Clinical Trials Group Research Articles

Pregnant Women, HIV, and Clinical Research to Prevent Perinatal Transmission in the 1990s

In 1994, American and French AIDS research showed that the drug AZT reduced the risk of HIV transmission from a pregnant HIV-positive woman to her fetus (perinatal transmission). Hailed as a breakthrough, the AIDS Clinical Trial Group protocol 076 (ACTG 076) soon became the standard of care in the US But ACTG 076 was too expensive for low-income countries where perinatal transmission rates were high; to find a more affordable prevention, the US principally funded studies in several low-income countries. Controversy over whether the short course of AZT studies was ethical, given their different standards of care and use of a placebo, erupted in 1997. These studies remain well known within the global health biomedical literature as illustrating differences between sending and receiving countries. But while rarely invoked within this literature, these two sets of studies have similarities that challenge this hierarchal division: both involved pregnant women as objects of clinical research instead of subjects of clinical care, reflective of the all-too-common focus in global health on disease containment rather than on health care, and both illustrate the ways the focus within global health has been on a solitary biomedical intervention rather than on discrimination, inequality, and poverty within and among countries.

Davids versus Goliaths: Pharma and academia threats to individual scientists and clinicians

Background We previously described experiences of clinicians who published adverse drug reaction reports. We now report on threats and intimidations leveled against clinicians and scientists who received publicly documented threats after communicating safety, efficacy, or data integrity findings contrary to corporate interests. Methods Data on threats and intimidations were obtained from transcripts of governmental hearings or agencies, university-affiliated reports, media interviews, and investigative journalism articles. Content and timing of threats and intimidation, subsequent harms, numbers of persons seriously injured or who died from individual toxicities, financial payments from sponsors related to safety, efficacy, or data integrity concerns, and civil settlements and criminal findings were evaluated. Findings Twenty-six individuals who communicated safety, efficacy, or data integrity concerns were targets of threats and intimidation from corporate employees (twenty-three individuals) or regulatory personnel (three). Seventeen individuals identified instances where pharmaceutical sponsors submitted fraudulent data in support of regulatory approval of a drug or device. Scientist and clinician communications were followed by drug/device withdrawals (fourteen drugs/devices), black box warnings (six drugs), withdrawal of a sponsor’s application for regulatory approval (one device), and delay of approval of a sponsor’s application for regulatory approval (one drug). Actions mainly occurred after persons communicated with pharmaceutical employees (fourteen). Intimidation efforts by corporate personnel included threats of lawsuits (eighteen individuals), hiring private investigators (nine), and public disparagement at conferences (eleven). Related intimidation efforts carried out by academia or regulatory agency superiors included threats of: loss of positions (six), loss of grant funding (two), delays in decisions regarding tenure (two); or reassignment to a low-level position (one). Academic harms included lost: hospital or university appointments (nine and six, respectively), grant funding (two), chairperson title of an international clinical trial group (one), and journal editorial board position (one). Corporate harms included payment of $1 million to defense attorneys in three cases filed against clinicians. Interpretation Threats and intimidation carried out by corporate employees and/or academic supervisors followed public communication of concerns regarding patient safety, drug efficacy, or data integrity, including instances where sponsors were identified as having submitted fraudulent data to regulatory or government agencies. Consideration should be given to filing criminal charges against pharmaceutical executives who are discovered by scientists or clinicians to have knowingly submitted fraudulent data to regulatory or governmental agencies, rather than causing the scientists and clinicians who submit such reports to risk losing their reputations and occupations.

Genitourinary Tract Tumors in Children: An Update.

Genitourinary tract tumors in children are less common than in adults. Most of these tumors have different genetic backgrounds, clinical presentation, and oncologic behavior than their adult counterpart. As a result of low prevalence in children, some of the treatment approaches and recommendations are based on treatment experience in adult patients. However, thanks to scientific and technological development, survival rates have risen considerably. This paper presents a review of the principal features of the tumors involving the genitourinary tract in children and an update in genetic background, diagnosis, and treatment. A narrative review was performed on published literature about genitourinary tract tumors in pediatric patients. Papers presented in English and Spanish literature were reviewed. PubMed, Science Direct, and SciELO databases were used to collect information and present this article. Kidney tumors are the most common type of genitourinary tumors in children. Among those, Wilms tumor represents the majority of cases and shows the successful work of clinical trial groups studying this tumor type. Other tumors involving the genitourinary tract in children include Rhabdomyosarcoma, Transitional cell carcinoma, Testicular, and Adrenal tumors. Genitourinary tract tumors in children represent significant morbidity and economic burden, so awareness in early diagnosis represents improvement in treatment, clinical, and oncological outcomes.

Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients.

Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily). Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction. Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group. Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age). Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated. Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co-treatment with 600 mg oral rifampin daily decreased the steady-state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/m2 ) PO BID without rifampin and 230/230 mg/m2 LPV/RTV PO BID with 10 mg/kg PO daily rifampin in pediatric patients. Sixteen mg/kg of super-boosted LPV (LPV/RTV 1:1) PO BID with 15 mg/kg PO daily rifampin achieved simulated LPV troughs >1 mg/L in ≥93% of virtual children weighing 3.0-24.9 kg, which was comparable with 10 mg/kg PO daily rifampin. Super-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children.

Mature Local Control and Reirradiation Rates Comparing Spine Stereotactic Body Radiation Therapy With Conventional Palliative External Beam Radiation Therapy

Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial. One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance-based local control and reirradiation rates for each treated spine segment. The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval [CI], 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P < .001). cEBRT (hazard ratio [HR], 3.48; 95% CI, 1.94-6.25; P < .001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12). Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort.

Association between state Medicaid policies and accrual of Black participants to cancer clinical trials.

1501 Background: Black individuals remain underrepresented in U.S. cancer clinical trials, partly due to financial barriers to participation. While coverage of the routine costs of trial participation has long been mandatory for Medicare and the commercially insured, only 16 states have enacted similar mandates for Medicaid enrollees. Given the disproportionate representation of Black individuals in state Medicaid programs, we hypothesized that such mandates may have led to improved accrual of Black participants to cancer clinical trials. Methods: We conducted a retrospective, quasi-experimental study using de-identified data from the ECOG-ACRIN Cancer Research Group to evaluate changes in the accrual of Black participants to cancer clinical trials associated with state-mandated Medicaid coverage of routine trial costs. The study population included non-elderly adults enrolled in therapeutic clinical trials for breast, colorectal, lung, or prostate cancer from 2000-2019. We employed a difference-in-differences approach with event-study specification to compare outcomes in states that mandated Medicaid coverage of routine trial costs relative to states that did not, before and after mandates were enacted. Outcomes included the proportion of trial participants who had Medicaid insurance (vs. non-Medicaid) and the proportion who were Black (vs. non-Black). Models adjusted for age, sex, cancer type, cancer stage, study phase, and study site (community vs. academic). Results: Among 24,321 trial participants (mean age 52.0 [SD 8.2] years, 82.8% female), 7.2% had Medicaid coverage and 10.5% were Black. Compared to states without Medicaid coverage mandates, states with mandates had a statistically significant increase in the proportion of Black trial participants in the first year following the mandate (+6.4 percentage points [95%CI 1.8% to 11.0%]) but not in subsequent years. There was no association between state mandates and the proportion of trial participants enrolled in Medicaid (effects ranged from -0.7 percentage points [95%CI -4.6% to 3.3%] in the first year after mandates to -3.9% [95%CI -8.6% to 0.8%] in the third year). Conclusions: State-mandated Medicaid coverage of the routine costs of trial participation was associated with a short-term increase in the proportion of Black trial participants. These findings suggest that Medicaid policies have the potential to improve representation of racial minority groups in cancer clinical trials, and support recent federal legislation mandating state Medicaid programs to cover trial participation costs as of January 2022. Our study was limited by use of data from only one large cancer research group, focus on only four common cancers, and limited power to analyze the policy impact for other racial and ethnic minority groups. Additional work is needed to replicate these findings in larger cohorts of trial participants.

Understanding barriers and facilitators to clinical trial participation among Black patients with multiple myeloma.

12137 Background: Currently, Black patients make up 20% of people living with multiple myeloma, yet they represent only 6% of participants in clinical trials.1 The underrepresentation of Black patients in clinical trials can contribute to outcome disparities thereby negatively impacting health equity in cancer treatment and outcomes.2 This project examined attitudes towards clinical trials among Black multiple myeloma patients and caregivers. Findings will inform the development of programs aimed at increasing clinical trial participation in this population. Methods: In 2021, the Cancer Support Community conducted an online survey to gain insights on barriers, facilitators, and perceptions of clinical trials among Black multiple myeloma patients and caregivers/care partners. Survey questions were informed by insights from prior focus groups. 94 patients and 101 caregivers were surveyed. Results: Most participants were male (62%) and African American (90%). 5% identified as African Caribbean and 5% as Black and Hispanic. The average age was 46 years. Just over half (51%) currently or previously participated in clinical trials. Of those who chose not to participate in a trial, the most common reasons were fear of side effects (46%) and fear of receiving a placebo (38%). Another barrier to participation reported was discomfort with being randomly assigned to a treatment (56%). Participants reported a significant level of distrust in medical research and doctors, saying that it was “very or somewhat likely” that doctors provide treatment as part of an experiment without patient consent (41%) and that they might be used as a “guinea pig” (25%). Of note, 57% of respondents said COVID had changed their attitude towards participating in clinical trials. 14 of 16 factors mentioned in our focus groups were affirmed by more than half of respondents as facilitating participation in a clinical trial. The top factors were: Understanding potential side effects (66%) My health care team speaks to me about trials (65%) Compensation offered for transportation, childcare, or time off work (62%) My family/community support my decision (61%). Conclusions: These findings are consistent with previous research which found that cancer patients reported the biggest attitudinal barriers to clinical trial participation were fear of side effects, distrust in medical research, and random assignment to clinical trial groups.3 Our study highlights that Blacks and African Americans living with multiple myeloma value multifactorial efforts to increase clinical trial participation: logistical and financial interventions, patient/provider communication, and culturally sensitive support and education programs. These programs can also work to improve health equity by reducing barriers to overall care and encouraging Blacks and African Americans living with multiple myeloma to be active members of their health care team.

Comparison of the results of treatment of patients with unrespectable NSCLC in the framework of clinical trials and in real world practice using pseudo-randomization.

e21049 Background: Local and international recommendations for anticancer treatment are formed and changed based on the results of clinical trials. A feature of most clinical trials is the strict criteria used to select “safe” patients without severe comorbidities. In real world practice, significant portion of patients do not meet all of these criteria (32%) [ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586241/ ], which raises a significant question about the consistency of treatment results demonstrated in studies with data obtained in routine clinical practice (RCP). The purpose of this work was to compare the results of treatment of patients with unrespectable NSCLC receiving first-line drug therapy in RCP and in the framework of international clinical trials using the method of pseudo-randomization (propency score analysis). Methods: The current analysis included 344 patients with inoperable NSCLC who received first-line drug therapy as part of RCP and 90 patients included in various non-TKI clinical trials irrespectively of IO use 2018-2019.Firstly, a direct comparison of performance indicators was done (progression-free survival) using the Kaplan-Meier method for all patients included in the study.At the second stage, in order to eliminate the influence of the imbalance of prognostic factors, a regression analysis was carried out. To form balanced cohorts, we used the propensity score matching analysis.The propensity to progression was assessed using logistic regression analysis in each individual patient, taking into account the basic clinical characteristics: age, gender, ECOG, histological form, regional lymph nodes, presence of distant metastases (mts), stage of the disease, mts of the lung parenchyma, liver mts, pleural mts, bone lesions, adrenal mts, mts lesions of distant lymph nodes, mts lesions of other areas, mts lesions of the brain, number of metastasis zones, components of the first-line therapy regimen. Patients of both arms treatment were matched in a 1:1 ratio based on their progression propensity score in increments of 0.15.After matching two homogeneous groups of patients were formed: 83 in the RCP group and 84 in the clinical trial therapy group. Results: In a direct comparison of the results of the treatment, progression-free survival in the group of patient who underwent treatment in clinical trials was significantly higher than within the RCP (6.4 months 95% CI 5.9–6.9 vs. 13.3 months 95% CI 8.1–18.5; log rank p &lt; 0.000).propensity score matching analysis showed a significantly longer time to progression in the clinical trials group of 13.3 months, 95% CI 8.3-18.3 versus 6.3 months. 95% CI 4.8-7.7; log rank p &lt; 0.000. Conclusions: Results obtained in clinical trial are substantially better than seen in RCP, this should be taken into consideration when extrapolating new research findings.

Empowering colorectal cancer patients and caregivers through clinical trials education in COLONTOWN.

e24129 Background: Clinical trials are increasingly part of the continuum of care for colorectal cancer patients, particularly those with metastatic disease. Yet most patients have limited knowledge about clinical trials, and many struggle to navigate the myriad barriers to enrollment. To bridge this gap, PALTOWN supports a broad array of activities in its COLONTOWN online community to help patients and caregivers interested in pursuing clinical trials. The function and impact of these activities is examined here. Methods: A comprehensive inventory of all clinical trial-related activity was conducted across three main sources: 1) resources and activity in COLONTOWN’s nine clinical trial-focused groups; 2) clinical trial materials posted in COLONTOWN UNIVERSITY, an online disease education center; and 3) patient feedback on clinical trial programming. Results: The MSS and MSI-High clinical trial groups in COLONTOWN serve more than 2,200 members, and more than 1,000 members are served by mutation- and location-specific trial groups. These groups have helped at least 187 members enroll in a clinical trial between 2019 and 2022. Among 10 trial-related activities, a majority (6/10) focused on sharing biomedical information, including : 1) patient-friendly descriptions of new trials; 2) explanations of trial results; 3) abstracts, articles, and videos from professional outlets such as ASCO Daily Post and OncLive; 4) patient-created resources on clinical trial basics in COLONTOWN UNIVERSITY; 5) “Doc Talks” by prominent CRC oncologists; and 6) patient advocates serving as information liaisons between patients and NCI Task Forces. A smaller number of activities (3/10) focused on psycho-social support from peers, including 1) accounts of patient experiences while seeking and participating in trials; 2) strategy discussions about how and when to pursue trials; and 3) “Alanna Project” database of members on a trial. COLONTOWN’s Clinical Trial Workshop (1/10) offers a novel approach to integrating biomedical education with psycho-social support via a four-week, peer-led clinical trial navigation program. Assessment of the cognitive and behavioral outcomes of the workshop demonstrate improvements in all four dimensions of health literacy: the ability to access, understand, appraise, and apply relevant information in the search for clinical trials. Conclusions: COLONTOWN's clinical trial programming offers comprehensive clinical trial education to patients and caregivers that leads to enrollment in trials. By embedding that education within a supportive community of peers, it enhances patients' capacity to collaborate with health care professionals in making informed decisions about clinical trials.

Dermatology: how to manage atopic dermatitis in patients with skin of colour.

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disease prevalent in all skin types but can differ in pathogenesis and clinical presentation. It has been documented in the literature that AD is more prevalent in Asian and Black individuals than in white individuals. Genetic variations as well as cultural and socioeconomic factors have important implications for susceptibility to AD and response to treatment in skin of colour. In this narrative review, we discuss differences in the epidemiology, pathophysiology, clinical presentation and treatment of AD in skin of colour. Additionally, we highlight the need for greater inclusivity of non-white ethnic groups in clinical trials to develop targeted treatments for diverse populations. Moreover, awareness of differences in AD presentation amongst non-white individuals may encourage patients to seek medical care earlier, leading to timely management and improved outcomes.

Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals.

Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.

Pregnancy and Metabolic-associated Fatty Liver Disease: A Clinical Update.

The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapidly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both mother and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the effects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of pregnancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.

Patient Experience in Clinical Trials: Quality of Life, Financial Burden, and Perception of Care in Patients With Multiple Myeloma or Lymphoma Enrolled on Clinical Trials Compared With Standard Care.

Patients' concerns regarding clinical trial (CT) participation include apprehension about side effects, quality of life (QoL), financial burden, and quality of care. We prospectively evaluated the experience of patients with multiple myeloma or lymphoma who were treated on CTs (CT group, n = 35) versus patients treated with standard approaches (non-CT group, n = 88) focusing on QoL, financial burden of care, and patients' perception of quality of care over a 1-year period. There were no significant differences in any of the patient-reported outcomes in CT versus non-CT groups. We observed an initial decline in overall QoL in the first 3 months across both groups, driven primarily by physical and functional well-being. QoL gradually improved and was above baseline by month 12. Patients reported highest improvement in the functional well-being subdomain. Patients in both groups reported high satisfaction with the quality of care received, and there were no differences in overall satisfaction, communication with team, or access to care. At baseline, 16%-19% of patients reported financial burden, which increased to a peak of 33% in the CT group and to 49% in the non-CT group over the course of 1 year. There was no significant difference in financial burden in the two groups overall. Most of the patients reported getting all the care that was deemed medically necessary in both groups. However, a significant proportion of patients reported having to make other kinds of financial sacrifices because of their cancer (CT group: 33% of patients at baseline and 21%-40% over 1 year; non-CT group: 19% at baseline and 25%-36% over 1 year). Patients treated on CTs reported comparable QoL and quality of care with the non-CT group. A high proportion of patients reported financial burden over time in both groups. Our findings can serve as a guide to educate patients regarding CT participation and highlight the need to address the significant financial burden experienced by patients with cancer.

Quality of life and associated factors among people receiving second-line anti-retroviral therapy in Johannesburg, South Africa

BackgroundStudies which examine quality of life (QOL) provide important insights that are needed to understand the impacts of HIV/AIDS anti-retroviral treatment (ART), comorbid conditions and other factors on the daily activities of people living with HIV/AIDS (PLH). This study aimed to determine the inter-relationships between clinical factors, behavioural, socio-demographic variables and QOL among PLH.MethodsThe secondary analysis used data collected from 293 people living with HIV/AIDS (PLH) receiving second-line ART in Johannesburg in a clinical trial which evaluated the non-inferiority of ritonavir-boosted darunavir (DRV/r 400/100 mg) compared to ritonavir-boosted lopinavir (LPV/r) over a 48 week-period. Physical functioning, cognitive and mental QOL were measured using the Aids Clinical Trial Group questionnaire. Exploratory factor analyses were used to examine the structure, the relationships between and the construct validity of QOL items. Structural equation models which tested the a priori-hypothesised inter-relationships between QOL and other variables were estimated and goodness of fit of the models to the data was assessed.ResultsPatients on darunavir presented with lower pill burden. Older patients and women were more likely to report lower QOL scores. Pill burden mediated the effects of age, sex and treatment regimen on physical functioning QOL and adverse effects; the effects of age, sex, treatment regimen and adverse effects on cognitive QOL; and the effects of sex on mental QOL.ConclusionQOL among PLH is associated with socio-demographic and clinical factors. Therefore, QOL could be enhanced by considering PLH characteristics, clinical factors such as regimen side-effects profile, management of comorbid conditions and mitigating risks such as potential adverse drug-to-drug interactions among patients on ART.

Improving the patient-reported outcome sections of clinical trial protocols: a mixed methods evaluation of educational workshops

IntroductionFailure to incorporate key patient-reported outcome (PRO) content in trial protocols affects the quality and interpretability of the collected data, contributing to research waste. Our group developed evidence-based training specifically addressing PRO components of protocols. We aimed to assess whether 2-day educational workshops improved the PRO completeness of protocols against consensus-based minimum standards provided in the SPIRIT-PRO Extension in 2018.MethodAnnual workshops were conducted 2011–2017. Participants were investigators/trialists from cancer clinical trials groups. Although developed before 2018, workshops covered 15/16 SPIRIT-PRO items. Participant feedback immediately post-workshop and, retrospectively, in November 2017 was summarised descriptively. Protocols were evaluated against SPIRIT-PRO by two independent raters for workshop protocols (developed post-workshop by participants) and control protocols (contemporaneous non-workshop protocols). SPIRIT-PRO items were assessed for completeness (0 = not addressed, 10 = fully addressed). Mann–Whitney U tests assessed whether workshop protocols scored higher than controls by item and overall.ResultsParticipants (n = 107) evaluated the workshop positively. In 2017, 16/41 survey responders (39%) reported never applying in practice; barriers included role restrictions (14/41, 34%) and lack of time (5/41, 12%). SPIRIT-PRO overall scores did not differ between workshop (n = 13, median = 3.81/10, interquartile range = 3.24) and control protocols (n = 9, 3.51/10 (2.14)), (p = 0.35). Workshop protocols scored higher than controls on two items: ‘specify PRO concepts/domains’ (p = 0.05); ‘methods for handling missing data’ (p = 0.044).ConclusionAlthough participants were highly satisfied with these workshops, the completeness of PRO protocol content generally did not improve. Additional knowledge translation efforts are needed to assist protocol writers address SPIRIT-PRO guidance and avoid research waste that may eventuate from sub-optimal PRO protocol content.

Prevalence of peripheral spondyloarthritis among patients with ultrasound‐confirmed enthesitis: Single‐center cross‐sectional study

The primary goal of this study was to determine the prevalence of peripheral spondyloarthritis (pSpA) in patients with ultrasonography (USG)-confirmed enthesitis. The secondary aim of the study was to reveal the demographic, clinical, and ultrasonographic differences of patients diagnosed with pSpA. Fifty-nine patients with USG-confirmed enthesitis were evaluated by a rheumatologist to evaluate if they met the Assessment of SpondyloArthritis International Society (ASAS) criteria for pSpA. Elementary lesions assessed by USG were based on the definition of the Outcome Measures in Rheumatology in Clinical Trials group which included hypoechogenicity, thickening, Doppler signal within 2mm of bone, enthesophytes, bone erosions, and calcifications. For all patients, clinical and demographic data included: age, gender, smoking habits, body mass index, comorbid diseases, symptom duration, enthesitis region, the presence of bilateral enthesitis, entheseal pain visual analog scale (0-10), standardized enthesitis count following Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and SPondyloArthritis Research Consortium Canada (SPARCC) enthesitis index. Eight (13.6%, 95% CI 6.0% to 25.0%) of 59 patients were diagnosed with pSpA according to the ASAS classification criteria. Participants diagnosed with pSpA had a longer duration of symptoms (54 vs 12months), were more likely to present bilateral enthesitis (87.5% vs 49%) with higher SPARCC (11 vs 3) and MASES (6.5 vs 2) scores and higher C-reactive protein (7 vs 3.2mg/L) concentrations. Entheseal Doppler signal and hypoechogenicity were also more frequently observed (50% vs 0% and 100% vs 49% respectively). Peripheral SpA is not uncommon among patients presenting with enthesitis and more likely in cases with prolonged, extensive, and bilateral enthesitis with entheseal hypoechogenicity and Doppler signal. Musculoskeletal ultrasonography can facilitate the diagnosis of pSpA in patients presenting with enthesitis.

An evaluation of trends in the representation of patients by age, sex, and diverse race/ethnic groups in bladder and kidney cancer clinical trials.

To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time. Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004. This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88, P = 0.002) and (OR 0.69, 95%CI 0.54-0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33-0.54, P < 0.001) and (OR 0.68, 95% CI 0.55-0.83, P < 0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72-0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64-0.81, P < 0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged. In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.

Comparison of the treatment results in patients with inoperable non-small cell lung cancer in clinical trials and in standard clinical practice using the pseudorandomization method

Rationale: Non-small cell lung cancer (NSCLC) is an aggressive disease with median survival of 1214 months in inoperable patients in the pre-immunotherapy era. Nowadays, under treatment with checkpoint inhibitors median survival is 1922 months. However, only a proportion of patients are sensitive to immune therapy. In this regard, inclusion into clinical trials remains a priority option for patients from medical perspective.&#x0D; Aim: To compare the results in NSCLC patients treated in accordance with the current clinical guidelines and in international clinical trials using the propensity score matching.&#x0D; Materials and methods: The study included data from 344 patients with histologically verified unresectable advanced NSCLC without activating mutations, who received the 1st line systemic medical therapy at various combinations (single agent chemotherapy, platinum doublet-based therapy, chemoimmunotherapy, single agent immunotherapy) within the compulsory health insurance (CHI), and from 90 patients, who received therapy in clinical trials. A direct comparison of long-term treatment results was carried out with the log-rank method. To exclude any influence of individual factors on survival rates, an univariate regression analysis and pseudorandomization accounting for these factors were carried out.&#x0D; Results: The direct comparison of the treatment results showed a higher progression-free survival rate in the patients treated according to clinical trial protocols, than in those treated under CHI (13.3 [95% confidence interval (CI) 8.118.5] months vs 6.4 [95% CI 5.96.9] months). Pseudorandomization of patients based on a combination of statistically significant parameters from the CHI and clinical trial groups showed a significantly longer time to progression in the trial group (13.3 [95% CI 8.318.3] vs 6.3 [95% CI 4.87.7] months).&#x0D; Conclusion: Participation in clinical trials is per se a factor that can significantly impact the longer duration of the treatment effect. This indicates the necessity of the most active use of this tool in clinical practice.

Creation of an Integrated Clinical Trial Database and Data Sharing for Conducting New Research by the Japan Lung Cancer Society

IntroductionAlthough data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. MethodsThe Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. ResultsA total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30–93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. ConclusionsThe integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

Reporting of Participant Race and Ethnicity in Published US Pediatric Clinical Trials From 2011 to 2020

Equitable representation of participants who are members of racial and ethnic minority groups in clinical trials enhances inclusivity in the scientific process and generalizability of results. To assess participant race and ethnicity in pediatric clinical trials published from 2011 to 2020. This cross-sectional study examined articles reporting pediatric clinical trials conducted in the US published in 5 leading general pediatric and 5 leading general medical journals from January 1, 2011, to December 31, 2020. Reporting of participant race and ethnicity and comparison of enrolled participants vs US census populations of pediatric racial and ethnic groups in published clinical trials. The study included 612 articles reporting pediatric clinical trials during the study period, with 565 618 total participants (median per trial, 200 participants [IQR, 90-571 participants]). Of the 612 articles, 486 (79.4%) reported participant race and 338 (55.2%) reported participant ethnicity. From 2011 to 2020, relative rates of reporting of participant race increased by 7.9% per year (95% CI, 0.2%-16.3% per year) and reporting of ethnicity increased by 11.4% per year (95% CI, 4.8%-18.4% per year). Among articles reporting race and ethnicity, the method of assignment was not reported in 261 of 511 articles (51.1%) and 207 of 359 articles (57.7%), respectively. Black/African American children were enrolled proportionally more than the US population of Black/African American children (odds ratio [OR], 1.88; 95% CI, 1.87-1.89). Hispanic/Latino children were enrolled commensurately with the US population of Hispanic/Latino children (OR, 1.02; 95% CI, 1.01-1.03). American Indian/Alaska Native (OR, 0.82; 95% CI, 0.79-0.85), Asian (OR, 0.56; 95% CI, 0.55-0.57), and Native Hawaiian/Pacific Islander (OR, 0.66; 95% CI, 0.61-0.72) children were enrolled significantly less compared with the respective US populations of these groups. White children were enrolled less than expected (OR, 0.84; 95% CI, 0.84-0.85) but represented 188 156 (46.0%) of participants in trials reporting race or ethnicity. This cross-sectional study revealed that the proportion of published pediatric clinical trials that reported participant race and ethnicity increased from 2011 to 2020, but participant race and ethnicity were still underreported. Disparities existed in pediatric clinical trial enrollment of American Indian/Alaska Native, Asian, and Native Hawaiian/Pacific Islander children. The greater representation of Black/African American children compared with the US population suggests inclusive research practices that could be extended to other historically disenfranchised racial and ethnic groups.