Per-protocol Treatment Research Articles

HCV Treatment Outcomes in PWID: Impact of Addiction History on SVR12

People who inject drugs (PWIDs) experience high rates of hepatitis C virus (HCV) infection, primarily due to needle sharing and limited healthcare access, resulting in a disproportionate disease burden within this population. This prospective study evaluated treatment outcomes in 432 adult patients with chronic hepatitis C (CHC) treated with direct-acting antivirals (DAAs) at the University Clinical Center of Serbia. Patients were categorized into two groups based on a history of drug addiction: PWIDs (163, 37.7%) and non-PWIDs (269, 62.3%). The PWID group was further categorized into subpopulations of problematic PWIDs (39, 23.9%), ex-PWIDs (124, 76.1%), and PWIDs on OST (96, 58.9%). The PWID group demonstrated significantly lower treatment adherence, with an intention-to-treat (ITT) rate of 82.8%, compared to 96.3% in the control group (p < 0.001). In contrast, no significant differences were observed in per-protocol (PP) outcomes between the two groups. Additionally, PWIDs were significantly younger (p < 0.001) and had higher rates of psychiatric disorders (p < 0.001), alcohol abuse (p < 0.001), and HCV genotype 1a (p < 0.001). Advanced fibrosis was predictor of PP treatment failure among PWIDs, while mood disorders and alcohol use disorder were associated with interruptions before the scheduled completion time. For non-PWIDs, older age and advanced fibrosis emerged as key predictors of PP treatment failure. The loss to follow-up was most commonly observed in the problematic PWID subgroup (p = 0.001). These findings highlight the importance of addressing barriers in PWIDs through integrated care strategies that concurrently manage addiction and HCV.

AB048. Evidence of effectiveness of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas.

Recurrent high-grade glioma (HGG) is a challenge with limited treatment options and a poor prognosis. We conducted an open-label phase II study: neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas (NCT04588987), and interim analysis showed very promising results. We are further searching for evidence of the effectiveness of this strategy. Patients with recurrent HGG received neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), and 14 days later received surgery for recurrent tumor resection. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200 mg) and 4 weeks after surgery with the daily apatinib (250 mg) until investigator assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). When patients suspected progress during per-protocol treatment, re-surgery for resection of lesion was done, and the tissue was further examined. Between October 9, 2020, and March 30, 2024, 24 patients were enrolled [19 glioblastomas, one World Health Organization (WHO) grade 4 diffuse astrocytoma, three anaplastic astrocytoma, and one anaplastic oligodendroglioma]. Nineteen patients with interim analysis data, and showed the median progression-free survival (PFS) was 4.8 months [95% confidence interval (CI): 4.4-5.2], the median OS was 12.9 months (95% CI: 9.3-16.4) respectively, with a median follow-up time of 17.5 months (95% CI: 9.0-26.1). There were two patients who suspected progress and received second surgery. One patient showed real tumor progression with active tumor cells. While another patient the histology revealed mainly necrosis with inflammatory cells. Five patients initially showed increased enhancement on magnetic resonance imaging (MRI) but without increased symptoms, and showed continuous improvement when receiving further treatment. This immuno-target combination neoadjuvant therapy in recurrent HGG demonstrated encouraging efficacy and revealed some evidence of efficacy, and worth to further investigate.

PEACE V—Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): Acute Toxicity of a Randomized Phase 2 Trial

BackgroundTreatment recommendations for patients with limited nodal recurrences are lacking, and different locoregional treatment approaches are currently being used. ObjectiveThe aim of this trial is to compare metastasis-directed therapy (MDT) with or without elective nodal pelvic radiotherapy (ENRT). Design, setting, and participantsPEACE V—Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM) is an international, phase 2, open-label, randomized, superiority trial (ClinicalTrials.gov identifier: NCT03569241). Patients diagnosed with positron emission tomography–detected pelvic nodal oligorecurrence (five or fewer nodes) following radical local treatment for prostate cancer were randomized in a 1:1 ratio between arm A (MDT and 6 mo of androgen deprivation therapy [ADT]) and arm B (ENRT [25 × 1.8 Gy] with MDT and 6 mo of ADT). Outcome measurements and statistical analysisWe report the secondary endpoint acute toxicity, defined as worst grade ≥2 Common Terminology Criteria for Adverse Events v4.0 gastrointestinal (GI) or genitourinary (GU) toxicity within 3 mo of treatment. The chi-square test was used to compare toxicity between treatment arms. We also compare the quality of life (QoL) using the European Organisation for Research and Treatment of Cancer QLQ C30 and PR25 questionnaires. Results and limitationsBetween June 2018 and April 2021, 196 patients were assigned randomly to MDT or ENRT. Ninety-seven of 99 patients allocated to MDT and 93 of 97 allocated to ENRT received per-protocol treatment. Worst acute GI toxicity proportions were as follows: grade ≥2 events in three (3%) in the MDT group versus four (4%) in the ENRT group (p = 0.11). Worst acute GU toxicity proportions were as follows: grade ≥2 events in eight (8%) in the MDT group versus 12 (13%) in the ENRT group (p = 0.95). We observed no significant difference between the study groups in the proportion of patients with a clinically significant QoL reduction from baseline for any subdomain score area. ConclusionsNo clinically meaningful differences were observed in worst grade ≥2 acute GI or GU toxicity or in QoL subdomains between MDT and ENRT. Patient summaryWe found no evidence of differential acute bowel or urinary side effects using metastasis-directed therapy and elective nodal radiotherapy for the treatment of patients with a pelvic lymph node recurrence.

An application programming interface implementing Bayesian approaches for evaluating effect of time-varying treatment with R and Python

IntroductionMethods and tools evaluating treatment effect have been primarily developed for binary type of treatment. Yet, treatment is rarely binary outside the experimental setting, varies by dosage, frequency and time. Treatment is routinely adjusted, initiated or stopped when being administered over a period of time.MethodsBoth Gaussian Process (GP) regression and Bayesian additive regression tree (BART) have been used successfully for handling complex setting involving time-varying treatments that is either adaptive or non-adaptive. Here, we introduce an application programming interface (API) that implements both BART and GP for estimating averaged treatment effect (ATE) and conditional averaged treatment (CATE) for the two-stage time-varying treatment strategies.ResultsWe provide two real applications for evaluating comparative effectiveness of time-varying treatment strategies. The first example evaluates an early aggressive treatment strategies for caring children with newly diagnosed Juvenile Idiopathic Arthritis (JIA). The second evaluates the persistent per-protocol treatment effectiveness in a large randomized pragmatic trial. The examples demonstrate the use of the API calling from R and Python, for handling both non-adaptive or adaptive treatments, with presences of partially observed or missing data issues. Summary tables and interactive figures of the results are downloadable.

Paper 33: Superior Improvements in Knee Pain and Function with a Novel Synthetic Medial Meniscus Replacement Prosthesis Compared to Non-surgical Care in Subjects with Knee Pain Following Partial Meniscectomy: Three-year Results from US Randomized Controlled Trial

Objectives: This study tests the hypothesis that subjects receiving the meniscus replacement prosthesis show superior improvements at 3 years with regards to knee-related pain, function, and quality of life compared to control subjects, through 3 years of follow-up. Methods: 127 subjects (61 investigational, 66 control) were included in the multicenter RCT. Subjects had one or more partial meniscectomies at least 6 months before trial entry and continued to have pain. Patient-reported knee pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS). Treatment failure was defined as any investigational subject who discontinued the per-protocol treatment by permanent prosthesis removal, or control subjects undergoing any surgical procedure on the index knee. Standard statistical methodology was used, two tailed t-test was used to compare groups at each time point. Results: Both groups improved over 24 months, but the control group showed a significant drop at 3 years. Controls experienced a 35% decline in KOOS Overall improvement between the 2-year and 3-year timepoint (15.9 declined to 10.4). The treatment group continued to improve over 3 years. The treatment group had significantly better outcomes scores that were greater than MCD for all KOOS subscales at 3 years (Figure 1). KOOS Overall and KOOS Pain for the investigational and control cohorts at 3 years were 28.8 vs 10.4 points, and 29.7 vs 15.4 points, respectively. Treatment cessation through 3 years was 67% greater in the control cohort than the investigational cohort (11.5% vs. 19.2%). Conclusions: Patients receiving the meniscal replacement prosthesis had clinically meaningful improvement of their patient reported outcomes scores at 3 years. These improvements were superior to the control treatment. The improvements were maintained over three years, whereas the control group declined after 2 years. The magnitude of change from baseline to 3 years remained superior for the investigational cohort, even for subjects undergoing device exchange or repositioning, compared to non-surgical care subjects.

Prevention of radiation-induced liver toxicity after interstitial HDR brachytherapy by pentoxifylline and ursodeoxycholic acid: patient compliance and outcome in a randomized trial

AimTo investigate the impact of pentoxifylline (PTX, 3 × 400 mg per day) and ursodeoxycholic acid (UDCA, 3 × 250 mg per day) administered for 12 weeks on radiation-induced liver toxicity.Materials and methodsInclusion criteria were liver metastases of extrahepatic malignancies undergoing HDR-BT. 36 patients were prospectively randomized to the medication (N = 18) or control arm (N = 18) and follow-up by hepatobiliary magnetic resonance imaging (MRI) was scheduled 6 and 12 weeks after local ablation by HDR-BT. We determined the threshold doses of fRILI by image fusion of MRI with the dosimetry data.Results32 patients completed the study schedule. Per-protocol treatment was limited to 8 patients in the medication group and 16 patients in the control group. 22 adverse events of any grade likely or certainly related to PTX were recorded in 12 patients leading to the discontinuation of the study medication in 7 patients and to a dose reduction of PTX in 2 patients. In the per-protocol population, statistical analysis failed to prove a reduction of fRILI 6 and 12 weeks after HDR-BT. The incidence of adverse effects attributed to PTX (70.6%) was well above the data found in the literature for its approved indication.ConclusionThe study endpoint was not met mainly attributed to the low statistical power of the small per-protocol cohort. Independently, PTX cannot be recommended for the reduction of radiation-induced liver toxicity in oncologic patients undergoing HDR-BT of liver metastases. Further studies might focus on a combination of UDCA with other potential drugs to help establish a preventive and tolerable regimen.

CORRECTION OF INSULIN RESISTANCE IN OBESE PATIENTS WITH MYOCARDIAL INFARCTION AND COMORBID METABOLIC SYNDROME

Objective. Insulin resistance (IR) is playing an essential role in the development of cardiovascular disease and has an adverse prognostic effect on the course of acute myocardial infarction (AMI) as a result of direct proatherogenic effects of IR and an adverse effect on myocardial contractility. The aim of the study was to evaluate the insulin resistance effects of multimodality therapy with dapagliflozin (Forxiga) and L-arginine/L-carnitine combination in overweight and obese patients with myocardial infarction.
 The aim of the study: to evaluate the insulin resistance effects of multimodality therapy with dapagliflozin (Forxiga) and L-arginine/L-carnitine combination in overweight and obese patients with myocardial infarction.
 Methods. The study enrolled 85 males with acute myocardial infarction with ST segment elevation; among these, there were 24 overweight patients (BMI within 25–29.9 kg/m2) and 36 patients with obesity (BMI >30 kg/m2). Normal body weight (BMI within 18–24.9 kg/m2) was documented in 25 study patients. The age of study subjects in the groups was 58.62±7.02 years on average. All patients were receiving standard of care treatment according to the protocols of the MoH of Ukraine [8]. Depending on the treatment program used, all patients were divided into three groups: Group 1 enrolled 25 patients who were receiving standard of care per-protocol treatment; Group 2 (test group) enrolled 28 patients where standard of care per-protocol treatment of MI was appended with L-arginine/L-carnitine combination (“TIVOR-L” by Yuria-Pharm Ltd.; marketing authorization No. UA/15067/01/01) as intravenous infusions for seven days at 100.0 ml once a day; Group 3 (test group) enrolled 32 patients who received dapagliflozin (10 mg/day) in addition to combination therapy (per-protocol treatment + L-arginine/L-carnitine combination). Control group enrolled 20 virtually healthy volunteers without cardiovascular disease.
 The presence of IR was assessed using HOMA-IR index. The severity of IR was determined based on the magnitude of the IR factor according to F. Caro. The patients were considered to have IR if the following criteria were met: HOMA > 2.77 and Caro index < 0.33; i.e. the higher the HOMA index and the lower the Caro index, the lower was the tissue sensitivity to insulin and the greater was the IR.
 Statistical analysis of study findings was performed using Statistica 10.0 package of statistical software and Microsoft Excel 2019.
 Results. Overweight and obese patients with MI + MS develop carbohydrate metabolism disorders, which are manifested by hyperglycemia, increased HOMA index and decreased Caro index. Insulin resistance is the main cause of the above disorders. The severity of insulin resistance was increasing in the presence of excessive body and obesity, as suggested by a significant reduction in Caro index. It is the presence of IR and carbohydrate metabolism disorders that contributed to the development of systolic-diastolic dysfunction of the myocardium in patients with ACS (MI).
 Conclusions. At baseline, overweight and obese patients with myocardial infarction develop a pronounced insulin resistance with carbohydrate metabolism disorders and reduced systolic-diastolic function of the heart. Multi-modality treatment with inclusion of L-carnitine/L-arginine combination and dapagliflozin in overweight and obese patients with myocardial infarction facilitated restoration of tissue sensitivity to insulin and improved carbohydrate metabolism and systolic-diastolic function of the heart in such comorbid patients.

Paper 30: Superior Improvements in Knee Pain and Function with a Novel Synthetic Medial Meniscus Replacement Prosthesis Compared to Non-surgical Care in Subjects with Knee Pain Following Partial Meniscectomy: Three-year Results from Two Prospective US Clinical Trials

Objectives:Results from 2 FDA-regulated clinical trials demonstrate superiority of a synthetic medial meniscus prosthesis to non-surgical care in treating persistent or recurrent knee pain following previous partial meniscectomy.Arthroscopic partial meniscectomy (APM) is the most common surgical treatment for symptomatic, irreparable meniscal tears that do not improve with non-surgical care. For many patients, APM is associated with improvements in knee pain and function, but a subset of patients report persistent or recurrent knee pain 1-2 years after APM surgery. Current treatment options for post-APM knee pain are limited, especially for patients considered too young for knee replacement. The polymeric medial meniscus prosthesis (NUsurfaceâ, Active Implants, Memphis TN) mimics the biomechanical function of the natural medial meniscus and provides relief from pain and improved function in subjects with knee pain following APM. The meniscus prosthesis met the primary endpoint of superiority over non-surgical care at 2 years. The current hypothesis was that investigational subjects maintained superior improvements in knee-related pain, function, and quality of life, compared to non-surgical subjects, through 3 years of follow-up.Methods:242 subjects (176 investigational, 66 control) treated in 2 prospective, concurrent clinical trials in the U.S., and pooled for analysis: a randomized controlled superiority trial (RCT) comparing the investigational device (investigational group) to non-surgical care (control), and a single-arm, prosthesis-only trial. Subjects had persistent knee pain and one or more previous partial meniscectomies at least 6 months before trial entry. Subject follow-up visits at 1.5 months, 6 months, 1, 2 and 3 year. Patient-reported knee pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS). Treatment cessation was defined as any investigational subject who discontinued the per-protocol treatment by permanent prosthesis removal, or control subjects undergoing any surgical procedure on the index knee. Investigational subjects who underwent subsequent surgical procedures on index knees (e.g. prosthesis exchange) remained in the trial. The investigational and control cohorts analyzed were compared at each time point using a two tailed t-test. All baseline cohort comparisons of demographics were not statistically different (p>0.05).Results:The magnitude of improvement from baseline to 3 years was statistically superior in the investigational cohort, compared to the control cohort for all 6 KOOS subscales (Figure 1), including the primary outcomes of KOOS Overall and KOOS Pain (Figure 1A, B). Improvement in KOOS Overall and KOOS Pain for the investigational and control cohorts at 3 years were 26.4 vs 10.4 points, and 26.9 vs 15.4 points, respectively (Figure 1). These data show a statistically significant improvement, exceeding a clinically meaningful improvement of ≥20 points versus controls as early as 6 months (20.0 vs 9.2 pts), continuing through the 3-year timepoint. Controls experienced a 35% decline in KOOS Overall improvement between the 2-year and 3-year timepoint (15.9 vs 10.4). Accountability of patients not available or yet reaching the 3-year follow-up time period are reflected in Table 1. Treatment cessation through 3 years was 31% greater in the control cohort than the investigational cohort (15.0% vs. 19.6%).Conclusions:Three-year results demonstrate statistically superior relief from post-APM knee pain and function compared to non-surgical care alone. At 3 years, the magnitude of change from baseline to 3 years significantly favored the investigational device compared to control treatments. Investigational subjects discontinued treatment at a far lower rate compared to control subjects. Investigational subjects who underwent a device exchange or repositioning procedure were able to continue therapy benefit with the medial meniscus prosthesis. In all KOOS subscales, the investigational subjects experienced superior improvements and outcomes at 3 years compared to non-surgical care subjects.Figure 1.Magnitude of improvement in KOOS Overall (A), Pain (B), Symptoms (C), Activities of Daily Living (ADL; D), Sports and Recreation (E), and Quality of Life (QOL; F) from baseline (BL) to each follow-up time point.Table 1.Numbers are patients available to complete the KOOS questionnaire; Numbers in parentheses are percentages of the baseline population.

Selection Criteria for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Treatment in Patients with Peritoneal Metastases.

Simple SummaryStandard treatment protocol for PIPAC consists of three procedures and completion of treatment has been shown to be prognostic of improved survival. The aim of this study was to identify predictors for completion of treatment. This retrospective multicentric cohort study included all patients with peritoneal metastases undergoing PIPAC at three PIPAC expert centers. Overall, 183 patients had 517 PIPACs. Bimodal treatment was found as an independent predictive factor for completing the three procedures (OR = 4.202, 95%CI [1.813, 10.630], p < 0.001), as well as prior bowel obstruction (OR = 0.389, 95%CI [0.153, 0.920], p = 0.037). In conclusion, the absence of ascites and prior bowel obstruction can help to select patients suitable for PIPAC. Best results seem to be achieved when PIPAC is combined with systemic chemotherapy.Background: The standard treatment protocol for PIPAC consists of three procedures. Completion of treatment has been shown to be prognostic of improved survival. The aim of this study was to identify predictors for completion of treatment. Methods: Retrospective multicentric cohort study of patients with peritoneal metastases undergoing PIPAC in three PIPAC expert centers. Per protocol (PP) treatment was defined as patients receiving ≥3 PIPACs and was compared to patients receiving <3. Results: Overall, 183 patients had 517 PIPACs. The main reasons for stopping PIPAC were disease progression in 50% patients, bowel obstruction in 15%, patient’s refusal to pursue in 10%, conversion to cytoreductive surgery in 7%, and medical reasons in 8%. Overall, 95 patients (52%) had PP treatment. The PP median OS was 17 vs. 7 months, p = 0.001. PP patients had r ascites (410 ± 100 mL vs. 960 ± 188 mL, p = 0.001), no prior history of bowel obstruction (12% vs. 24%, p = 0.028), and more bimodal treatment (39% vs. 13%, p < 0.001). After multiple regression, bimodal treatment was found as an independent predictive factor for completing PP (OR = 4.202, 95%CI [1.813, 10.630], p < 0.001), along with prior bowel obstruction (OR = 0.389, 95%CI [0.153, 0.920], p = 0.037). Conclusion: The absence of ascites and prior bowel obstruction can help to select patients suitable for PIPAC. Best results seem to be achieved when PIPAC is combined with systemic chemotherapy.

Use of Machine Learning to Estimate the Per-Protocol Effect of Low-Dose Aspirin on Pregnancy Outcomes

In randomized clinical trials (RCTs), per-protocol effects may be of interest in the presence of nonadherence with the randomized treatment protocol. Using machine learning in per-protocol effect estimation can help avoid model misspecification owing to strong parametric assumptions, as is common with standard methods (eg, logistic regression). To demonstrate the use of ensemble machine learning with augmented inverse probability weighting (AIPW) for per-protocol effect estimation in RCTs and to evaluate the per-protocol effect size of aspirin on pregnancy. This secondary analysis used data from 1227 women in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a multicenter, block-randomized, double-blind, placebo-controlled clinical trial of the effect of daily low-dose aspirin on pregnancy outcomes in women at high risk of pregnancy loss. Participants were recruited at 4 university medical centers in the US from June 15, 2007, to July 15, 2012. Women were followed up for 6 menstrual cycles for attempted pregnancy and 36 weeks of gestation if pregnancy occurred. Follow-up was completed on August 17, 2012. Data analyses were performed on July 9, 2021. Daily low-dose (81 mg) aspirin taken at least 5 of 7 days per week for at least 80% of follow-up time relative to placebo. Pregnancy detected using human chorionic gonadotropin (hCG) levels. Among the 1227 women included in the analysis (mean SD age, 28.74 [4.80] years), 1161 (94.6%) were non-Hispanic White and 858 (69.9%) adhered to the protocol. Five machine learning models were combined into 1 meta-algorithm, which was used to construct an AIPW estimator for the per-protocol effect. Compared with adhering to placebo, adherence to the daily low-dose aspirin protocol for at least 5 of 7 days per week was associated with an increase in the probability of hCG-detected pregnancy of 8.0 (95% CI, 2.5-13.6) more hCG-detected pregnancies per 100 women in the sample, which is substantially larger than the estimated intention-to-treat estimate of 4.3 (95% CI, -1.1 to 9.6) more hCG-detected pregnancies per 100 women in the sample. These findings suggest that a low-dose aspirin protocol is associated with increased hCG-detected pregnancy in women who adhere to treatment for at least 5 days per week. With the presence of nonadherence, per-protocol treatment effect estimates differ from intention-to-treat estimates in the EAGeR trial. The results of this secondary analysis of clinical trial data suggest that machine learning could be used to estimate per-protocol effects by adjusting for confounders related to nonadherence in a more flexible way than traditional regressions. ClinicalTrials.gov Identifier: NCT00467363.

Response and Toxicity Patterns Seen in Patients Treated With Combination Immunotherapy and Radiotherapy in the UNSCARRed (UNresectable Squamous Cell Carcinoma treated With Avelumab and Radical Radiotherapy) Study

Combination immunotherapy (IO) with radiotherapy (RT) is theorized to have additive/synergistic effect in treating cancers. PD-1/PD-L1 blockade and RT have both shown very good response rates in cutaneous squamous cell carcinoma (cuSCC) independently. Combination of RT & IO is currently understudy in the UNSCARRed trial. The response/toxicities to RT & IO can be unpredictable, and thus we review here the patterns of response and toxicities seen to date in trial patients.Patients with nonmetastatic unresectable cuSCC were enrolled in UNSCARRed, a single arm study delivering five q2 week cycles of avelumab (PD-L1 inhibitor) with 60-66 Gy / 30-33# RT starting with cycle 2. The patterns of cuSCC response and toxicities experienced by these patients were reviewed as per clinical / imaging studies, pathologic analysis and CTCAE 5.0 criteria, respectively. Biomarker testing including PD-L1 staining is a secondary objective of the trial.7 out of 20 patients have completed the experimental treatment. Median age was 80, and common sites of disease was scalp and head & neck. All except one patient completed the per-protocol treatment, with one patient omitting the last IO cycle due to chest pain. Common toxicities include grade 1-2 dermatitis (all), grade 1 fatigue (3), grade 1 dry mouth (2), and grade 2 cutaneous infections (3). One patient had grade 3 bleeding from tumor site, one had grade 2 hepatitis. All toxicities resolved in follow-up. 6 out of 7 patients experienced an objective response. One patient had progression on treatment with early discontinuation and one experienced biopsy-confirmed pseudoprogression on treatment, but then went on the have a complete response.Patterns of response for RT+IO can be complex compared to RT alone with a potential for progression, pseudoprogression or partial/complete response. Toxicities are limited and easily treated, with patients in this advanced age cohort showing combination of RT+IO appeared feasible with good response. This trial was registered on Clinicaltrials.gov, NCT#:03737721.

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival

BackgroundSeveral therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab...

Superior Improvements in Knee Pain and Function with a Novel Synthetic Medial Meniscus Replacement Implant Compared to Non-surgical Care in Subjects with Knee Pain Following Partial Meniscectomy: Two-year Results from Two Prospective US Clinical Trials

Objectives:Arthroscopic partial meniscectomy (APM) is the most common surgical treatment for symptomatic, irreparable meniscal tears that do not improve with non-surgical care. For many patients, APM is associated with improvements in knee pain and function, but a subset of patients reports persistent or recurrent knee pain 1-2 years after APM surgery. Current treatment options for post-APM knee pain are limited, especially for patients considered too young for knee replacement. The polymeric medial meniscus implant mimics the biomechanical function of the natural medial meniscus and is intended to provide relief from pain and improved function in subjects with knee pain following APM. Two FDA-regulated clinical trials were conducted in the United States and pooled for analysis, to assess superiority of a synthetic medial meniscus implant to non-surgical care in treating persistent or recurrent knee pain following previous partial meniscectomy. The hypothesis was that the meniscus implant is superior to non-surgical care for improvements in composite measures of knee-related pain, function, and quality of life at 2 years of follow-up.Methods:242 patients (176 investigational, 66 control) were treated in 2 prospective, concurrent clinical trials in the U.S.: a randomized controlled superiority trial (RCT) comparing the medial meniscus implant to non-surgical care (control) and a single-arm, implant-only trial. Eligible subjects had persistent knee pain and one or more previous partial meniscectomies at least 6 months before trial entry. Treated subjects returned for follow-up visits at 1.5 months, 6 months, 1 year, and 2 years. Patient-reported knee pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The primary patient-reported outcomes were 2 KOOS subscales: KOOS Pain and KOOS Overall. KOOS success was defined as subjects who achieved either (1) KOOS Pain ≥86.1 at 2 years and KOOS Overall ≥86.2 at 2 years or (2) a ≥20-point improvement from baseline to 2 years in KOOS Pain and KOOS Overall, with KOOS Pain ≥40 at 2 years. Treatment cessation was defined as any subject who discontinued the per-protocol treatment by permanent implant removal (implant group) or any surgical procedure on the index knee (control group). Implant subjects who underwent subsequent surgical procedures on index knees (e.g. implant exchange) remained in the trial. The two treatment groups were well-matched, except for baseline KOOS Sports and Recreation. Statistical analyses adjusted for high vs low baseline KOOS Sports and Recreation using 2-factor analysis of variance (ANOVA) for continuous variables and 2x2 logistic regression for dichotomous variables.Results:Sixteen subjects (6.6%; 14 control, 2 implant) were lost to follow-up or withdrew from the study over 2 years. The magnitude of improvement from baseline to 2 years was significantly greater in the implant group compared to control for 5 of 6 KOOS subscales (Figure 1), including the primary outcomes of KOOS Overall and KOOS Pain (Figure 1A,B). The proportion of subjects who achieved KOOS success was significantly higher in the implant group (63.4%) than the control group (27.9%), which remained true with or without the adjustment for baseline KOOS Sports and Recreation (P<.0001 in each case). Treatment cessation through 2 years was less frequent in the implant group (10.5%) compared to the control group (17.3%), but the difference was not statistically significant (P=.19).Conclusions:Two-year results from 2 prospective, concurrent, US clinical trials demonstrate that the synthetic meniscus implant provides superior relief from post-APM knee pain when compared to treatment with non-surgical care alone. In addition, the magnitude of change from baseline to 2 years in the primary patient-reported outcomes and the rate of KOOS success significantly favored the implant group compared to the control group. Subjects in the implant group tended to discontinue treatment at a lower rate compared to subjects in the control group, but the difference was not statistically significant. Subjects treated with the implant who underwent a device exchange or repositioning procedure were able to continue treatment therapy with the medial meniscus implant. Overall, the implant group experienced superior improvements and outcomes at 2 years compared to subjects receiving non-surgical care alone.

Generalizing the per-protocol treatment effect: The case of ACTG A5095

Generalizing the per-protocol treatment effect: The case of ACTG A5095

Generalizing the per-protocol treatment effect: The case of ACTG A5095.

Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population. We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008-2014. Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2 years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was -0.4 (95% confidence interval: -6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was -0.9 (95% confidence interval: -6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio = 0.95, 95% confidence interval: 0.68, 1.32) and -0.7 (95% confidence interval: -6.7, 5.5) for the per-protocol comparison (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population.

Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus

BackgroundWhile neoadjuvant chemoradiation therapy (nCRT) with subsequent surgery is the treatment of choice for patients with locally advanced or node-positive squamous cell carcinoma of the esophagus (SCC) suitable for surgery, patients who are unsuitable for surgery or who refuse surgery should be treated with definite chemoradiation therapy (dCRT). Purpose of this study was to compare toxicity and oncologic outcome of dCRT with either cisplatin and 5-fluoruracil (CDDP/5FU) or carboplatin and paclitaxel (Carb/TAX) in patients with SCC.MethodsTwenty-two patients who received dCRT with carboplatin (AUC2, weekly) and paclitaxel (50 mg per square meter of body-surface area, weekly) were retrospectively compared to 25 patients who were scheduled for dCRT with cisplatin (20 mg/m2/d) and 5-fluoruracil (500 mg/m2/d) on day 1–5 and day 29–33. For the per-protocol (PP) analysis, PP treatment was defined as complete radiation therapy with at least 54Gy and at least three complete cycles of Carb/TAX or complete radiation therapy with at least 54Gy and at least one complete cycle of CDDP/5FU. While patients who were scheduled for dCRT with Carb/TAX received a significantly higher total radiation dose (median dose 59.4Gy vs. 54Gy, p < 0.001) than patients who were scheduled for dCRT with CDDP/5FU, no significant differences were seen for other parameters (age, sex, TNM-stage, grading and tumor extension).ResultsForty-seven patients (25 patients treated with CDDP/5FU and 22 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 41 of 47 patients (23 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis. Severe myelotoxicity (≥ III°) was seen in 52% (CDDP/5FU) and 55% of patients (Carb/TAX), respectively (p = 1.000). In the univariate binary logistic regression analysis, patients age was the only factor associated with an increased risk of ≥ III° myelotoxicity (hazard ratio 1.145, 95% CI 1.035; 1.266; p = 0.009). Regarding treatment efficiency, no significant differences were seen for overall survival (OS) and freedom from relapse (FFR) between both treatment groups.ConclusionMyelotoxicity and oncologic outcome under dCRT were not different for patients with SCC of the esophagus treated with either CDDP/5FU or Carb/TAX. The putative equivalence of dCRT with Carb/TAX in this setting should be further investigated in prospective trials. However, our data reveal that the risk of significant myelotoxicity increases with patient age and therefore other chemotherapy regimens might be evaluated in elderly patients.

Wednesday, September 26, 2018 1:00 PM – 2:00 PM Interventional Pain Management: 30. Two-year outcomes of patients treated with BVN ablation for the relief of chronic low back pain: results of the SMART trial

BACKGROUND CONTEXT Thirty percent of Americans have low back pain (LBP) at any given time, leading to approximately 50 million physician visits in the U.S. annually. For patients with chronic low back pain (CLBP), the etiology can be difficult to diagnose and then treat using either current nonsurgical therapies, with inherent patient adherence challenges, or surgical interventions, with associated long recovery times. Antonacci et al, following anatomic study, proposed that a portion of pain previously ascribed to the disc actually emanates from the vertebral body endplate nociceptors which communicate to the central nervous system (CNS) through the basivertebral nerve (BVN). We report on the two-year outcome data of the treatment arm patients in the SMART trial, which studied RF BVN ablation to treat CLBP. PURPOSE To determine the longer term efficacy of basivertebral nerve ablation, for the treatment of chronic low back pain. STUDY DESIGN/SETTING Prospective, randomized, double-blinded, sham control study that was an FDA approved clinical trial. Fifteen sites in the US and three in Germany participated. PATIENT SAMPLE Skeletally mature patients with chronic (>6 months), isolated low back (lumbar) pain and no neurogenic leg pain, who had not responded to at least six months of nonoperative management (conservative care) were eligible for the SMART study. Recent MRI had to demonstrate either Type 1 or 2 Modic changes at three or less contiguous vertebral bodies. OUTCOME MEASURES ODI, Safety, VAS. METHODS A total of 128 patients, from the per-protocol treatment arm of the SMART trial, a double-blind sham-controlled randomized trial, were followed for up to 24 months. ODI and VAS instruments were used to collect patient reported outcomes at baseline, 2 weeks, 6 weeks, 3 months, 6 months, 12 months, and 24 months. RESULTS ODI and VAS data were available on 106 and 104 patients at 24 months respectively. The mean baseline ODI in the treatment arm was 42.4, decreasing to 22.6 at 12 months and 18.8 at 24 months. The mean baseline VAS in the treatment arm was 6.73, decreasing to 3.96 at 12 months and 3.13 at 24 months. Using a paired t-test comparing the 12 and 24-month VAS observations, the mean score at 24 months was significantly improved compared to 12 months (3.80 vs. 3.13, p=.004). CONCLUSIONS The SMART trial demonstrates that BVN ablation is statistically and clinically superior to the sham intervention, and that the degree of ODI improvement is approximately one disability category. Longitudinal follow-up of these patients demonstrates that ablation of the BVN for the relief of CLBP is a durable procedure with continuing improvement in patient reported ODI and VAS scores at up to two years. FDA DEVICE/DRUG STATUS Intracept System (Approved for this indication).

Long-term outcome of concurrent chemoradiotherapy with elective nodal irradiation for inoperable esophageal cancer.

Elective nodal irradiation (ENI) might improve overall survival in patients with inoperable esophageal cancer. We conducted a retrospective analysis to assess the long‐term survival and toxicity of esophageal cancer patients treated with ENI versus conventional‐field irradiation (CFI). All data in the present study were based on our institutional experience from 2000 to 2005 of patients with inoperable esophageal cancer treated with ENI or CFI plus two concurrent cycles of paclitaxel/cisplatin. Based on the inclusion and exclusion criteria, 89 patients were included in the analysis. Of these patients, 51 were treated with ENI, whereas 38 were treated with CFI. For the per‐protocol population, the patients in the ENI group significantly improved in terms of their 10‐year disease‐specific overall survival (43.1% vs 10.5%, P = 0.019), 10‐year disease‐free survival (36.7% vs 10.2%, P = 0.040) and 10‐year local recurrence‐free survival (47.2% vs 17.2%, P = 0.018) compared with the CFI group. Aside from radiation esophagitis, the incidence of grade 3 or greater acute toxicities did not differ between the two groups. Multivariate analysis showed that radiation field, tumor length and clinical stage were independent prognostic factors associated with OS. Concurrent chemoradiotherapy with ENI improves both disease‐specific overall survival and loco‐regional control in patients with inoperable esophageal cancer receiving per‐protocol treatment. The regimen has a manageable tolerability profile.

High‐Dose Extended‐Release Lansoprazole (Dexlansoprazole) and Amoxicillin Dual Therapy for Helicobacter pylori Infections

Helicobacter pylori infections have become increasingly difficult to treat. To examine whether amoxicillin and high-dose dexlansoprazole would reliably achieve an H. pylori eradication rate of ≥90%. An open-label prospective pilot study of H. pylori eradication in treatment-naïve subjects with active H. pylori infection (positive by two tests). amoxicillin 1 g and dexlansoprazole 120 mg each twice a day at approximately 12-hour intervals for 14 days. Success was accessed by urea breath test. An effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as an unacceptable result. After 13 subjects were entered (12 men, one woman; average age of 54 years), the prespecified stopping rule of six treatment failures was achieved (i.e., the 95% confidence interval excluded achieving the required 90% success rate even if the proposed study of 50 completed patients were entered) and enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 53.8%; (7/13); 95% CI = 25-80%. Compliance was 100%. Three patients (23%) reported side effects, all of which were mild and none interrupted therapy. Theoretically, dual PPI plus amoxicillin should reliably eradicate H. pylori provided nearly neutral intragastric pH can be maintained. Clearly, dexlansoprazole, despite being administered at high dose and twice a day (i.e., total daily dose 240 mg), failed to achieve an intragastric milieu consistent with dual PPI plus amoxicillin therapy being an effective anti-H. pylori regimen.

Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials

Assessing per-protocol (PP) treatment efficacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal treatment effects in compliers, these methods do not apply to a common class of trials where (a) the primary objective compares survival curves, (b) it is inconceivable to assign participants to be adherent and event free before adherence is measured, and (c) the exclusion restriction assumption fails to hold. HIV vaccine efficacy trials including the recent RV144 trial exemplify this class, because many primary endpoints (e.g., HIV infections) occur before adherence is measured, and nonadherent subjects who receive some of the planned immunizations may be partially protected. Therefore, we develop methods for assessing PP treatment efficacy for this problem class, considering three causal estimands of interest. Because these estimands are not identifiable from the observable data, we develop nonparametric bounds and semiparametric sensitivity analysis methods that yield estimated ignorance and uncertainty intervals. The methods are applied to RV144. Supplementary materials for this article are available online.