore treatment effects in patient subgroups using post hoc analyses of data from part 2 of the dexpramipexole Phase II study. Subjects with amyotrophic lateral sclerosis (ALS) received dexpramipexole 300 mg/day or 50 mg/day for 24 weeks. Treatment effects on the slope of the revised ALS Functional Rating Score (ALSFRS-R) and Combined Assessment of Function and Survival (CAFS) were evaluated in dichotomized subgroups: riluzole use, gender, site of symptom onset. Other subgroups were dichotomized using median baseline values for age, ALSFRS-R, slow vital capacity, symptom duration, diagnostic delay, and progression rate. Results showed that there was a 21% reduction in ALSFRS-R decline favoring the 300-mg vs. 50-mg arm (p = 0.177); mean CAFS ranking was significantly higher in the 300-mg vs. 50-mg arm (52.4 vs. 41.1; p = 0.046). Trends were recapitulated in virtually all subgroups. Generally, ALSFRS-R decline was reduced and CAFS rankings were higher in the 300-mg vs. 50-mg arm across subgroups. CAFS rankings were significantly higher in the 300-mg vs. 50-mg arm among subjects with ALSFRS-R scores ≤35, symptom duration <18.7 months, or progression rate ≥ 0.7 points/month (p < 0.03). In conclusion, the observed benefit of 300- vs. 50-mg dexpramipexole on functional decline and survival was generally consistent among subjects regardless of baseline characteristics.

Positron emission tomography assessment of 8-OH-DPAT-mediated changes in an index of cerebral glucose metabolism in female marmosets

As part of a larger experiment investigating serotonergic regulation of female marmoset sexual behavior, this study was designed to (1) advance methods for PET imaging of common marmoset monkey brain, (2) measure normalized FDG uptake as an index of local cerebral metabolic rates for glucose, and (3) study changes induced in this index of cerebral glucose metabolism by chronic treatment of female marmosets with a serotonin 1A receptor (5-HT(1A)) agonist. We hypothesized that chronic treatment with the 5-HT(1A) agonist 8-OH-DPAT would alter the glucose metabolism index in dorsal raphe (DR), medial prefrontal cortex (mPFC), medial preoptic area of hypothalamus (mPOA), ventromedial nucleus of hypothalamus (VMH), and field CA1 of hippocampus. Eight adult ovariectomized female common marmosets (Callithrix jacchus) were studied with and without estradiol replacement. In a crossover design, each subject was treated daily with 8-OH-DPAT (0.1mg/kg SC daily) or saline. After 42-49 days of treatment, the glucose metabolism radiotracer FDG was administered to each female immediately prior to 30 min of interaction with her male pairmate, after which the subject was anesthetized and imaged by PET. Whole brain normalized PET images were analyzed with anatomically defined regions of interest (ROI). Whole brain voxelwise mapping was also used to explore treatment effects and correlations between alterations in the glucose metabolism index and pairmate interactions. The rank order of normalized FDG uptake was VMH/mPOA>DR>mPFC/CA1 in both conditions. 8-OH-DPAT did not induce alterations in the glucose metabolism index in ROIs. Voxelwise mapping showed a significant reduction in normalized FDG uptake in response to 8-OH-DPAT in a cluster in medial occipital cortex as well as a significant correlation between increased rejection of mount attempts and reduced normalized FDG uptake in an overlapping cluster. In conclusion, PET imaging has been used to measure FDG uptake relative to whole brain in marmoset monkeys. Voxelwise mapping shows that 8-OH-DPAT reduces this index of glucose metabolism in medial occipital cortex, consistent with alterations in female sexual behavior.

Clinical Trial Subgroups

Heart disease is the leading cause of death in women in the United States.1 To combat this phenomenon, professional guidelines for primary and secondary prevention as well as sex-specific guidelines for women have been developed and promulgated.2–4 Despite these efforts, there remains some controversy surrounding the benefits of statin therapy in women,5 although a 2004 meta-analysis clearly demonstrated benefits for secondary prevention on nonmortal cardiovascular events.6 In light of these data, current secondary prevention guidelines endorse statin therapy as a class IA recommendation for all patients recovering from an acute coronary syndrome, not just men.7 Article see p 328 Despite these recommendations for the use of statin therapy as an effective means for secondary prevention, it remains unclear whether the intensity of lipid-lowering therapy is important. In fact, the entire concept of treating patients to target lipid values, rather than treating on the basis of risk, has been questioned.8 In light of this concern, the current study by Truong et al,9 in this issue of Circulation: Cardiovascular Quality and Outcomes , examines the sex-specific benefits of more-intensive statin therapy after acute coronary syndromes in women. Using data from the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial,10 the authors conducted a thorough analysis of outcomes stratified by sex and extended the existing literature by exploring treatment effects among women according to …

A Randomized Pilot Clinical Trial of the Safety of Pioglitazone in Treatment of Patients With Alzheimer Disease

To evaluate the safety of the peroxisome proliferator-activated receptor gamma agonist pioglitazone in nondiabetic patients with Alzheimer disease (AD) and to explore treatment effect sizes on clinical outcomes. Double-blind, placebo-controlled randomized controlled trial of 18-month duration. Two academic medical center outpatient clinics. Nondiabetic patients meeting research criteria for probable AD were enrolled. Twenty-five of 29 subjects completed the study; no withdrawals were attributable to adverse effects. Subjects received pioglitazone (Actos), titrated to 45 mg daily, or matching placebo, and 200 IU of vitamin E daily. Patients maintained treatment with cholinesterase inhibitors and could begin memantine therapy when it became available during the study. The primary outcome was frequency of reported adverse effects (AEs). Secondary outcomes were measures of cognition, activities of daily living, neuropsychiatric symptoms, and global function. Peripheral edema was the principal AE occurring more frequently in subjects taking pioglitazone than placebo (28.6% vs 0%). This is consistent with the known AE profile of pioglitazone. No group differences in laboratory measures were identified. No significant treatment effect was observed on exploratory analysis of clinical efficacy. Pioglitazone was generally well tolerated in this pilot study. There were no serious or unanticipated adverse events or clinical laboratory changes attributable to pioglitazone over a long-term exposure in nondiabetic patients with AD. The tolerability of pioglitazone in this population and peroxisome proliferator-activated receptor gamma effects in laboratory models of AD support further study of this drug class in earlier disease stages. clinicaltrials.gov Identifier: NCT00982202.

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients

IntroductionPurpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels.MethodsIn Germany, patients receiving protein C concentrate (Ceprotin®, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study.ResultsComplete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03).ConclusionsThis retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.

Stereotactic Body Radiotherapy for Liver Malignancies: Prospective QOL Results

Stereotactic Body Radiotherapy for Liver Malignancies: Prospective QOL Results

Acupuncture for tinnitus: A series of six n = 1 controlled trials

To explore patient perceived benefits of acupuncture for tinnitus. Controlled n=1 trials, with two phases A and B. Six patients with tinnitus. Primary outcome was Daily Diary records related to four tinnitus symptoms: loudness of tinnitus; pitch of tinnitus; waking hours affected with tinnitus; quality of sleep. Secondary outcomes were the Tinnitus Handicap Inventory (THI) and Measure Your Medical Outcome Profile (MYMOP). Patients received a course of 10 acupuncture treatments over a 2-week period. Daily Diary entries related to the four tinnitus symptoms were recorded by patients for 14 days pre-treatment (phase A) and 14 days post-treatment (phase B). A hierarchical Bayesian model was used to combine the results from the individual patients to obtain estimates of the population and individual patient treatment effects, incorporating random variations at both levels (between patients and within patient). Tinnitus Handicap Inventory (THI) and Measure Your Medical Outcome Profile (MYMOP) were recorded at assessment points pre-treatment and post-treatment. Six patients participated in the trials, each receiving 10 treatments and completing all Daily Diary entries and outcome measures. For the of symptoms of loudness and pitch, there were variable treatment effects between patients, with a trend for the median overall reduction for loudness of -2.49 (-5.04, 0.02) and for pitch -1.39 (-3.74, 0.89), 95% credibility intervals being shown in brackets. For the other two symptoms, the waking hours affected and quality of sleep, patients' responses were more consistent, with amore credible overall median reduction for affected waking hours of -2.76 (-3.94, -1.63) and for quality of sleep -2.72 (-3.45, -2.03). The THI and MYMOP measures showed a trend of improvement after treatment. The n=1 trial methodology, with an AB design and Bayesian analysis, can be considered of value in exploring treatment effects for small numbers of patients receiving individualised treatments, as is common within complementary medicine. When the treatment effects from six patients were synthesized, the results of this study suggest that acupuncture may have a beneficial role in the treatment of tinnitus.

Use of generalized estimating equations in a trial in influenza to explore treatment effects over time

AbstractFor trials with repeated measurements of outcome, analyses often focus on univariate outcomes, such as analysis of summary measures or of the last on‐treatment observation. Methods which model the whole data set provide a rich source of approaches to analysis. For continuous data, mixed‐effect modelling is increasingly used. For binary and categorical data, models based on use of generalized estimating equations account for intra‐subject correlation and allow exploration of the time course of response, as well as providing a useful way to account for missing data, when such data can be maintained as missing in the analysis. The utility of this approach is illustrated by an example from a trial in influenza. Copyright © 2004 John Wiley &amp; Sons Ltd.