A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

PURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

Non-Pharmacological Approaches for Pain Management in Sickle Cell Disease: Development of a Mindfulness-Based Intervention

Background: Sickle Cell Disease (SCD) is a genetic hematological disorder that affects more than 7 million people globally (NHLBI, 2009). It is estimated that 50% of adults with SCD experience pain on most days, with 1/3 experiencing chronic pain daily (Smith et al., 2008). Persons with SCD also experience higher levels of pain catastrophizing (feelings of helplessness, pain rumination and magnification) than other chronic pain conditions, which is associated with increases in pain intensity, pain behavior, analgesic consumption, frequency and duration of hospital visits, and with reduced daily activities (Sullivan, Bishop, & Pivik, 1995; Keefe et al., 2000; Gil et al., 1992 & 1993). Therefore effective interventions are needed that can successfully be used manage pain and pain-related outcomes (e.g., pain catastrophizing) in persons with SCD. A review of the literature demonstrated limited information regarding the feasibility and efficacy of non-pharmacological approaches for pain in persons with SCD, finding an average effect size of .33 on pain reduction across measurable non-pharmacological studies. Second, a prospective study on persons with SCD that received care for a vaso-occlusive crisis (VOC; N = 95) found: (1) high levels of patient reported depression (29%) and anxiety (34%), and (2) that unemployment was significantly associated with increased frequency of acute care encounters and hospital admissions per person. Research suggests that one promising category of non-pharmacological interventions for managing both physical and affective components of pain are Mindfulness-based Interventions (MBIs; Thompson et al., 2010; Cox et al., 2013). The primary goal of this dissertation was thus to develop and test the feasibility, acceptability, and efficacy of a telephonic MBI for pain catastrophizing in persons with SCD and chronic pain.

Methods: First, a telephonic MBI was developed through an informal process that involved iterative feedback from patients, clinical experts in SCD and pain management, social workers, psychologists, and mindfulness clinicians. Through this process, relevant topics and skills were selected to adapt in each MBI session. Second, a pilot randomized controlled trial was conducted to test the feasibility, acceptability, and efficacy of the telephonic MBI for pain catastrophizing in persons with SCD and chronic pain. Acceptability and feasibility were determined by assessment of recruitment, attrition, dropout, and refusal rates (including refusal reasons), along with semi-structured interviews with nine randomly selected patients at the end of study. Participants completed assessments at baseline, Week 1, 3, and 6 to assess efficacy of the intervention on decreasing pain catastrophizing and other pain-related outcomes.

Results: A telephonic MBI is feasible and acceptable for persons with SCD and chronic pain. Seventy-eight patients with SCD and chronic pain were approached, and 76% (N = 60) were enrolled and randomized. The MBI attendance rate, approximately 57% of participants completing at least four mindfulness sessions, was deemed acceptable, and participants that received the telephonic MBI described it as acceptable, easy to access, and consume in post-intervention interviews. The amount of missing data was undesirable (MBI condition, 40%; control condition, 25%), but fell within the range of expected missing outcome data for a RCT with multiple follow-up assessments. Efficacy of the MBI on pain catastrophizing could not be determined due to small sample size and degree of missing data, but trajectory analyses conducted for the MBI condition only trended in the right direction and pain catastrophizing approached statistically significance.

Conclusion: Overall results showed that at telephonic group-based MBI is acceptable and feasible for persons with SCD and chronic pain. Though the study was not able to determine treatment efficacy nor powered to detect a statistically significant difference between conditions, participants (1) described the intervention as acceptable, and (2) the observed effect sizes for the MBI condition demonstrated large effects of the MBI on pain catastrophizing, mental health, and physical health. Replication of this MBI study with a larger sample size, active control group, and additional assessments at the end of each week (e.g., Week 1 through Week 6) is needed to determine treatment efficacy. Many lessons were learned that will guide the development of future studies including which MBI strategies were most helpful, methods to encourage continued participation, and how to improve data capture.

Essays on the Role of Government Incentives in the Private Provision of Social Goods

The economic rationale for public intervention into private markets through price mechanisms is twofold: to correct market failures and to redistribute resources. Financial incentives are one such price mechanism. In this dissertation, I specifically address the role of financial incentives in providing social goods in two separate contexts: a redistributive policy that enables low income working families to access affordable childcare in the US and an experimental pay-for-performance intervention to improve population health outcomes in rural India. In the first two papers, I investigate the effects of government incentives for providing grandchild care on grandmothers’ short- and long-term outcomes. In the third paper, coauthored with Manoj Mohanan, Grant Miller, Katherine Donato, and Marcos Vera-Hernandez, we use an experimental framework to consider the the effects of financial incentives in improving maternal and child health outcomes in the Indian state of Karnataka.

Grandmothers provide a significant amount of childcare in the US, but little is known about how this informal, and often uncompensated, time transfer impacts their economic and health outcomes. The first two chapters of this dissertation address the impact of federally funded, state-level means-tested programs that compensate grandparent-provided childcare on the retirement security of older women, an economically vulnerable group of considerable policy interest. I use the variation in the availability and generosity of childcare subsidies to model the effect of government payments for grandchild care on grandmothers’ time use, income, earnings, interfamily transfers, and health outcomes. After establishing that more generous government payments induce grandmothers to provide more hours of childcare, I find that grandmothers adjust their behavior by reducing their formal labor supply and earnings. Grandmothers make up for lost earnings by claiming Social Security earlier, increasing their reliance on Supplemental Security Income (SSI) and reducing financial transfers to their children. While the policy does not appear to negatively impact grandmothers’ immediate economic well-being, there are significant costs to the state, in terms of both up-front costs for care payments and long-term costs as a result of grandmothers’ increased reliance on social insurance.

The final paper, The Role of Non-Cognitive Traits in Response to Financial Incentives: Evidence from a Randomized Control Trial of Obstetrics Care Providers in India, is coauthored with Manoj Mohanan, Grant Miller, Katherine Donato and Marcos Vera-Hernandez. We report the results from “Improving Maternal and Child Health in India: Evaluating Demand and Supply Side Strategies” (IMACHINE), a randomized controlled experiment designed to test the effectiveness of supply-side incentives for private obstetrics care providers in rural Karnataka, India. In particular, the experimental design compares two different types of incentives: (1) those based on the quality of inputs providers offer their patients (inputs contracts) and (2) those based on the reduction of incidence of four adverse maternal and neonatal health outcomes (outcomes contracts). Along with studying the relative effectiveness of the different financial incentives, we also investigate the role of provider characteristics, preferences, expectations and non-cognitive traits in mitigating the effects of incentive contracts.

We find that both contract types input incentive contracts reduce rates of post-partum hemorrhage, the leading cause of maternal mortality in India by about 20%. We also find some evidence of multitasking as output incentive contract providers reduce the level of postnatal newborn care received by their patients. We find that patient health improvements in response to both contract types are concentrated among higher trained providers. We find improvements in patient care to be concentrated among the lower trained providers. Contrary to our expectations, we also find improvements in patient health to be concentrated among the most risk averse providers, while more patient providers respond relatively little to the incentives, and these difference are most evident in the outputs contract arm. The results are opposite for patient care outcomes; risk averse providers have significantly lower rates of patient care and more patient providers provide higher quality care in response to the outputs contract. We find evidence that overconfidence among providers about their expectations about possible improvements reduces the effectiveness of both types of incentive contracts for improving both patient outcomes and patient care. Finally, we find no heterogeneous response based on non-cognitive traits.

Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.

BACKGROUND: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel. METHODS AND RESULTS: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs. CONCLUSIONS: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.