Statistical and Methodological Considerations for Randomized Controlled Trial Design in Physical Medicine and Rehabilitation.

ABSTRACT: Well-designed randomized controlled clinical trials assessing treatments in the field of physical medicine and rehabilitation are essential for evidence-based patient care. However, there are challenges unique to clinical trials in physical medicine and rehabilitation due to complex health interventions in this field. We highlight routinely encountered empirical challenges and provide evidence-based recommendations on statistical and methodological approaches for the design and conduct of randomized controlled trials. Some of the issues addressed include challenges with blinding treatment groups in a rehabilitation setting, heterogeneity in treatment therapy, heterogeneity of treatment effects, uniformity in patient-reported outcome measures, and effect on power with varying scales of information. Furthermore, we discuss challenges with estimation of sample size and power, adaption to poor compliance with treatment and missing outcomes, and preferred statistical approaches for longitudinal data analysis. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Appraise the complexities of interventions in physical medicine and rehabilitation and how these challenges impact the conduct of clinical trials; (2) Develop an analytical strategy for poor treatment compliance and missing outcomes that can compromise the causal effect sought in a randomized clinical trial; and (3) Recognize the role of a data and safety monitoring board in a clinical trial. LEVEL: Advanced. ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Incidence and Clinical Risk Factors of Post-Operative Complications following Primary Total Hip Arthroplasty: A 10-Year Population-Based Cohort Study.

Background: Total hip arthroplasty (THA) has become a growing treatment procedure for debilitating hip pathologies. Patients experienced post-operative complications and revision surgeries according to large THA registries. To fully understand the short-term and long-term post-operative outcomes following THA, the purpose of this study is to examine the incidence of post-operative complications following primary THA and to examine how this trend has changed over 10 years within community hospitals in the US using large databases. Methods: This study queried the State Inpatient Database (SID) for primary THA between 2006 and 2015. Individual patients were followed forward in time until the first instance of a post-operative complication. The multivariable logistic regression analyses were computed to examine which post-operative complications were independent predictors of pre-operative comorbidities. Results: Median age of patients was 67 years, and 56% of patients were female. Females with avascular necrosis (AVN) as an indication for THA had a 27% higher risk of complication. Females with osteoarthritis (OA) as an indication for THA had a 6% higher risk of complication. Post-operative complications occurred with higher frequencies in the first two months of THA and the highest risks of THA complications within the first 6 months. Conclusion: The most common indication is OA in elders with primary THA. Females and those of black ethnicity showed the greatest risks of THA complications. Data from our large study can be used to understand post-operative complications and readmissions after THA. Our study also provides data on risk factors associated with these complications.

Comparative Time to Improvement in Nonoperative and Operative Treatment of Rotator Cuff Tears.

BACKGROUND: Comparative time to recovery after operative and nonoperative treatment for rotator cuff tears is an important consideration for patients. Hence, we compared the time to achieve clinically meaningful reduction in shoulder pain and function after treatment. METHODS: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing operative or nonoperative treatment was recruited. After propensity score weighting, the Kaplan-Meier method was used to estimate the time to achieve a minimal clinically important difference (MCID), >30% reduction, and >50% reduction in the Shoulder Pain and Disability Index (SPADI) and the American Shoulder and Elbow Surgeons (ASES) scores. (In our analysis, both ASES and SPADI were coded such that a lower number corresponded to a better outcome; thus, the word "reduction" was used to indicate improvement in both ASES and SPADI scores.) A 2-stage test was conducted to detect a difference between the 2 groups. RESULTS: In this cohort, 96 patients underwent nonoperative treatment and 73 patients underwent a surgical procedure. The surgical treatment group and the nonoperative treatment group were significantly different with respect to SPADI and ASES scores (p < 0.05). The maximum difference between groups in achievement of the MCID for the SPADI scores was at 3.25 months, favoring the nonoperative treatment group. The probability to achieve the MCID was 0.06 (95% confidence interval [CI], 0.00 to 0.12) for the surgical treatment group compared with 0.40 (95% CI, 0.29 to 0.50) for the nonoperative treatment group. The surgical treatment group had a greater probability of achieving >50% reduction in SPADI scores at 15.49 months (0.20 [95% CI, 0.12 to 0.29] for the surgical treatment group compared with 0.04 [95% CI, 0.00 to 0.09] for the nonoperative treatment group). The surgical treatment group had a greater probability of achieving >50% reduction in ASES scores at 24.74 months (0.96 [95% CI, 0.84 to 0.99] for the surgical treatment group compared with 0.66 [95% CI, 0.53 to 0.75] for the nonoperative treatment group). The differences for >30% reduction in SPADI and ASES scores and the MCID for ASES scores were not significant. CONCLUSIONS: Patients undergoing nonoperative treatment had significantly better outcomes in the initial follow-up period compared with patients undergoing a surgical procedure, but this trend reversed in the longer term. These data can be used to inform expectations for nonoperative and operative treatments for rotator cuff tears. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Incidence and Impact of Persistent Viremia on SVR Rates in Patients Receiving Direct-Acting Antiviral Therapy.

Rates of persistent viremia (PV) while on direct-acting antiviral therapy were low (5.7%) in a real-world cohort of 983 patients. High sustained virologic response rates were achieved both in patients with PV (92.9%) and those with rapid virologic response (96.5%), without significant differences.

Pharmacologic management of HCV treatment in patients with HCV monoinfection vs. HIV/HCV coinfection: Does coinfection really matter?

INTRODUCTION: Sustained virologic response (SVR) rates in patients with hepatitis C virus (HCV) monoinfection and human immunodeficiency virus (HIV)/HCV coinfection treated with direct acting antiviral (DAA) therapy are similar in clinical trials. The objective of this study was to examine differences in patient characteristics, drug-drug interactions, and treatment pathways between these groups in a real-world clinical setting. METHODS: We performed an ambispective review of patients prescribed DAA therapy between September 2015 and April 2018 at a tertiary academic center. The primary endpoint was time from a decision to treat to treatment initiation. Secondary endpoints included patient characteristics; frequency and type of DAA medication interactions; frequency, type, and timing of antiretroviral therapy (ART) changes; and treatment outcomes. RESULTS: Three hundred and twelve patients were included. Almost half (43%) were HIV/HCV coinfected. Patients with HIV/HCV coinfection were more likely to be African American (p<0.001), have a diagnosed psychiatric disorder (p<0.001) and have a higher pill burden (p = 0.014). Patients with HIV/HCV coinfection were more likely to report an alcohol abuse history (p<0.001), injection drug use history (p<0.024), or active use of illicit substances (p = 0.019). In a multivariable regression model assessing the primary endpoint, time to treatment initiation was increased in patients requiring a change in ART therapy (OR = 9.2, p < 0.001) or a non-ART medication adjustment (OR = 2.4, p = 0.003), and in patients with Medicaid (OR = 6.7, p < 0.001). After controlling for all these factors, HIV/HCV coinfection still significantly impacted time to treatment initiation (OR = 1.7, p = 0.020). The groups had similar rates of drug interaction frequency, treatment completion, observed SVR, and side effects. CONCLUSIONS: Patients with HIV/HCV coinfection are more likely to have a variety of factors that add complexities to HCV treatment. In addition to these challenges, patients with HIV/HCV coinfection experience a longer time to treatment initiation while patients with HCV monoinfection were more frequently lost to care. Care delivery models may incorporate this data to improve patient engagement, access, and outcomes.

Closing the Gap: Identifying Rates and Reasons for Nonadherence in a Specialty Population.

BACKGROUND: Adherence to specialty and nonspecialty medications is often calculated using pharmacy claims data. However, specialty medication regimens are complex and may require periods of intentional gaps in therapy. Common adherence calculations are insufficient in identifying reasons for gaps in therapy. Because adherence reporting is a growing measure of quality care for specialty pharmacy accreditation and payer and manufacturer contracts, a better understanding of the rates and reasons for nonadherence within a specialty population is needed. OBJECTIVE: To identify rates and reasons for misidentified and true nonadherence in patients who are prescribed specialty medications. METHODS: A single center, retrospective cohort study was conducted using pharmacy claims data between March 2017 and February 2018. Medication adherence was calculated using proportion of days covered (PDC). Electronic medical records of a random 10% sample of nonadherent patients (PDC < 80%) were manually reviewed to identify reasons for nonadherence. Patients were then classified as either (a) misidentified as nonadherent (i.e., a provider-directed discontinuation or disruption of treatment that varies from the prescribed administration schedule or transfer of the prescription to an external pharmacy) or (b) truly nonadherent (discontinuation or disruption of treatment that varies from the prescribed administration instruction that is not directed or recommended by the provider or health care team). RESULTS: Of the 7,488 included prescription records from 18 specialty areas, 1,059 met criteria for nonadherence. 105 prescription records (representing 105 unique patients) were manually reviewed; most of these patients (58%) were truly nonadherent, driven by inability to contact patients for refills (59%). However, 40% were misidentified as nonadherent, most due to provider-directed medication holding (69%). Two percent of patients were nonadherent for unknown reasons. CONCLUSIONS: Many patients classified as nonadherent based on pharmacy claims experienced gaps in therapy due to medically appropriate reasons. Methods to better measure and identify true nonadherence are needed to efficiently and adequately affect specialty medication adherence behavior. DISCLOSURES: This study received funding support from CTSA Award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Study findings and conclusions are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Zuckerman reports research support from Sanofi and Gilead Sciences, unrelated to this study. The other authors have nothing to disclose. A poster based on the data from this study was presented at AMCP Nexus 2018 on October 24, 2018, in Orlando, FL.

High rates of medication adherence in patients with pulmonary arterial hypertension: An integrated specialty pharmacy approach.

Phosphodiesterase-5 inhibitors (PDE-5I) have demonstrated improvement in disease symptoms and quality of life for patients with pulmonary arterial hypertension (PAH). Despite these benefits, reported adherence to PDE-5I therapy is sub-optimal. Clinical pharmacists at an integrated practice site are in a unique position to mitigate barriers related to PAH therapy including medication adherence and costs. The primary objective of this study was to assess medication adherence to PDE-5I therapy within an integrated care model at an academic institution. The secondary objective was to assess the impact of out-of-pocket (OOP) cost, frequency of dosing, adverse events (AE) and PAH-related hospitalizations on medication adherence. We performed a retrospective cohort analysis of adult patients with PAH who were prescribed PDE-5I therapy by the center's outpatient pulmonary clinic and who received medication management through the center's specialty pharmacy. We defined optimal medication adherence as proportion of days covered (PDC) ≥ 80%. Clinical data including AEs and PAH-related hospitalizations were extracted from the electronic medical record, and financial data from pharmacy claims. Of the 131 patients meeting inclusion criteria, 94% achieved optimal adherence of ≥ 80% PDC. In this study population, 47% of patients experienced an AE and 27% had at least one hospitalization. The median monthly OOP cost was $0.62. Patients with PDC<80% were more likely to report an AE compared to patients with PDC≥ 80% (p = 0.002). Hospitalization, OOP cost, and frequency of dosing were not associated with adherence in this cohort. Patients receiving PDE-5I therapy through an integrated model achieved high adherence rates and low OOP costs.

Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans.

Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery.

The adoptive transfer of engineered T cells for the treatment of cancer, autoimmunity, and infectious disease is a rapidly growing field that has shown great promise in recent clinical trials. Nuclease-driven genome editing provides a method in which to precisely target genetic changes to further enhance T cell function in vivo. We describe the development of a highly efficient method to genome edit both primary human CD8 and CD4 T cells by homology-directed repair at a pre-defined site of the genome. Two different homology donor templates were evaluated, representing both minor gene editing events (restriction site insertion) to mimic gene correction, or the more significant insertion of a larger gene cassette. By combining zinc finger nuclease mRNA delivery with AAV6 delivery of a homologous donor we could gene correct 41% of CCR5 or 55% of PPP1R12C (AAVS1) alleles in CD8(+) T cells and gene targeting of a GFP transgene cassette in >40% of CD8(+) and CD4(+) T cells at both the CCR5 and AAVS1 safe harbor locus, potentially providing a robust genome editing tool for T cell-based immunotherapy.

Homology-driven genome editing in hematopoietic stem and progenitor cells using ZFN mRNA and AAV6 donors.

Genome editing with targeted nucleases and DNA donor templates homologous to the break site has proven challenging in human hematopoietic stem and progenitor cells (HSPCs), and particularly in the most primitive, long-term repopulating cell population. Here we report that combining electroporation of zinc finger nuclease (ZFN) mRNA with donor template delivery by adeno-associated virus (AAV) serotype 6 vectors directs efficient genome editing in HSPCs, achieving site-specific insertion of a GFP cassette at the CCR5 and AAVS1 loci in mobilized peripheral blood CD34+ HSPCs at mean frequencies of 17% and 26%, respectively, and in fetal liver HSPCs at 19% and 43%, respectively. Notably, this approach modified the CD34+CD133+CD90+ cell population, a minor component of CD34+ cells that contains long-term repopulating hematopoietic stem cells (HSCs). Genome-edited HSPCs also engrafted in immune-deficient mice long-term, confirming that HSCs are targeted by this approach. Our results provide a strategy for more robust application of genome-editing technologies in HSPCs.