Publications by authors named "Jason Liao"

103 Publications

Pembrolizumab plus pomalidomide and dexamethasone for relapsed or refractory multiple myeloma (KEYNOTE-183): subgroup analysis in Japanese patients.

Int J Hematol 2021 Jun 15;113(6):777-784. Epub 2021 Apr 15.

Nagoya City University Hospital, Nagoya, Japan.

The global, randomized, open-label KEYNOTE-183 phase 3 study was closed early after an interim analysis showed unfavorable risk-benefit when pembrolizumab was added to pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). This subgroup analysis reported outcomes in 27 Japanese patients randomly assigned to receive pembrolizumab plus pomalidomide and dexamethasone (n = 15) or pomalidomide and dexamethasone alone (n = 12). Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). After a median (range) follow-up of 9.6 (1.4-15.3) months in Japanese patients, median PFS [6.5 vs 2.8 months; hazard ratio (HR) 0.16 (95% CI 0.03-0.83)] and OS [not reached vs 14.8 months; HR 0.46 (95% CI 0.05-4.20)] seemed to favor the pembrolizumab plus pomalidomide and dexamethasone arm. Objective response rate was numerically higher in this group (47%) than in the pomalidomide and dexamethasone group (25%). The safety profile was consistent with that of the overall study population. No deaths were attributed to a study drug by the investigators. Although adding pembrolizumab to pomalidomide and dexamethasone did not show unfavorable risk-benefit in the Japanese subgroup of KEYNOTE-183, the analysis is limited by short follow-up and small sample size, which affects the generalizability of the results.
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http://dx.doi.org/10.1007/s12185-021-03139-1DOI Listing
June 2021

Inferring latent heterogeneity using many feature variables supervised by survival outcome.

Stat Med 2021 06 5;40(13):3181-3195. Epub 2021 Apr 5.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

In cancer studies, it is important to understand disease heterogeneity among patients so that precision medicine can particularly target high-risk patients at the right time. Many feature variables such as demographic variables and biomarkers, combined with a patient's survival outcome, can be used to infer such latent heterogeneity. In this work, we propose a mixture model to model each patient's latent survival pattern, where the mixing probabilities for latent groups are modeled through a multinomial distribution. The Bayesian information criterion is used for selecting the number of latent groups. Furthermore, we incorporate variable selection with the adaptive lasso into inference so that only a few feature variables will be selected to characterize the latent heterogeneity. We show that our adaptive lasso estimator has oracle properties when the number of parameters diverges with the sample size. The finite sample performance is evaluated by the simulation study, and the proposed method is illustrated by two datasets.
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http://dx.doi.org/10.1002/sim.8972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237103PMC
June 2021

Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study.

Cardiovasc Diagn Ther 2021 Feb;11(1):120-129

Monash Cardiovascular Research Centre, Clayton, Australia.

Background: Technological advances in arterial wall imaging permit the opportunity to visualize coronary atherosclerotic plaque with sufficient resolution to characterize both its burden and compositional phenotype. These modalities have been used extensively in clinical trials to evaluate the impact of lipid lowering therapies on serial changes in disease burden. While the findings have unequivocally established that these interventions have the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved, their impact on plaque phenotype is less certain. More recently optical coherence tomography (OCT) has been employed with a number of studies demonstrating favorable effects on both fibrous cap thickness (FCT) and the size of lipid pools within plaque in response to statin treatment.

Methods: The phase 3, multi-center, double-blind HUYGENS study will assess the impact of incremental lipid lowering with the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab, on plaque features using serial OCT imaging, in statin-treated patients following an acute coronary syndrome (ACS). Subjects with non-ST-elevation ACS (n=150) will be randomized 1:1 into two groups to receive monthly injections of evolocumab 420 mg or placebo.

Results: The primary endpoint is the effect of evolocumab on coronary atherosclerotic plaques will be assessed by OCT at baseline and at week 50.

Conclusions: The HUYGENS study will determine whether intensified lipid lowering therapy with evolocumab in addition to maximally tolerated statin therapy will have incremental benefits on high-risk features of coronary artery plaques.

Trial Registration: This study was registered on Clinicaltrials.gov (NCT03570697).
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http://dx.doi.org/10.21037/cdt-20-684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944215PMC
February 2021

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

Nicotine Tob Res 2021 May;23(6):992-1001

Department of Public Health Sciences, Penn State College of Medicine, Pennsylvania State University, Hershey, PA.

Introduction: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC).

Methods: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation.

Results: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%).

Conclusions: This study supports a VLNC standard in cigarettes.

Implications: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.
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http://dx.doi.org/10.1093/ntr/ntaa247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150128PMC
May 2021

Using artificial intelligence tools in answering important clinical questions: The KEYNOTE-183 multiple myeloma experience.

Contemp Clin Trials 2020 12 18;99:106179. Epub 2020 Oct 18.

Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA.

The phase III, randomized, active-controlled, multicenter, open-label KEYNOTE-183 study (NCT02576977) evaluating pomalidomide and low dose dexamethasone (standard-of-care [SOC]) with or without pembrolizumab in patients with refractory or relapsed and refractory multiple myeloma (rrMM) was placed on full clinical hold by the US FDA on July 03, 2017 due to an imbalance in the number of deaths between arms. Clinically-led subgroup analyses are typically used to shed light on clinical findings. However, this approach is not always successful. We propose a systematic approach using the artificial intelligence tools to identifying risk factors and subgroups contributing to the overall death (prognostic) or to the excess death observed in the pembrolizumab plus SOC arm (predictive) of the KEYNOTE-183 study. In KEYNOTE-183, with a data cutoff date of June 02, 2017, we identified plasmacytoma as a prognostic factor, and ECOG performance status as a predictive factor of death. In addition, a qualitative interaction was observed between ECOG performance status and the treatment arm. The subsequent subgroup analysis based on ECOG performance status confirmed that more deaths were associated with pembrolizumab plus SOC versus SOC alone in patients with ECOG performance status 1.
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http://dx.doi.org/10.1016/j.cct.2020.106179DOI Listing
December 2020

Pembrolizumab plus lenalidomide and dexamethasone in treatment-naive multiple myeloma (KEYNOTE-185): subgroup analysis in Japanese patients.

Int J Hematol 2020 Nov 19;112(5):640-649. Epub 2020 Sep 19.

Japanese Red Cross Medical Center, Tokyo, Japan.

The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.
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http://dx.doi.org/10.1007/s12185-020-02953-3DOI Listing
November 2020

Dynamic RMST curves for survival analysis in clinical trials.

BMC Med Res Methodol 2020 08 27;20(1):218. Epub 2020 Aug 27.

Merck & Co., Inc, North Wales, PA, 19454, USA.

Background: The data from immuno-oncology (IO) therapy trials often show delayed effects, cure rate, crossing hazards, or some mixture of these phenomena. Thus, the proportional hazards (PH) assumption is often violated such that the commonly used log-rank test can be very underpowered. In these trials, the conventional hazard ratio for describing the treatment effect may not be a good estimand due to the lack of an easily understandable interpretation. To overcome this challenge, restricted mean survival time (RMST) has been strongly recommended for survival analysis in clinical literature due to its independence of the PH assumption as well as a more clinically meaningful interpretation. The RMST also aligns well with the estimand associated with the analysis from the recommendation in ICH E-9 (R1), and the test/estimation coherency. Currently, the Kaplan Meier (KM) curve is commonly applied to RMST related analyses. Due to some drawbacks of the KM approach such as the limitation in extrapolating to time points beyond the follow-up time, and the large variance at time points with small numbers of events, the RMST may be hindered.

Methods: The dynamic RMST curve using a mixture model is proposed in this paper to fully enhance the RMST method for survival analysis in clinical trials. It is constructed that the RMST difference or ratio is computed over a range of values to the restriction time τ which traces out an evolving treatment effect profile over time.

Results: This new dynamic RMST curve overcomes the drawbacks from the KM approach. The good performance of this proposal is illustrated through three real examples.

Conclusions: The RMST provides a clinically meaningful and easily interpretable measure for survival clinical trials. The proposed dynamic RMST approach provides a useful tool for assessing treatment effect over different time frames for survival clinical trials. This dynamic RMST curve also allows ones for checking whether the follow-up time for a study is long enough to demonstrate a treatment difference. The prediction feature of the dynamic RMST analysis may be used for determining an appropriate time point for an interim analysis, and the data monitoring committee (DMC) can use this evaluation tool for study recommendation.
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http://dx.doi.org/10.1186/s12874-020-01098-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534804PMC
August 2020

Analysis of time-to-event data using a flexible mixture model under a constraint of proportional hazards.

J Biopharm Stat 2020 09 26;30(5):783-796. Epub 2020 Jun 26.

Biostatistics and Research Decision Sciences, Merck & Co., Inc ., North Wales, Pennsylvania, USA.

Cox proportional hazards (PH) model evaluates the effects of interested covariates under PH assumption without specified the baseline hazard. In clinical trial applications, however, the explicitly estimated hazard or cumulative survival function for each treatment group helps to assess and interpret the meaning of treatment difference. In this paper, we propose to use a flexible mixture model under the PH constraint to fit the underline survival functions. Simulations are conducted to evaluate its performance and show that the proposed mixture PH model is very similar to the Cox PH model in terms of estimating the hazard ratio, bias, confidence interval coverage, type-I error and testing power. Application to several real clinical trial examples demonstrates that the results from this approach are almost identical to the results from Cox PH model. The explicitly estimated hazard function for each treatment group provides additional useful information and helps the interpretation of hazard comparisons.
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http://dx.doi.org/10.1080/10543406.2020.1783283DOI Listing
September 2020

Approximate confidence limit for the reference scaled bioequivalence with a parallel design.

J Biopharm Stat 2020 03 27;30(2):231-243. Epub 2019 Aug 27.

Early Development Biostatistics, Novartis Pharmaceuticals Corporation, Cambridge, MA, USA.

The reference scaled bioequivalence has been proposed with many successful applications for the highly variable products. The statistical properties for the reference scaled bioequivalence have been studied for the commonly used crossover design. However, a crossover design may not be feasible in a real application such as the biosimilar study, instead a parallel design is a more timely and cost-effective choice. In this paper, the approximate upper confidence interval limit for the linearized criteria in the reference scaled bioequivalence from a parallel design is derived. The performance of the approximation is evaluated through the simulation. The simulation results show that this approximation performs well and gives reasonable power and well-controlled type I error.
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http://dx.doi.org/10.1080/10543406.2019.1657438DOI Listing
March 2020

Circulating microRNAs in plasma before and after radical prostatectomy.

Urol Oncol 2019 11 14;37(11):814.e1-814.e7. Epub 2019 Aug 14.

Smith Institute for Urology, Zucker School of Medicine at Hofstra/Northwell, Northwell Cancer Institute, New Hyde Park, NY.

Purpose: MicroRNAs (miRNAs/miRs) as circulating biomarkers for prostate cancer have yet to be determined. We examined whether circulating miRNAs in plasma could be employed as biomarkers of disease among men treated for prostate cancer by radical prostatectomy (RP).

Methods: The expression of 17 preselected circulating miRNAs associated with prostate cancer (miR-381, -34a, -365, -122, -375, -1255b, -34b, -450b-5p, -885-5p, -1260, -150, -378, -671-3p, -148a, and -224) or high-grade prostate cancer (miR-28 and -100) in plasma at prostate biopsy was examined in pre- and post-RP plasma of prostate cancer patients using real-time PCR and compared using Wilcoxon signed-ranked test. Wilcoxon rank sum test was used to compare the expression of miRNAs in pre-RP plasma between pathologic tumor stage (T2 vs. T3) and Gleason score (6-7 [3 + 4] vs. ≥ 7 [4 + 3]) groups. Partial correlation coefficient between the expression of miRNAs in pre-RP plasma and serum prostate-specific antigen (PSA) level at RP, adjusting for age, was calculated.

Results: Twenty-nine men, aged 43 to 77 years, were included. Median follow-up time after RP was 55 days. There was no significant change in the expression of miRNAs in plasma from before to after RP. However, higher expression of miR-34a, -378, and 450b-5p in pre-RP plasma was observed among T3 compared to T2 patients (P values = 0.01). Overall, there were no statistically significant relationships observed between the expression of these circulating miRNAs and Gleason score and serum PSA at RP.

Conclusions: There was no significant change in the expression of circulating miRNAs in plasma from before to approximately 2 months after RP. This finding may be due to the lack of immediate effect RP may have on the expression of circulating miRNAs. However, higher expression of miR-34a, -378, and -450b-5p in plasma was found among patients with more advanced disease at RP. A longer follow-up time after RP is warranted to investigate RP's possible influence on circulating miRNAs among men treated for prostate cancer and to evaluate miRNAs' diagnostic potential for prostate cancer.
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http://dx.doi.org/10.1016/j.urolonc.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7088453PMC
November 2019

Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.

Lancet Haematol 2019 Sep 18;6(9):e459-e469. Epub 2019 Jul 18.

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).

Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.

Findings: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.

Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
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http://dx.doi.org/10.1016/S2352-3026(19)30110-3DOI Listing
September 2019

A flexible parametric survival model for fitting time to event data in clinical trials.

Pharm Stat 2019 10 29;18(5):555-567. Epub 2019 Apr 29.

Biostatistics and Research Decision Sciences, Merck & Co., Inc, North Wales, Pennsylvania, USA.

Time-to-event data are common in clinical trials to evaluate survival benefit of a new drug, biological product, or device. The commonly used parametric models including exponential, Weibull, Gompertz, log-logistic, log-normal, are simply not flexible enough to capture complex survival curves observed in clinical and medical research studies. On the other hand, the nonparametric Kaplan Meier (KM) method is very flexible and successful on catching the various shapes in the survival curves but lacks ability in predicting the future events such as the time for certain number of events and the number of events at certain time and predicting the risk of events (eg, death) over time beyond the span of the available data from clinical trials. It is obvious that neither the nonparametric KM method nor the current parametric distributions can fulfill the needs in fitting survival curves with the useful characteristics for predicting. In this paper, a full parametric distribution constructed as a mixture of three components of Weibull distribution is explored and recommended to fit the survival data, which is as flexible as KM for the observed data but have the nice features beyond the trial time, such as predicting future events, survival probability, and hazard function.
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http://dx.doi.org/10.1002/pst.1947DOI Listing
October 2019

Trial Design and Statistical Considerations on the Assessment of Pharmacodynamic Similarity.

AAPS J 2019 04 3;21(3):47. Epub 2019 Apr 3.

Janssen Research & Development Inc, Spring House, PA, USA.

Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection. For PD data that have high baseline variability, one conventional similarity assessment method was to apply baseline-normalization followed by the standard bioequivalence (BE) test (Lancet Haematol. 4:e350-61, 2017, Ann Rheum Dis. 2017). This study showcased the drawbacks of the conventional method for PD data that were close to inhibition saturation, as the baseline-normalization significantly skewed the distribution of the PD data toward non-log-normal. In such cases, the standard BE test can produce an inflated type I error. Alternatively, ANCOVA, when applied to the un-normalized PD data with the baseline as a covariate, produced a satisfactory type I error with sufficient power. Therefore, ANCOVA was recommended for equivalence test of PD markers that has a saturated inhibition profile and high variability at baseline. Moreover, the relationship between PD readouts and drug potency was used to explore the sensitivity of the PD endpoint and it could help justify the equivalence margins, since the standard 80% to 125% BE margin often does not apply to PD. Finally, a decision tree was proposed to help guide the design of the PD equivalence study in the choice of PD endpoints and statistical methods.
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http://dx.doi.org/10.1208/s12248-019-0321-2DOI Listing
April 2019

Effect of Cigarette Rod Length on Smokers Switching to SPECTRUM Cigarettes.

Am J Health Behav 2019 03;43(2):380-392

Professor of Public Health Sciences and Psychiatry, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA.

Cigarettes vary in rod length but are generally thought of as a constant unit. In this study, we evaluated whether the rod length of participants' usual brand cigarettes affected their perceptions and smoking habits when switching to SPECTRUMs. Data were analyzed for 341 participants smoking their own brand cigarettes for one week and after switching to normal nicotine content (11.6 mg) SPECTRUMs for 2 weeks. Changes in perceptions of cigarette attributes and biomarkers of smoke exposure were evaluated using linear mixed models among 3 groups: usual length short (ULS, 72 mm); medium/king (ULM, ~84 mm); and long (ULL ≥ 100 mm). Among the 3 cigarette length groups, only ULL smokers' rated SPECTRUMs significantly less strong, harder to draw, lower in taste, and lower in enjoyment (p < .03) compared to usual brand. Among all groups, satisfaction was significantly lower for SPECTRUMs (p < .02). Cigarettes per day (CPD) increased significantly more for ULL (+4.75 CPD) as compared to ULM (+1.38 CPD) (p < .001). When switching to SPECTRUMs, cotinine-per-cigarette decreased among all groups, and exhaled carbon monoxide increased significantly in ULL and ULM smokers (p < .001). People who smoked long cigarettes had the largest changes in perceptions and use when switching to SPECTRUM research cigarettes.
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http://dx.doi.org/10.5993/AJHB.43.2.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419764PMC
March 2019

Acceptability of SPECTRUM Research Cigarettes among Participants in Trials of Reduced Nicotine Content Cigarettes.

Tob Regul Sci 2018 Jan;4(1):573-585

Penn State Tobacco Center of Regulatory Science (TCORS), Penn State College of Medicine, Department of Public Health Sciences.

Objectives: SPECTRUM research cigarettes (SPECTRUMs) are being used in trials evaluating the effects of switching to reduced nicotine content (RNC) cigarettes. Because smokers have a high brand affinity, we evaluated if they were willing to switch and continue smoking normal nicotine content (NNC) SPECTRUMs.

Methods: We asked smokers (N = 341) to rate their own brand of cigarettes and NNC SPECTRUMs (after 2 weeks of use) using subjective measures including satisfaction, reward, taste, and craving reduction. We measured plasma cotinine, exhaled carbon monoxide (CO), and cigarettes per day (CPD), and recorded reasons for dropping out.

Results: After 2 weeks, 95% of participants chose to continue using SPECTRUMs for an additional 18 weeks. Moreover, 67% said SPECTRUMs were as good as or better than their own brand, and 65% said they would consider purchasing them. Ratings of satisfaction, reward, and craving reduction were 10%-15% lower on SPECTRUMs than on their own brand (p < .01). There were no differences in these ratings between menthol and non-menthol smokers.

Conclusions: Menthol and non-menthol SPECTRUMs are acceptable to smokers. Lower SPECTRUM ratings were likely due to brand switching and did not hinder study retention.
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http://dx.doi.org/10.18001/TRS.4.1.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338451PMC
January 2018

Pulmonary and other health effects of electronic cigarette use among adult smokers participating in a randomized controlled smoking reduction trial.

Addict Behav 2019 04 29;91:95-101. Epub 2018 Oct 29.

Penn State University, Department of Public Health Sciences, Tobacco Center of Regulatory Science, College of Medicine, 500 University Dr., Hershey, PA 17033, United States.

Background: There is limited evidence about the effects of dual electronic cigarette (e-cig) and combustible cigarette use on lung health or other health outcomes. Studies that have evaluated these outcomes have not included estimates of e-cig or cigarette exposure in the analyses.

Materials And Methods: Data analyzed were from 263 smokers participating in a randomized controlled trial designed to encourage participants to reduce their combustible cigarette use by substituting with an e-cig or a non-electronic cigarette substitute (cig-sub). t-tests were used to evaluate changes from baseline at 1 month and 3 months in lung function, blood pressure, pulse, exhaled carbon monoxide, and weight. Linear mixed effects models were used to test associations between health outcomes and study product group, including exposure to the study products (e-cig and cig-sub times used and days used in the past 7 days) and cigarettes per day (CPD).

Results: There were few significant differences between the groups for lung function indices at any time point in the unadjusted analyses. There were significant reductions in diastolic blood pressure and pulse at 1 month in the unadjusted analyses for those in the e-cig group compared to the cig-sub group. CPD decreased significantly more for the e-cig group than for the cig-sub group at both time points. There were no significant associations between any measured health outcomes and group in the linear mixed effects models.

Conclusion: E-cig use did not contribute to significant changes in health outcome markers as compared with use of a non-electronic cig-sub.
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http://dx.doi.org/10.1016/j.addbeh.2018.10.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358505PMC
April 2019

Tumor-promoting effects of pancreatic cancer cell exosomes on THP-1-derived macrophages.

PLoS One 2018 1;13(11):e0206759. Epub 2018 Nov 1.

Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.

Pancreatic ductal adenocarcinoma (PDAC) tumor growth is enhanced by tumor-associated macrophages (TAMs), yet the mechanisms by which tumor cells and TAMs communicate are not fully understood. Here we show that exosomes secreted by PDAC cell lines differed in their surface proteins, lipid composition, and efficiency of fusing with THP-1-derived macrophages in vitro. Exosomes from AsPC-1, an ascites-derived human PDAC cell line, were enriched in ICAM-1, which mediated their docking to macrophages through interactions with surface-exposed CD11c on macrophages. AsPC-1 exosomes also contained much higher levels of arachidonic acid (AA), and they fused at a higher rate with THP-1-derived macrophages than did exosomes from other PDAC cell lines or from an immortalized normal pancreatic ductal epithelial cell line (HPDE) H6c7. Phospholipase A2 enzymatic cleavage of arachidonic acid from AsPC-1 exosomes reduced fusion efficiency. PGE2 secretion was elevated in macrophages treated with AsPC-1 exosomes but not in macrophages treated with exosomes from other cell lines, suggesting a functional role for the AsPC-1 exosome-delivered arachidonic acid in macrophages. Non-polarized (M0) macrophages treated with AsPC-1 exosomes had increased levels of surface markers indicative of polarization to an immunosuppressive M2-like phenotype (CD14hi CD163hi CD206hi). Furthermore, macrophages treated with AsPC-1 exosomes had significantly increased secretion of pro-tumoral, bioactive molecules including VEGF, MCP-1, IL-6, IL-1β, MMP-9, and TNFα. Together, these results demonstrate that compared to exosomes from other primary tumor-derived PDAC cell lines, AsPC-1 exosomes alter THP-1-derived macrophage phenotype and function. AsPC-1 exosomes mediate communication between tumor cells and TAMs that contributes to tumor progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206759PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211741PMC
April 2019

Utility of Early Postoperative Magnetic Resonance Imaging After Glioblastoma Resection: Implications on Patient Survival.

World Neurosurg 2018 Dec 12;120:e1171-e1174. Epub 2018 Sep 12.

Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.

Background: The standard of care for glioblastoma is surgical resection followed by combination temozolomide and radiation. Magnetic resonance imaging (MRI) is used preoperatively for tumor resection planning. In some instances, MRI is also obtained postoperatively to assess for any complications and to determine extent of resection. There is some question whether early routine postoperative imaging of patients after tumor resection is beneficial to long-term outcomes, especially with the increased scrutiny of increasing health care costs.

Methods: In this study we retrospectively analyze patients with glioblastoma treated at our institution, comparing the difference in overall survival and treatment regimens between patients who had early postoperative MRI versus patients who did not.

Results: We determine that in our cohort of 125 patients, those with early postoperative MRI had no statistically significant overall survival difference compared with patients with no early postoperative MRI (P = 0.996). The median survival for the group with postoperative MRI was 378 days (95% confidence interval [CI], 242-443 days), and the median survival for the group without postoperative MRI was 308 days (95% CI, 203-445 days). Early postoperative MRI also did not significantly alter therapeutic regimens.

Conclusions: Although early postoperative MRI may not significantly affect patient overall survival from a statistical standpoint or therapeutic regimens, this type of imaging may be important to hone resident and attending skill. We encourage other institutions to perform similar analyses to determine the overall survival benefit of early postoperative imaging after glioma resection for patients with glioblastoma.
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http://dx.doi.org/10.1016/j.wneu.2018.09.027DOI Listing
December 2018

Pre- and post-magnetic resonance imaging features of suspicious internal mammary lymph nodes in breast cancer patients receiving neo-adjuvant therapy: Are any imaging features predictive of malignancy?

Breast J 2018 11 31;24(6):997-1000. Epub 2018 Jul 31.

Department of Radiology, Division of Breast Imaging, Penn State Health, Milton S. Hershey Medical Center, Hershey, Pennsylvania.

Internal mammary lymph nodes constitute a major lymphatic chain draining the breast and a route of spread for breast cancer metastases. Both physiologic and metastatic internal mammary lymph nodes enhance on breast magnetic resonance imaging, and the clinical significance of their prevalence, size, and morphology when visualized in a patient with breast cancer remains unknown. We studied the characteristics of internal mammary lymph nodes visualized on breast MRI studies before and after neo-adjuvant therapy in twenty-three patients with newly diagnosed breast cancer. A measured decrease in internal mammary lymph node size on post-neo-adjuvant therapy MRI indicated metastatic involvement. Determining suspicious features of internal mammary nodes on initial diagnostic MRI can aid radiologists in reporting probable IMLN metastases and may alter the course of care for patients with breast cancer. This study concludes that metastatic internal mammary lymph nodes should be considered when more than two ipsilateral internal mammary lymph nodes measuring 6 mm or greater are seen on diagnostic MRI in a patient with newly diagnosed breast cancer.
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http://dx.doi.org/10.1111/tbj.13102DOI Listing
November 2018

Characteristics of pulmonary complications in non-Hodgkin's lymphoma patients treated with rituximab-containing chemotherapy and impact on survival.

Ann Hematol 2018 Dec 21;97(12):2373-2380. Epub 2018 Jul 21.

Division of Pulmonary and Critical Care Medicine, Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.

Patients with non-Hodgkin's lymphoma (NHL) receiving rituximab-containing chemotherapy are at risk of developing respiratory complications, but comprehensive information on these complications and their impact on survival is lacking. We performed a retrospective cohort analysis on 123 NHL patients who received rituximab-containing chemotherapy between 2009 and 2016 in order to describe the incidence, etiologies and effect on survival of respiratory complications defined by new or worsening respiratory symptoms requiring diagnostic work-up or hospitalization. Thirty patients (24%) developed respiratory complications during a follow-up time of 825 (555-1338) days after chemotherapy. They had a higher prevalence of congestive heart failure and lung or pleural involvement at diagnosis as compared to patients who did not develop complications. Overall, 58 episodes of pulmonary complications were observed after median (interquartile) times from the first and last rituximab doses of 205 (75-580) days and 27 (14-163) days respectively. Infectious etiologies accounted for 75% of the respiratory complications, followed by heart failure exacerbation, lymphomatous involvement, and ARDS. Two Pneumocystis jirovecii pneumonias were observed, and no complication was ascribed to rituximab toxicity. Respiratory complications required ICU admission in 19 cases (33%) and invasive mechanical ventilation in 14 cases (24%). Using a time-dependent Cox regression analysis, we observed that the occurrence of respiratory complications was associated with a 170% increase in death hazard (hazard ratio 2.65, 95% CI 1.60-4.40, p = 0.001). In conclusion, respiratory complications in NHL patients receiving chemotherapy are relatively frequent, severe, and mostly infectious and are associated with increased mortality.
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http://dx.doi.org/10.1007/s00277-018-3448-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102168PMC
December 2018

Characteristics of Adult Cigarette Smokers Who "Relight" and the Effects of Exposure to Tobacco Smoke Constituents.

Nicotine Tob Res 2019 08;21(9):1206-1212

Department of Public Health Sciences, Penn State Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, PA.

Introduction: About half of smokers relight their cigarette, a habit that is a risk factor for chronic bronchitis and possibly lung cancer. Little is known about the characteristics of smokers who relight and their dependence on nicotine. It is unknown whether relighting affects exposure to tobacco smoke constituents. This study examined the characteristics of relighters of usual brand cigarettes and whether relighting affects exposure to selected tobacco smoke constituents.

Methods: We explored relighting status and frequency, using baseline data from 248 adult smokers participating in studies of reduced nicotine cigarettes in relation to demographic and cigarette characteristics, smoking behaviors, nicotine dependence, biomarkers of exposure (exhaled carbon monoxide, blood cotinine), and biomarkers of oxidative stress (ratio of oxidized/reduced glutathione).

Results: 69.4% (n = 172) of subjects reported relighting, and they relit an average of five cigarettes out of 20. Both relighters and non-relighters smoked a mean of 20 cigarettes per day (p = .6). Relighting was significantly associated with higher nicotine dependence, use of longer rod cigarettes, older age, lower income, and unemployment. There were no significant associations between relighting and blood cotinine, exhaled carbon monoxide or measures of oxidized/reduced blood glutathione.

Conclusions: The majority of subjects were relighters, who had higher levels of nicotine dependence than non-relighters. Relighters had similar levels of plasma cotinine and exhaled carbon monoxide to non-relighters.

Implications: No study has compared the cigarette characteristics and biomarkers of exposure of adult cigarette smokers who relight with those who do not. Relighting behavior was common in our sample and was associated with low income, not currently working, higher nicotine dependence, cigarette rod length, daily cigarette use years, and a lifetime history of depressed mood.
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http://dx.doi.org/10.1093/ntr/nty138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698945PMC
August 2019

Sample size allocation in multiregional equivalence studies.

Pharm Stat 2018 09 17;17(5):570-577. Epub 2018 Jun 17.

Myovant Sciences, Brisbane, CA, USA.

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.
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http://dx.doi.org/10.1002/pst.1871DOI Listing
September 2018

Ecological momentary assessment of smoking behaviors in native and converted intermittent smokers.

Am J Addict 2018 03;27(2):131-138

Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.

Background And Objectives: About 22% of adult smokers in the U.S. are intermittent cigarette smokers (ITS). ITS can be further classified as native ITS who never smoked daily and converted ITS who formerly smoked daily but reduced to intermittent smoking. Ecological momentary assessment (EMA) was conducted to determine the behaviors and experiences that are associated with the decision to smoke.

Methods: The study included 24 native ITS and 36 converted ITS (N = 60) from the Pennsylvania Adult Smoking Study. A baseline questionnaire, daily log, and an EMA smoking log that assessed emotions, activities, and smoking urges was filled out with each cigarette for 1 week to capture 574 smoking sessions.

Results: Both groups had very low levels of cigarette dependence. Both groups were more tempted to smoke in positive or negative situations than situations associated with habituation. EMA showed that the most common emotional state during smoking sessions was positive (47%), followed by negative (32%), neutral (16%), and mixed (5%) emotions. Smokers were more likely to smoke during activities of leisure (48%) than during performative duties (29%), social (16%) or interactive occasions (7%). Converted ITS were more likely to smoke alone compared to native ITS (p < .001).

Discussion And Conclusions: ITS report minimal levels of dependence when captured on traditional scales of nicotine dependence, yet experience loss of autonomy and difficulty quitting. The majority of the ITS reported positive emotions and leisure activities while smoking, and smoked during the evening.

Scientific Significance: The current paper identifies environmental and behavioral factors that are associated with smoking among ITS in real time. (Am J Addict 2018;27:131-138).
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http://dx.doi.org/10.1111/ajad.12690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864119PMC
March 2018

Circulating microRNAs in plasma as potential biomarkers for the early detection of prostate cancer.

Prostate 2018 05 31;78(6):411-418. Epub 2018 Jan 31.

Department of Population Health Science and Policy and Department of Thoracic Surgery, Ichan School of Medicine at Mount Sinai, New York, New York.

Background: MicroRNAs (miRNAs) have been linked to prostate cancer (PC) risk; however, their role as a screening biomarker for PC has yet to be determined. We examined whether circulating miRNAs in plasma could be potential biomarkers for the early detection of PC among men undergoing prostate needle biopsy.

Methods: Men who had a prostate biopsy due to an abnormal screening test were recruited. Linear regression was used to examine the association between miRNAs in plasma and PC status and to model individual miRNA expression on serum PSA and age to calculate the partial correlation coefficient (r).

Results: There were 134 men, aged 46-86 years, included, with 66 men with a PC diagnosis (cases), eight men with no PC diagnosis but atypical lesion, and 60 men without a PC diagnosis (controls). The most statistically significant PC circulating miRNAs were miR-381, miR-34a, miR-523, miR-365, miR-122, miR-375, miR-1255b, miR-34b, miR-450b-5p, and miR-639 after adjusting for age (P-values ≤0.05); however, they were no longer statistically significant after P-value adjustment for multiple comparisons. MiR-671-3p was differentially expressed between black and white cases (P-value = 0.03). Moderate positive correlations with serum PSA were observed for miR-381 overall and among controls (r = 0.43-0.60; P-values ≤0.05) and miR-34a among cases (r = 0.46; P-value = 0.02).

Conclusions: There was no miRNA associated with PC diagnosis after adjusting for age and P-values; however, moderate correlations between miRNAs and serum PSA were observed. Further investigation between miRNAs and PC risk is warranted in a larger population at high risk for PC.
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http://dx.doi.org/10.1002/pros.23485DOI Listing
May 2018

The predictive potential of hyponatremia for glioblastoma patient survival.

J Neurooncol 2018 May 25;138(1):99-104. Epub 2018 Jan 25.

Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.

Glioblastoma is a devastating malignancy with a dismal survival rate. Currently, there are limited prognostic markers of glioblastoma including IDH1, ATRX, MGMT, PTEN, EGFRvIII, and others. Although these biomarkers for tumor prognosis are available, a surgical biopsy must be performed for these analyses, which has morbidity involved. A non-invasive and readily available biomarker is sought after which provides clinicians prognostic information. Sodium is an electrolyte that is easily and quickly obtained through analysis of a patient's serum. Hyponatremia has been shown to have a predictive and negative prognostic indication in multiple cancer types, but the role of glioblastoma patients' serum sodium at the time of diagnosis in predicting glioblastoma patient survival has not been determined. We assessed whether hyponatremia at the time of glioblastoma diagnosis correlates to patient survival and show that in our cohort of 200 glioblastoma patients, sodium, at any level, did not significantly correlate to glioblastoma survival, unlike what is seen in multiple other cancer types. We further demonstrate that inducing hyponatremia in an orthotopic murine model of glioblastoma has no effects on tumor progression and survival.
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http://dx.doi.org/10.1007/s11060-018-2774-zDOI Listing
May 2018

Correction to Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

Trials 2017 12 15;18(1):598. Epub 2017 Dec 15.

Department of Public Health Sciences, Penn State Tobacco Center of Regulatory Science, Pennsylvania State University, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.

Correction: The title of the original publication [1] had an error; furthermore there were errors in Fig. 2. The corrected version of the title and of Fig. 2 can be found below in this Erratum.
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http://dx.doi.org/10.1186/s13063-017-2356-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732394PMC
December 2017

Effects of Black Raspberry on Dibenzo[]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity.

Cancer Prev Res (Phila) 2018 03 20;11(3):157-164. Epub 2017 Nov 20.

Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania.

We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[]pyrene (DB[]P) to its active fjord region diol epoxide (DB[]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the gene in the mouse oral cavity. We showed that BRB inhibited DB[]PDE-induced DNA damage ( < 0.05) and mutagenesis ( = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly ( < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly ( < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839973PMC
March 2018

Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

Trials 2017 Jul 3;18(1):300. Epub 2017 Jul 3.

Department of Public Health Sciences, Penn State Tobacco Center of Regulatory Science, Pennsylvania State University, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.

Background: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes.

Methods/design: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine-containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences.

Discussion: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects.

Trial Registration: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013.
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http://dx.doi.org/10.1186/s13063-017-2038-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496140PMC
July 2017
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