Heart failure clinical trial enrollment at a rural satellite hospital

Abstract

Introduction:

Heart failure is a clinical condition that notably affects the lives of patients in rural areas. Partnering of a rural satellite hospital with an urban academic medical center may provide geographically underrepresented populations with heart failure an opportunity to access to controlled clinical trials (CCTs).

Methods:

We report our experience in screening, consenting and enrolling subjects at the VCU Health Community Memorial Hospital (VCU-CMH) in rural South Hill, Virginia, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospitals (VCU-MCV), Richmond, VA. Subjects were enrolled in a clinical trial sponsored by the National Institutes of Health and assigned to treatment with an anti-inflammatory drug for heart failure or placebo. We used the electronic health record and remote guidance and oversight from the VCU-MCV resources using a close-loop communication network to work with local resources at the facility to perform screening, consenting and enrollment.

Results:

One hundred subjects with recently decompensated heart failure were screened between January 2019 and August 2021, of these 61 are enrolled to date: 52 (85%) at VCU-MCV and 9 (15%) at VCU-CMH. Of the subjects enrolled at VCU-CMH, 33% were female, 77% Black, with a mean age of 52 ± 10 years.

Conclusion:

The use of a combination of virtual/remote monitoring and guidance of local resources in this trial provides an opportunity for decentralization and access of CCTs for potential novel treatment of heart failure to underrepresented individuals from rural areas.

1. Introduction

Heart failure is a leading cause of death in the United States. The American Heart Association predicted that there are 6.3 million people with heart failure in the United states [1]. There are an estimated 23 million people with heart failure world wide [2]. According to the United States Federal Drug Administration (FDA) drug trial snapshot summary report (2015–19), cardiovascular diseases account for the highest number of clinical trials participants [3]. Despite this, cardiovascular clinical trials are affected by a lack of diversity inclusive of minority subjects (i.e. Black Americans 4%), rural residents, and low income individuals [3]. Clinical trials are not available in rural areas for a variety of reasons and the lack of geographically accessible clinical trial sites impedes participation especially of rural residents and such a population is consequently underrepresented in clinical trials [4,5]. We herein report our experience of screening, consenting, and enrolling subjects in a clinical trial sponsored by the National Institutes of Health (Interleukin-1 blockade in recently decompensated heart failure) at a rural satellite hospital using tele-medicine, remote monitoring, and institutional oversight.

2. Methods

2.1. Clinical setting

VCU Health Community Memorial Hospital (VCU-CMH) is a 70-bed community hospital located in South Hill, VA, USA. It is a part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospital (VCU-MCV). VCU-CMH serves the rural and underserved population from southern Virginia and northern North Carolina, a geographical area that is designated as healthcare shortage area by the Health Resources and Service Administration (HRSA) [6,7]. VCU-CMH primarily serves the Mecklenburg, Lunenburg, and Brunswick counties in the state of Virginia and Halifax, Warren, and Northampton counties of the state of North Carolina. It serves to a total population of one hundred thousand, which includes females (51.3%), persons 65 years or older (25.9%), Black Americans (34%), and Hispanic or Latino or other ethnic minorities (4%) [8]. The geographical area includes an economically disadvantaged population with 20% persons below the poverty line with an annual household income of twenty thousand dollars or less [8].

2.2. Clinical trial

We describe an example of a controlled clinical trial (CCT) activated at VCU-CMH entitled REDHART2 (Recently Decompensated Heart failure Anakinra Response Trial 2) (ClinicalTrials.gov Identifier: NCT03797001). The REDHART2 study is a phase II clinical trial of anakinra or placebo to improve aerobic exercise capacity in subjects with recently decompensated systolic heart failure. We used local resources, remote monitoring, and oversight from the lead institution VCU-MCV. A close loop communication network was established using shared electronic health records, office sponsored program and institutional review board.

REDHART2 randomizes subjects in a 2:1 ratio to either Anakinra group or placebo: 68 subjects will be randomized to treatment arm who will receive Anakinra 100 mg daily for 24 weeks, and 34 subjects will be randomized to placebo arm for 24 weeks, in addition to standard of care per guideline directed medical therapy (GDMT) which may include diuretics, β-adrenergic receptor blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, neprilysin inhibitors, aldosterone blockers, isosorbide dinitrate, hydralazine, digoxin, ivabradine, aspirin, and statins. The primary objective of REDHART2 is to study the effects of IL-1 blockade with anakinra on parameters of aerobic exercise capacity (peak VO2) using cardiopulmonary exercise test (CPX) after 24 weeks of active treatment. Secondary objectives will study the effects of anakinra on inflammatory biomarkers, structural and functional echocardiographic data, and non- invasive hemodynamics.

2.3. Institutional review board oversight

The study was reviewed and approved by the VCU Institutional Review Board (IRB) in Richmond, VA. The IRB protocol listed both VCU-MCV and VCU-CMH as locations for screening, and recruitment.

2.4. Research team

The principal investigators and main research coordinators are located on the VCU-MCV Hospital campus, and they managed a team of investigators and coordinators locally. Two physicians (a cardiologist and an internist) participated as investigators at VCU-CMH. They were trained using videoconferencing by the principal investigators. The team meets virtually periodically. All members of the team had remote access to the shared electronic health record (EHR) for VCU-MCV and VCU-CMH Hospitals.

2.5. Coordination and nursing

The principal coordinators and the principal investigators were responsible for communicating with the study team at VCU-CMH. Nurses at VCU-CMH were trained by research nurses from the main research team at VCU-MCV using virtual meetings.

2.6. Screening

VCU-CMH served the role of a satellite referral center for the clinical trial enrollment. Subjects are identified by several means, direct patient contact by the treating physicians, and manual screening of the new daily admission list on the EHR by the research team. A physician on the research team performs a thorough clinical assessment and chart review of enrollment to evaluate for all the inclusion and exclusion criteria. In the scenario any pertinent information needed to determine eligibility may be missing, additional testing may be performed only after the patient has provided informed consent. Cost of the additional testing was billed to the study account.

2.7. Recruitment and consenting

After confirmation of inclusion and exclusion criteria, the subject is approached either by the one of the investigators at VCU-CMH or remotely via virtual means by an investigator of VCU-MCV. A paper copy of the IRB approved informed consent form was provided to each patient, including those approached remotely. Subjects are approached either in person or using a secure connection on a tablet device equipped with a video-camera. After the patient has sufficient time to review the informed consent form, and have any questions answered, the patient is asked to sign the form. An original copy of the consent is stored in the EHR and provided to the patient.

2.8. Alternate consent group

The subjects who are eligible to enroll in the study but decline to participate were asked to sign an alternative consent that allowed the research team to access the EHR for a period of six months after the enrollment. A follow up telephone call is made at the end of six months period if needed to ascertain vital status and incidence of new events. This alternate consent group provides an estimate of the event rate in a group free of other research interventions.

2.9. Study design and follow-up

The screening assessment and highly sensitive C-reactive protein (hsCRP) testing is done at VCU-CMH. After screening and consenting at VCU-CMH, a baseline clinical visit is performed within two weeks of discharge from the hospital at VCU-MCV. During the baseline visit, scheduled at VCU-MCV, a clinical assessment, medication reconciliation, cardiopulmonary exercise testing, echocardiography, non-invasive hemodynamics/bioimpedance, safety laboratory profile (complete blood count, and renal function), and biomarkers including highly sensitive c-reactive protein (hSCRP), and N-terminal pro b-type natriuretic peptide (NT-proBNP), and investigational therapy dispensing are performed.

A short-term clinical evaluation is performed in visit 1.5 (14 ± 3 days of enrollment), to determine tolerability of the treatment and side effects, medication reconciliation and completion of a complete blood cell count with differential and basic metabolic panel is performed at VCU-CMH or VCU-MCV.

Subsequent visits are scheduled at VCU-MCV, including visit 2 (42 ± 7 days), visit 3 (84 ± 7 days) and visit 4 (128 ± 14 days). These visits include a clinical safety evaluation as well as assessment of the endpoints as summarized in Table 1. Additional visits are scheduled as needed at VCU-CMH or VCU-MCV. Visits 1, 2, 3, and 4 are completed in the clinical research unit (CRU) at VCU-MCV. Subjects are reimbursed with a $50 gift card to compensate for the travel related expenses for each follow up visit. Additional research only biomarkers are stored for single batch analysis in future at the end of the study. Prior to each CPX, a Kansas City Cardiomyopathy Questionnaire (KCCQ), the Duke Activity Status Index (DASI) questionnaires, and the Patient Health Questionnaire-9 (PHQ-9) is completed by all study subjects [8–10].

Table 1.

Schematic representation of study visits and locations.

	Screening (≤14 days from discharge)	Visit 1 (Baseline)	Visit 1.5 (14 ± 3 days)	Visit 2 (42 ± 7 days)	Visit 3 (84 ± 7 days)	Visit 4 (128 ± 14 days)	Urgent visit (as needed)
Location	VCU-CMH	VCU-MCV	VCU-CMH or VCU-MCV	VCU-MCV	VCU-MCV	VCU-MCV	VCU-CMH or VCU-MCV
Screening	X
Consenting	X
Clinical assessment *	X	X	X	X	X	X	X
Biomarkers and safety labs		X	X	X	X	X	X
Investigational therapy dispensing		X		X	X
CPX, echo, BIA		X		X	X	X

Abbreviations: BIA = bio-impendance analysis; CPX = cardiopulmonary exercise testing; VCU-CMH = Virginia Commonwealth University Community Memorial Hospital; VCU-MCV = Virginia Commonwealth University Medical College of Cardiology campus.

^*Clinical assessment includes history and physical, medication reconciliation, and assessment of adverse events.

2.10. Investigational treatment

Anakinra or placebo (vehicle) is dispensed in small syringes 0.67 mL in volume. It is provided to the patient for daily subcutaneous injection. The syringes for anakinra or placebo are dispensed in identical syringes so that neither the patient nor the physician will be able to distinguish between anakinra or placebo. Adherence to the investigational treatment is addressed by count of syringes and completion of all study visits.

2.11. Adverse effect monitoring

Subjects participating in the study are encouraged to contact the research team at any time with concerns or perceived changes in health status. Disease related data including changes in symptoms (or new symptoms), functional capacity, vital signs (including weight), renal function, or any significant changes in medications are assessed in each visit. All adverse effects (AEs) must be graded for severity and relationship to study product. A dedicated AEs form is used to capture pertinent information about the event. Monitoring for AEs and reporting per regulations is regulated by the team of investigators at CRSU.

2.12. Enrollment results

The target enrollment is set for 102 subjects, and we anticipated to have 50% of subjects to be of historically underrepresented minorities. Enrollment was activated on January 2, 2019, and as of August 31, 2021, we have enrolled 61 subjects. We enrolled 9 (15%) patients from VCU-CMH, of which 3 (33%) were females, and 7 (77%) were self-referred to as Black or African Americans. Mean age was 52 ± 10 years (Table 2).

Table 2.

Clinical and demographic characteristics of patients enrolled.

	VCU-MCV	VCU-CMH
N	52	9
Age, years	57 (11)	52 (10)
Males, N (%)	32 (62%)	6 (67%)
Race
White, N (%)	13 (25%)	2 (22%)
Black, N (%)	39 (75%)	7 (78%)

2.13. Billing

Billing coordination was managed by the Clinical Research Unit at the VCU-MCV Hospital and facilitated as a single business entity and using a single EHR.

3. Discussion

Telemedicine, mobile healthcare teams, supply-chain management, use of local resources, institutional oversight, and safety monitoring has been increasingly advocated for as a model for decentralization of clinical trials [11]. We recently reported our experience of decentralizing CCTs using a similar model during the COVID-19 pandemic [12]. Decentralization of CCTs in our previous experience was challenged by the immature digital infrastructure, limited experience with the approach and the perception of the regulatory barriers [12]. Effective use of telemedicine facilitated the expansion of the CCT beyond the geographical, and economic barriers amidst a global pandemic. Herein we share our experience of decentralization of a heart failure CCT to a rural-satellite hospital using tele-medicine. We were able to include an otherwise underrepresented patient population and provide access to novel therapy to the underserved. (See Fig. 1)

Fig. 1.

Schema of patient recruitment for the REDHART2 trial at a rural satellite hospital (VCU-CMH). Utilization of remote working modalities and training of local manpower provided an opportunity for decentralization and access of controlled clinical trials. Legend. REDHART2: Recently Decompensated Heart failure Anakinra Response Trial 2. EHR: electronic health record. VCU-CMH: VCU Health Community Memorial Hospital. VCU-MCV: VCU Health Medical College of Virginia Hospital.

The ongoing REDHART2 trial was preceded by the recently completed pilot REDHART study [13], supported by a R34 NHLBI pilot clinical trial grant. It randomly assigned 60 subjects with recently decompensated systolic heart failure to one of 3 strategies: 1) short-term treatment with anakinra for 14 days followed by placebo for 10 weeks; 2) longer-term treatment with anakinra for 12 weeks; 3) placebo for 12 weeks [15]. An additional group of eligible subjects who declined participation in the study was enrolled in an observational study to evaluate the rate of heart failure hospitalizations. Anakinra treatment for 12 weeks led to a significant improvement in peak aerobic exercise capacity (peak VO2), whereas anakinra treatment for 2 weeks did not. No significant changes were seen in placebo. The hospital readmission rate at 6 months was 5% in anakinra 12-week treatment group, 30% in the placebo group, 32% in the anakinra 2-week group, and 35% in the observational group of eligible subjects who were not randomized to treatment. The REDHART2 study is designed to expand and confirm the beneficial effect of sustained anakinra treatment (24 weeks). The investigators eagerly await to see the results.

Traditionally there has been an urban-rural difference in between mortality, morbidity, access to care, and cost of care, in several clinical conditions [14] including heart failure [15]. This disparity in healthcare outcomes is attributable to several public health factors including lower income, educational level, less medical insurance, and higher prevalence of risk factors in rural areas [13]. Further rural patients have limited access to novel therapies and CCTs.

Trial execution through local health providers, remote monitoring, and the use of technology can bridge the geographical boundaries and barriers to access healthcare. The enrollment results demonstrate an accelerated enrollment and representation of a diverse community that is otherwise not represented in CCTs and enhancing the heterogeneity. Such an initiative also widened the outreach of large institutions and improvised access to care. Telemedicine, and uniform access to EHRs were the decisive factors in our project. Telemedical management systems have been used in facilitating care of heart failure patients [16,17]. The current guidelines recommend remote monitoring and interrogation of cardiac implantable electronic devices (CIED), combined with annual in person evaluation [18]. In execution of this trial for patients with CIED care was coordinated with electrophysiology department, and data from remote monitoring of devices was used whenever appropriate. Considering the increasing role of telemedicine, it can be effectively used in conductance of CCTs, recruitment and follow-ups. Enrollment of patients from rural areas in our experience was challenged by the geographical distance from the VCU-MCV campus as the main clinical site for baseline and follow up visits. While a travel reimbursement model was used, establishing satellite research facilities, and mobile research clinics in rural areas can facilitate easy execution of CCTs.

4. Conclusion

The use of a combination of virtual/remote monitoring and guidance of local resources in this trial provides an opportunity for decentralization of clinical trials. It can expand the access to the individuals often underrepresented because of barriers to access controlled clinical trials of potential novel treatment of heart failure.