Contemporary Clinical Trials

The ESSAG-trial protocol: A randomized controlled trial evaluating the efficacy of offering a self-sampling kit by the GP to reach women underscreened in the routine cervical cancer screening program

In Flanders (Belgium), women not screened for cervical cancer (CC) within the last three years receive an invitation letter from the regional screening organization, the Centre for Cancer Detection (CCD), encouraging them to have a cervical specimen taken by their general practitioner (GP) or gynecologist. However, the coverage for CC screening remains suboptimal (63%). The offer of a self-sampling kit (SSK, for HPV testing) by a GP may trigger participation among women who do not attend regular screening. The ESSAG-trial is a cluster-randomized controlled trial with three arms, each including 1125 women aged 31-64 years, who were not screened for CC in the last 6 years. In arm A, GPs offer a SSK when eligible women consult for any reason. In arm B, women receive a personal GP signed invitation letter including an SSK at their home address. In the control arm, women receive the standard invitation letter from the CCD. The primary outcome is the response rate at three months after inclusion. Secondary outcomes are: screen test positivity; compliance with foreseen follow-up among screen-positives; costs per invited and per screened women; as well as contrasts between trial arms and between socio-demographic categories. The ESSAG-trial will assess the effect of GP-based interventions using SSKs on CC screening participation among hard-to-reach populations. Findings will inform policymakers about feasible strategies on increasing CC screening that may be rolled-out throughout the whole region. ClinicalTrials.gov: NCT05656976.

Addressing disparities in the uptake of genetic counseling and testing in African American women; rationale, design and methods

Genetic counseling and testing (GCT) informs risk reduction and management strategies in women at risk for carrying a pathogenic variation in the BRCA1 or BRCA2 (BRCA1/2) genes. African American (hereinafter referred to as Black) women are less likely to receive GCT services for hereditary breast and ovarian cancer (HBOC). The objective of this work was to examine existing literature regarding successful culturally tailored GCT interventions for Black women and to describe the rationale and protocol for a randomized feasibility trial to test the efficacy of a culturally tailored GCT intervention. The For Our Health (FOH) study is a two-arm randomized control trial designed to test the efficacy of a video intervention to promote the uptake of GCT among Black women with a high risk of HBOC. The culturally tailored video intervention targets key beliefs, knowledge gaps, misconceptions, and key anticipated emotions relevant for GCT. After completing the baseline survey, 50 women at risk of HBOC will be randomized (1:1) to one of two trial arms: a YouTube video intervention or a publicly available fact sheet. Final assessments will immediately follow receipt of either video or fact sheet. Few studies have tested interventions to improve GCT uptake among Black women. The FOH trial will fill an important scientific gap in knowledge regarding strategies to reduce disparities in GCT among Black women at risk of HBOC.

A study protocol for a cluster randomized pragmatic trial for comparing strategies for implementing primary HPV testing for routine cervical cancer screening in a large health care system

Limited guidance exists regarding implementation strategies that best facilitate cancer screening practice substitution and achieve optimal stakeholder-centered outcomes. Here we describe the protocol for a randomized pragmatic trial comparing two implementation strategies to facilitate substitution of primary HPV screening for Pap and HPV co-testing to perform routine cervical cancer screening of women aged 30-65 years at Kaiser Permanente Southern California (KPSC). Twelve service areas within KPSC will be randomized to a "centrally-administered system-wide implementation + local-tailored implementation" strategy or a "centrally-administered system-wide implementation only" strategy. The centrally-administered strategy comprises clinician and staff educational activities. Sites in the local-tailored arm will then conduct a structured local needs assessment followed by site-specific selection and deployment of implementation interventions. Surveys and interviews will be conducted among women and providers from the primary care and ob/gyn departments prior to the system-wide transition, shortly after the transition, and after the completion of local-tailored interventions. A stakeholder advisory committee will assist with study design, defining stakeholder-centered outcomes, and developing data collection tools. The primary outcome of interest is uptake of primary HPV screening. Secondary provider-centered outcomes include provider knowledge, delivery of patient education, satisfaction with the practice substitution process, and resistance to primary HPV screening. Secondary patient-centered outcomes include patient knowledge, stigma, and satisfaction with the screening process. Intervention fidelity will also be measured via surveys. Findings from this study will help inform future use of a local-tailored implementation strategy for adopting primary HPV screening at large health care systems. Findings may also be applicable to other types of practice substitution.

Increasing breast, cervical, and colorectal cancer screening among rural women: Baseline characteristics of a randomized control trial

Rural women suffer disproportionately from breast, cervical, and colorectal cancer mortality compared to those in urban areas. Screening behaviors for these three cancers share many similar beliefs and barriers. Unfortunately, published interventions have not attempted to simultaneously bring women up to date with screening for three cancers (breast, cervical, and colorectal) even though multiple behavior change interventions are effective. The aim of this randomized controlled study was to compare the effectiveness of a mailed interactive and tailored DVD vs. DVD plus telephonic patient navigation (DVD + PN) vs. Usual Care (UC) to increase the percentage of rural women (aged 50-74) up to date for breast, cervical, and colorectal cancer screening. Nine hundred eighty-three participants needing one, two, or three cancer screening tests were consented and randomized to one of three groups. Prior to randomization, women were assessed for baseline characteristics including sociodemographics, health status, and cancer screening test beliefs. Screening status was assessed by medical record review. At baseline, the average age of participants was 58.6 years. Nineteen percent of the sample was not up to date with screenings for all three cancers. Colorectal cancer had the highest percentage of women (69%) who were not up to date with screening followed by cervical (57%) and then breast cancer (41%). Sixty percent of women reported receiving a reminder for mammography; 30%, for cervical cancer screening; 15% for colonoscopy; and 6% for FOBT/FIT. Increasing adherence to colorectal cancer screening may be the most urgent need among all screening tests. This clinical trial is registered at clinicaltrials.gov with identifier NCT02795104.

Design of a pragmatic randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for increasing cervical cancer screening uptake in a U.S. healthcare system: The STEP trial

Mailing HPV self-sampling kits to overdue individuals increases cervical cancer screening adherence; offering self-sampling to previously adherent individuals has not been evaluated in the U.S. Given heterogeneity of the U.S. health system and population, data are needed to optimize how HPV self-sampling is offered to individuals who are overdue, due after successful past screening, or have an unknown screening history. STEP is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system, designed to compare different outreach approaches for offering HPV self-sampling in populations defined by prior screening behavior (previously-adherent, overdue, or unknown screening history). Over 14 months, eligible individuals were identified through electronic medical record (EMR) data and randomized to Usual Care (UC), Education (UC + educational materials about cervical cancer screening), Direct-Mail (UC + Education + a mailed self-sampling kit) or Opt-In (UC + Education + option to request a kit), depending on screening history. The primary objective is to compare screening completion by outreach approach and screening history. Secondary objectives include evaluating incremental cost-effectiveness of outreach approaches, and identifying patient preference for, and satisfaction with, HPV self-screening, and barriers to abnormal results follow-up (measured through interviews and focus groups). The trial was designed to generate data that U.S. health systems can use to inform primary HPV screening implementation strategies that incorporate HPV self-sampling options to improve screening access, adherence, and patient satisfaction. The objective of this report is to describe the rationale and design of this pragmatic trial.

Expanding access to cancer genetic care for cancer survivors: Rationale and design for a randomized controlled trial of a chatbot-based genetic education and testing

Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial

Restricted mean survival time based on Wu-Kolassa estimator compared to Kaplan-Meier estimator

Randomized clinical trial protocol: Acceptability and feasibility of combination treatment for cervical precancer among South African women living with HIV (ACT 2)

Global efforts to eliminate cervical cancer currently focus on expanding access to human papillomavirus (HPV) vaccination and cervical screening. However, these efforts lack equal investment in the treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3), particularly among women living with human immunodeficiency virus (HIV; WLWH). This gap leaves a generation of WLWH at high risk of persistent/recurrent CIN2/3 and progression to cervical cancer, as standard surgical treatments are less effective in this population. We conducted a randomized, placebo-controlled trial to evaluate the acceptability and feasibility of combination treatment for CIN2/3 among WLWH in South Africa. As part of the trial, 180 WLWH with CIN2/3 were randomly allocated (1:1) to undergo loop electrosurgical excision procedure (LEEP) followed by self-administration of 8 doses of intravaginal 5% 5-fluorouracil (5FU) or placebo cream (one dose every other week for 16 weeks). Women were followed for 24 weeks. The primary outcomes were acceptability and feasibility (safety, tolerability, adherence, retention). Secondary outcomes included (a) regression of cervical disease to cervical intraepithelial neoplasia grade 1 (CIN1) or normal histology and (b) clearance of the high-risk HPV (hrHPV) genotype(s) detected at baseline. This feasibility trial was conducted in preparation for a large-scale effectiveness trial of LEEP combined with intravaginal 5FU for CIN2/3 among WLWH. If proven acceptable, feasible, and effective, topical 5FU may be repurposed as a low-cost, self-administered adjuvant treatment to reduce persistent/recurrent CIN2/3 and progression to cervical cancer in this high-risk population. ClinicalTrials.gov, NCT05413811.

Increasing HPV vaccine promotion by dental providers: A clinical trial protocol

Human papillomavirus is a prevalent DNA virus and the leading cause of both oropharyngeal and cervical cancer. Despite the availability of an effective vaccine (HPV-V), uptake is below national targets. A behavioral intervention, Increasing HPV Vaccine Uptake - Delivered in Dental Settings (HPV-V Uptake-DDS), was developed to support dental providers in promoting HPV-V to their patients to help close this gap. This protocol for an efficacy trial of HPV-V Uptake-DDS is designed to increase HPV-V promotion by dental practitioners, and subsequent vaccine uptake among adolescent and young adult patients. The trial will be conducted in dental clinics in a single midwestern health system utilizing a prospective, two-arm, parallel, cluster-randomized controlled design. Eighteen clinics will be randomly assigned to either the intervention or usual care. The intervention includes didactic training, clinical decision support tool embedded in the electronic dental record, tip sheet, patient education handout, and practitioner performance reports. The primary outcome is change in HPV-V promotion by practitioners. Secondary outcomes include change in HPV-V uptake by patients and changes in three behavioral mechanisms: practitioner knowledge, self-efficacy, and fear of negative consequences related to HPV-V promotion. Outcomes will be captured from the electronic health record, practitioner surveys, patient or guardian surveys, and state vaccination registries. The protocol for a clinical trial will test the efficacy of the intervention and the measurement of behavioral mechanisms of action will inform which components of the intervention of needed to address barriers in different practice settings.

Living Well: Protocol for a web-based program to improve quality of life in rural and urban ovarian cancer survivors

Ovarian cancer (OC) survivors commonly experience chronic symptoms including anxiety, depression, sleep disturbances, fatigue, physical symptoms, poor health-related quality of life (HRQOL), and a generally poor prognosis. Additionally, factors such as social isolation, stress, and depression are associated with key biological processes promoting tumor progression and poorer survival. Accessible psychosocial interventions to improve HRQOL and clinical outcomes are needed. This need is particularly true in rural settings where survivors may have less access to clinic-based support systems. The Living Well Study, a cluster-randomized Phase II multi-site clinical trial, is designed to evaluate the efficacy of a group-based, web-delivered psychosocial intervention (Mindful Living) verses a Health Promotion active control (Healthy Lifestyles) in increasing HRQOL and decreasing perceived stress (primary outcomes), depressive mood, anxiety, and fatigue (secondary outcomes) for 256 OC survivors who are <5 years post-primary therapy. Mindful Living targets key concerns of OC survivors and teaches stress reduction skills and coping strategies utilizing cognitive behavioral, mindfulness, and acceptance and commitment therapies. Healthy Lifestyles provides lifestyle information including exercise, nutrition, sleep, and other survivorship topics. Interventions consist of 11 consecutive weekly group sessions lasting 1.5-2 h led by trained facilitators and two booster sessions. Participants complete psychosocial questionnaires at baseline, post-intervention, at 6-months, and at 12-months. A subset completes bloodspots for analysis of inflammatory biology. Easily accessible psychosocial interventions addressing key concerns of OC survivors are an unmet need. The Mindful Living intervention has the potential to substantially enhance HRQOL and decrease distress in OC survivors. Trial registrationclinicaltrials.gov Identifier: NCT04533763.

A dose-reduction HPV vaccine immunobridging trial of two HPV vaccines among adolescent girls in Tanzania (the DoRIS trial) – Study protocol for a randomised controlled trial

Human papillomavirus (HPV) infection is the primary cause of cervical cancer. In 2018, the World Health Organization (WHO) Director General announced his commitment to eliminate cervical cancer, with HPV vaccination as a priority. However, the costs of setting up a multi-dose HPV vaccination programme remain a barrier to its introduction. We are conducting a randomised-controlled trial of reduced dose schedules of HPV vaccine in Tanzania to establish whether a single dose produces immune responses that will be effective in preventing cervical cancer. 930 girls aged 9-14 years in Mwanza, Tanzania, were randomised to one of 6 arms, comprising 3 different dose schedules of the 2-valent (Cervarix) and 9-valent (Gardasil-9) HPV vaccines: 3 doses; 2 doses given 6 months apart; or a single dose. All participants will be followed for 36 months; those in the 1 and 2 dose arms will be followed for 60 months. Trial outcomes focus on vaccine immune responses including HPV 16/18-specific antibody levels, antibody avidity, and memory B cell responses. Results will be immunobridged to historical cohorts of girls and young women in whom efficacy has been demonstrated. This is the first randomised trial of the single dose HPV vaccine schedule in the target age group. The trial will allow us to examine the quality and durability of immune responses of reduced dose schedules in a population with high burden of malaria and other infections that may affect vaccine immune responses. Initial results (24 months) are expected to be published in early 2021.

A Flexible Individualised ExeRcise programme for cancer patients during ChEmotherapy (FIERCE): Protocol for a randomised controlled feasibility trial

Exercise is an important tool which has been shown to help patients manage many of the side effects of their cancer treatment, reduce toxicities, and improve prognosis. The benefits of exercise have been well documented, however, performing regular exercise during treatment remains a challenge for most patients. The Flexible Individualised ExeRcise programme for cancer patients during ChEmotherapy (FIERCE) is an exercise programme that has been co-designed by healthcare professionals and people with a personal lived experience of chemotherapy. The primary aim of this study is to examine the feasibility of delivering the FIERCE programme for cancer patients during chemotherapy. The FIERCE study is a randomised controlled feasibility trial which will include 50 participants who are scheduled to receive chemotherapy for the treatment of breast, colorectal, or ovarian cancer. Participants will be randomly allocated to Group 1: FIERCE programme, or Group 2: Self-managed pedometer programme in a 2:1 ratio. Participants will be enrolled in the study for the duration of their chemotherapy treatment. The primary outcome of feasibility will be measured using a mixed-methods approach. Secondary outcomes of cardiorespiratory fitness, muscular strength, skeletal muscle mass, physical function, fatigue, and quality of life will be measured at baseline (T0) and post-intervention (T1). The FIERCE feasibility study aims to explore if a flexible, individualised exercise programme will support individuals to be active during chemotherapy treatment. If proven to be feasible, a large-scale randomised controlled trial will be undertaken focusing on the efficacy of the FIERCE programme on different health outcomes. The study is registered with ClinicalTrials.gov, registration number: NCT06280885.

Design of a pragmatic trial integrating human papillomavirus (HPV) self-sampling into primary care to reduce cervical cancer screening disparities in Somali American individuals: The Isbaar project

Somali American individuals have lower cervical cancer screening rates than the U.S. general population. Offering HPV self-sampling in primary care clinics could increase screening rates in Somali American individuals by addressing screening barriers. The Isbaar Project is a Hybrid Type 2 effectiveness-implementation study of a patient-centered, culturally tailored HPV self-sampling intervention for Somali American individuals. Guided by the Consolidated Framework for Implementation Research and Social Cognitive Theory, we conducted focus groups with Somali American individuals, and interviews with clinicians and clinic staff to inform refinement and development of implementation strategies. HPV self-sampling was then implemented as a usual care screening option at 3 community-based primary care clinics in Minneapolis, Minnesota in February 2023. The primary objective is to assess the effect of implementing in-clinic HPV self-sampling on screening completion in Somali American individuals. The secondary objective is to assess the effect of implementing HPV self-sampling on screening completion in all patients. Using difference-in-difference methods, we will evaluate changes in screening rates one-year pre and post implementation and compare changes with control clinics followed over the same time period. Using RE-AIM, we will conduct a post-implementation mixed methods analysis of processes and strategies needed to successfully implement HPV self-sampling in primary care. The study was designed to evaluate a real-world in-clinic HPV self-sampling intervention for Somali American individuals, generating data on both effectiveness and implementation applicable to other community-based clinics in the U.S. The objective of this report is to describe the rationale and design of the study.

Use of real-world data for HPV vaccine trial follow-up in the Nordic region

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.

A multi-site trial of an electronic health integrated physical activity promotion intervention in breast and endometrial cancers survivors: MyActivity study protocol

Despite the known benefits of moderate-to-vigorous physical activity (MVPA) for breast and endometrial cancer survivors, most are insufficiently active, interventions response is heterogeneous, and MVPA programming integration into cancer care is limited. A stepped care approach, in which the least resource-intensive intervention is delivered first and additional components are added based on individual response, is one strategy to enhance uptake of physical activity programming. However, the most effective intervention augmentation strategies are unknown. In this singly randomized trial of post-treatment, inactive breast and endometrial cancer survivors (n = 323), participants receive a minimal intervention including a Fitbit linked with their clinic's patient portal and, in turn, the electronic health record (EHR) with weekly feedback delivered via the portal. MVPA progress summaries are sent to participants' oncology team via the EHR. MVPA adherence is evaluated at 4, 8, 12, 16 and 20 weeks; non-responders (those meeting ≤80% of the MVPA goal over previous 4 weeks) at each timepoint are randomized once for the remainder of the 24-week intervention to one of two "step-up" conditions: (1) online gym or (2) coaching calls, while responders continue with the minimal Fitbit+EHR intervention. The primary outcome is ActiGraph-measured MVPA at 24 and 48 weeks. Secondary outcomes include symptom burden and functional performance at 24 and 48 weeks. This trial will inform development of an effective, scalable, and tailored intervention for survivors by identifying non-responders and providing them with the intervention augmentations necessary to increase MVPA and improve health outcomes. Clinical Trials Registration # NCT04262180.