The impact of COVID-19 on clinical research: the PIPPRA and MEDRA experience

Protocol design

The PIPPRA feasibility study was designed following extensive work in intervention development, guided by the Medical Research Council complex intervention framework (Craig et al., 2008). This development work included systematic reviews, (Larkin & Kennedy, 2014; Larkin et al., 2016a; Larkin et al., 2015a; Larkin et al., 2015b), physical activity monitor validation, and qualitative research with people who have RA and healthcare professionals (Larkin et al., 2016a; Larkin et al., 2016b; Larkin et al., 2017). The aim of this pilot RCT was to examine the feasibility of a physiotherapist-led, behaviour change theory informed, physical activity intervention to promote physical activity in people who have RA who have low levels of physical activity. The primary deliverables of the PIPPRA pilot study were to determine the rate of recruitment to the study and the acceptability of the intervention to participants as well as test the feasibility of the intervention on disease focused outcome measures.

The MEDRA project was a 12-week pilot randomised, controlled dietary intervention study in Irish adults living with RA. The MEDRA project aims to explore the effect of implementing either a Mediterranean type diet (MED Diet) or the Irish Healthy Eating Guidelines on the inflammatory profile, disease activity and quality of life in adults living with RA in Ireland. The MEDRA project aimed to provide data on the habitual dietary intakes of adults with RA in Ireland and their baseline adherence to key components of either the MED Diet or the Healthy Eating Guidelines, in the absence of such data in literature to date (Raad et al., 2021). MEDRA also aimed to evaluate the effects of implementing the traditional Mediterranean diet adapted for the Irish culture compared to the Irish Healthy Eating Guidelines on inflammatory profile, disease activity and quality of life of adults with RA. With its specific design, the MEDRA study aimed to identify the attitudes, beliefs, and perceived barriers towards adhering to a MED Diet in an Irish context and under dietetic supervision.

This paper seeks to outline the experience of two clinical rheumatology research projects in the Republic of Ireland across the first year (March 2020 – March 2021) of the COVID-19 global pandemic.

Inclusion criteria

Inclusion criteria for PIPPRA were as follows; participants aged 18 years or older, rheumatologist confirmed diagnosis of RA, independently mobile and low levels of physical activity as categorised on the Godin-Shephard Leisure-time Physical Activity Questionnaire (Godin, 2011). PIPPRA exclusion criteria were use of a mobility aid, not fluent in English, already physically active as per the Godin-Shephard Leisure-time Physical Activity Questionnaire (Godin, 2011). Eligible participants for the MEDRA study included those who were aged ≥ 18 years with a definite diagnosis of RA according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria (Aletaha et al., 2010). Participants were excluded if they have commenced any nutritional supplements or a new dietary regime in the month prior to study enrolment. Women who were pregnant, breastfeeding or planning to become pregnant were also not included.

Participants for both the PIPPRA and MEDRA projects were originally recruited from two hospital rheumatology clinics, one urban and one rural. Both assessment and intervention sessions for PIPPRA and MEDRA were to be delivered in person at a clinical research facility, located in the grounds of a large urban hospital, as per the study protocol.

Recruitment and assessment

The target recruitment rate for PIPPRA was four participants per month for one year (N=48). A target of 40 participants, with 20 participants in both the control and intervention groups, for completion of the study was set. This sample size was expected to provide sufficient data to meet the primary outcomes of the PIPPRA project. A definitive sample size of a large-scale RCT will be determined from the results of this trial. PIPPRA recruitment commenced on 1^st October 2019. Assessments were conducted at baseline, eight and 24 weeks (total assessments N=144). Assessments were conducted by independent assessors (LL – physiotherapist; MR - research manager) who were blinded to participant allocation. Assessments consist of a battery of self-report questionnaires (self-report physical activity - Yale Physical Activity Survey; behaviour change - Theory of planned behaviour questionnaire; quality of life - Quality of Life in Rheumatoid Arthritis; pain – visual analogue scale over past seven days; fatigue - Bristol RA Fatigue Multi-dimensional Questionnaire; functional ability - Health Assessment Questionnaire; sleep – Pittsburgh Sleep Quality Index), objective physical activity measurement using the ActivPAL™ activity monitor and disease activity (Disease Activity Score-28). DAS-28 requires blood sample collection for erythrocyte sedimentation rate (ESR) to calculate the DAS-28 score. Blood sample collection was conducted by a research nurse. Assessments for PIPPRA were to be completed by March 2021.

Recruitment for MEDRA commenced on 1^st February 2020. The target sample size was (N=44), allowing for a 10% drop-out rate over the 12-week study period. Participants in the MEDRA study were expected to attend three face-to-face appointments at baseline (week 0), mid-intervention (week 6) and post-intervention (week 12). All study appointments were conducted with the study Registered Dietitian (RD) at the same research facility as the PIPPRA study. Study appointments for both diet groups included a nutritional educational session on how to adopt the key principles of either target diets, anthropometric measurements including height, weight, waist circumference and mid-upper arm circumference as well as blood sampling for ESR, C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α), interleukin 6 and 10, performed by a qualified research nurse. Given that the recruitment of participants and study appointments were to run simultaneously; it was expected that data collection for the MEDRA study would be completed by October 2020.

Intervention

PIPPRA participants were randomised to the intervention or control group. Randomisation was conducted independently, by a biostatistician (AS) and project research assistants (AM, TP). Participant allocation was concealed to both assessors and sessional physiotherapists. Intervention sessions were delivered by two physiotherapists (LH, LK). Sessional physiotherapists were blinded to assessment data. The intervention group received four 1:1 60-minute sessions (total target intervention sessions N=80). The intervention was delivered over eight weeks, with one session in Week 1, Week 3, Week 5, and Week 7. Intervention and control groups receive a physical activity information leaflet, which outlined the physical activity guidelines for people who have RA (Rausch Osthoff et al., 2018).

MEDRA participants were randomly allocated to either a MED Diet group or the Healthy Eating group using a permuted block randomisation scheme with 1:1 ratio allocation. Randomisation was conducted by an independent statistician at the University of Limerick, who was not involved in the conduct of the RCT. To guarantee concealment of allocation, participants were randomised once written informed consent has been obtained. As with most dietary intervention studies and for the purpose of the MEDRA study, blinding to intervention was not possible. All study appointments were to be conducted with the study Registered Dietitian (RD) at the same research facility as the PIPPRA study. Study appointments for both diet groups included a nutritional educational session on how to adopt the key principles of either diet intervention. Participants in both intervention groups were provided with printed resources to inform participants of the principles of the assigned diet as well as food hampers to demonstrate each eating pattern.

PIPPRA amendments

The PIPPRA project was paused for four months from April 2020 to August 2020. The PIPPRA project resumed on a face-to-face basis in August 2020. PIPPRA participants attended for assessment and intervention face-to-face until late October 2020. From October 2020 onwards participants were hesitant to attend face-to-face sessions, coinciding with the Republic of Ireland’s second lockdown which commenced on 22^nd October 2020. In December 2020, the PIPPRA project sought ethical and funder approval to move assessments and intervention delivery to virtual platforms, or telephone audio where participants were unable/unwilling to access a virtual platform. Virtual sessions mimicked in-person sessions in questioning and discussion style. Due to project time and personnel constraints piloting of virtual platform assessment and intervention delivery was not feasible. The proposed virtual platform was Microsoft Teams. Subsequently participants requested to use other virtual platforms, namely Zoom and Whatsapp, to access video calls, as the participants were more familiar with accessing and using these virtual platforms. These requests were facilitated. Access to virtual platforms proved challenging for some participants who were not familiar with videocalls. To enhance engagement, the PIPPRA research assistants (AM, TP) conduct a trial video call with intervention participants, prior to session 1 of their intervention. Participants expressed a preference for phone audio calls for assessments and this request was then facilitated. Changing assessments to a telehealth/audio platform also required revision in the assessment methods. The DAS-28 was removed from the assessment, due to an inability to collect a blood sample. The ActivPAL activity monitor was posted to participants, instead of being applied by the assessor (LL) in a face-to-face assessment. The postal package included an information leaflet on ActivPAL application and wear instructions and Tegaderm for application. Participants were advised on ActivPAL application by the assessor (LL) during the assessment. ActivPALs were set to record from the date and time of the assessment. Participants returned the ActivPAL by post to the assessor (LL) and were reimbursed for postal costs via vouchers. Thus, there was minimal additional burden on ActivPAL application and return.

MEDRA amendments

Recruitment and assessment of participants became very difficult given the ongoing COVID 19 public health situation. In addition, many concerns that were raised by recruited participants regarding their discomfort at the idea of coming to the hospital for appointments. Therefore, the MEDRA research team decided to modify the study design in August 2020 and to deliver the dietary intervention via telehealth methods through Zoom meetings. The rationale for shifting to a web-based/telehealth approach is that it is a safe, convenient, and potentially the most inclusive way to collect data and capture diverse dietary perspectives across Ireland while avoiding face-to-face contact with participants. Shifting to telehealth, however, also meant rethinking those primary outcome measures of the study that involved blood sampling and anthropometric assessment. In November 2020 and upon obtaining ethical approval for the new study design, recruitment of study participants resumed through a collaboration with the patient organisation ‘Arthritis Ireland’ and through their social media platforms. This new collaboration facilitated access to prospective participants. Recruitment through outpatient rheumatology clinics in University Hospital Limerick resumed through poster advertisement only.

Recruitment

PIPPRA recruitment commenced at rheumatology clinics on 1^st October 2019. MEDRA recruitment commenced at rheumatology clinics on 1^st February 2020. Recruitment at rheumatology clinics ceased on 3^rd March 2020. At the time of recruitment cessation, n=48 participants had consented to participation in the PIPPRA study. PIPPRA had reached its recruitment target in six months. MEDRA had recruited 18 participants at the time of recruitment cessation. MEDRA switched from face-to-face to online recruitment with 20% (n=35/44) deviation in recruitment.

Assessments

As of December 2020, n=20 participants have commenced in the PIPPRA study, n=16 were awaiting baseline assessment (attempting to schedule), n=6 withdrew and n=6 were lost to follow-up prior to baseline. Pre-trial amendments, the PIPPRA trial protocol planned for the delivery of n=55 assessments for participants who had commenced in the study. N=22 assessments were conducted between October 2019 and March 2020 (Figure 3). N=5 assessments were conducted between August and October 2020 (Figure 3). No assessments occurred in November-December 2020 due to participant hesitancy in attending for assessment with increased public health restrictions. Participants invited to attend assessments during this two month period declined in-person assessment at that time and cited the concern about COVID-19 as the reason for declining attendance. The impact of COVID-19 restrictions resulted in n=33 (60%) negative deviations from assessment protocol.

Figure 3. PIPPRA assessments completed pre and during the COVID-19 pandemic.

Source for daily COVID-19 case data: #COVIDWATCHIRL via https://covidwatcheu-npa.shinyapps.io/covid/?covidtrends.

PIPPRA, Physiotherapist-led Intervention to Promote Physical Activity in Rheumatoid Arthritis; COVID-19, coronavirus disease 2019.

For MEDRA n=18 participants who had consented to participation at face-to-face clinics were awaiting baseline assessments in March 2020. Of these n=18 participants, only n=2 agreed to proceed with telehealth delivery of the dietary intervention (Figure 4). N=16 were lost, primarily due to limited technological literacy. The two participants who agreed to participate in the telehealth delivery of the study had full access to a smartphone and the internet. N=42 were recruited through Arthritis Ireland, the national arthritis patient organisation, between November 2020 and January 2021. All recruited participants had full access to a laptop or a smartphone. No assessment sessions were conducted in 2020, resulting in a 100% deviation from protocol.

Figure 4. MEDRA recruitment.

MEDRA, MEDiterranean diet in Rheumatoid Arthritis; COVID-19, coronavirus disease 2019.

Interventions completed

Trial protocol planned for the delivery of n=36 intervention sessions for participants who had commenced in the PIPPRA study. N=26 intervention sessions were delivered between November 2019 and March 2020. N=6 intervention sessions were conducted between August and October 2020. No intervention delivery occurred in November-December 2020 due to participant hesitancy in attending for intervention with increased public health restrictions. The impact of COVID-19 restrictions resulted in n=10 (27%) negative deviations from intervention delivery protocol. In the MEDRA project, no intervention sessions had been completed by March 2020. No intervention sessions were conducted in 2020, resulting in a 100% negative deviation from MEDRA intervention protocol. N=40 intervention sessions were conducted between January and March 2021, a one-year deviation from original protocol.

The data presented outlines the progress of the PIPPA and MEDRA trials in the first year of the COVID-19 pandemic. The final CONSORT flow diagrams for both trials are included to provide an overall view of participant flow through the PIPPRA (Figure 5) and MEDRA (Figure 6) projects which completed in 2022 and 2023 respectively.

Figure 5. PIPPRA CONSORT 2010 Flow Diagram.

Figure 6. MEDRA CONSORT 2010 Flow Diagram.

Summary of main findings

This paper presents the impact of the COVID-19 pandemic on two rheumatology clinical research projects. Significant challenges arose during the first ten months of the projects that necessitated changes to original trial protocols, which resonates with the experiences of clinical research globally (Bierer et al., 2020). This impacted trial recruitment, participant assessment and intervention delivery and necessitated changes in trial protocol to ensure that clinical research could progress in a safe and acceptable manner for both research participants and trial staff. Our paper provides an insight into the trial management issues that arose in conducting clinical research during a global pandemic. These issues spanned the entire research project, from recruitment, to assessments and intervention delivery.

Comparison with existing literature

Among our patient population of people living with RA, participant hesitancy and/or fear about attending face-to-face clinical research session in a clinical research facility located adjacent to an acute hospital proved to be a significant barrier to proceeding with PIPPRA and MEDRA as per the original trial protocols. COVID-19 fear has been reported to impact mental health through traditional and social media coverage which is unrelenting (Su et al., 2021). The impact of COVID-19 on mental health has been widely reported, with some research reporting that it has negatively impacted approximately 70% of people living with chronic conditions (Chudasama et al., 2020). Indeed, the authors of that global survey also found that changes in healthcare services for health issues other than COVID-19 had moderate or severe effects on patients since the COVID-19 outbreak (Chudasama et al., 2020). Worry about contracting COVID-19 was high amongst people with arthritis, with a higher proportion of self-isolation amongst people who have arthritis due to their condition compared to others their age (Glintborg et al., 2021). In our experience, some of the MEDRA and PIPPRA participants’ hesitancy and COVID-19 fear around engaging in clinical research was influenced by family members, including adult children. This experience is evidenced elsewhere and demonstrates that fear of COVID-19 affected access to healthcare during the pandemic (Smolić et al., 2023).

Strengths and limitations

This novel paper outlines the process of how two clinical research trials responded to the challenge presented by the COVID-19 pandemic to the conduct of clinical research. The decision-making process and amendments implemented to the PIPPRA and MEDRA trials are clearly outlined. The strategies implemented provide information for future clinical research and highlight the importance of risk assessment and risk management strategies in the planning of clinical research trials. The authors could not have foreseen the impact a global pandemic would have on the PIPPRA and MEDRA studies. However, the experiences of both trials highlight the need to prepare for alternative methods of trial delivery, and to plan for the implications of moving a face-to-face trial to telehealth and vice versa. This paper addresses the first 10 months of the global pandemic and does not report on the effectiveness of amendments made to the PIPPRA and MEDRA trials. The results of the impact of amending both trials will be analysed and reported in the future, at which point the authors will evaluate if the steps taken were appropriate and effective.

Implications for research and policy

Recruitment strategies for both studies required amendments. It became apparent for the PIPPRA and MEDRA studies that participants who had originally consented to participation due to the pandemic were uncontactable or unwilling to engage with telehealth delivery of the study. This was particularly evident in the MEDRA study where 89% (n=16) withdrew from telehealth delivery of project. Thus, additional recruitment strategies were implemented. Virtual recruitment has significant a benefit; that recruitment is not restricted to one locality or rheumatology service. This could be considered a more inclusive recruitment strategy and result in greater transferability of results from the MEDRA study. In PIPPRA’s case, additional recruitment occurred via clinicians engaged in the rheumatology service clinics who referred interested patients to the PIPPRA research team. In February 2021, face-to-face clinics were limited to high priority cases and operated at just 25% capacity of a typical clinic. Most patients attending such clinics did not meet PIPPRA study inclusion criteria. Telephone clinics were run by the rheumatology clinical nurse specialists who assisted the PIPPRA team in study recruitment. This experience demonstrates the importance of effective and collaborative research-clinical partnerships (Albert et al., 2019), where clinicians act as important gatekeepers to potential research participants. In MEDRA, although limited to people with access to social media accounts, recruitment through social media platforms led to a larger reach of people living with RA and recruitment was highly successful. Thus, consideration must be given to recruitment locations for future research, given that those who engage in clinical research studies may be dependent on this recruitment site and also the mode (face-to-face or telehealth) by which clinical research is conducted. Furthermore, those who engage with clinical research are likely to be highly interested and motivated to engage, as demonstrated by Scanlonet al. (2021) who found that trust and attitude were predictive of research participation. In contrast fears associated with research risks, work responsibilities, and fear of discovering a serious illness have been cited as barriers to participation in enrolment in rheumatology clinical research (Sandhu et al., 2022). Thus transferability of results must be considered in that regard.

Protocol and method changes were required in both PIPPRA and MEDRA. Such changes required ethical approval, and in the case of PIPPRA, funder approval also. In the Republic of Ireland, local research ethics committees responded promptly to requested changes to previously approved clinical research trials. The need to amend trial protocols was recognised and indeed advocated for internationally (European Commission et al., 2020). The required changes brought new trial management challenges. As previously stated, participant withdrawal due to no not wanting to or not being able to engage with virtual clinical research was an issue. Some previously enrolled participants in the PIPPRA study requested telephone audio calls only, which proved difficult for participants who were in the intervention group. From an assessment perspective, the collection of objective physical activity data was facilitated through the posting of the ActivPAL3™ activity monitor to participants. This required a reallocation of budget funds, as it was not a project cost that was required in the original trial protocol.

Communicating with participants posed a significant challenge for the PIPPRA project. For example, some participants had consented and enrolled in January/February 2020 but were difficult to contact after the official resumption of the project in August 2020. This included participants not responding to phone calls or text messages or phone numbers no longer being in use. This aligns with the experience of communicating with patients in clinical practice during the pandemic. Bos et al. (2021) reported that 57% of rheumatologists in Denmark had difficulty in reaching patients (i.e., phone not being answered). It is plausible that patient priorities have changed during the global pandemic. Participating in a clinical research trial may have been a priority in early 2020; however, competing demands, e.g. working from home, managing home-schooling, pandemic fatigue or simply lack of interest due to the wider situation, may have impacted participant motivation to engage with the PIPPRA and MEDRA studies.

Trial assessments required changes due to the switch from face-to-face assessment to phone/telehealth assessment. The DAS28 was removed from both the PIPPRA and MEDRA assessments, as examination of swollen or tender joints and collection of blood samples to calculate the score was not possible. The consequence of this is that an objective measure of disease activity will be absent from the analysis of effectiveness of each intervention on disease activity and should be examined in future research if possible. The challenges of conducting such assessments have been acknowledged from the clinical practice perspective by the American College of Rheumatology, who highlighted the practical difficulties for rheumatology clinicians due to the lack of a direct musculoskeletal exam as well as inability to remotely monitor changes in the musculoskeletal exam over time (American College of Rheumatology, 2020). Challenges that accompany the use of telehealth/telehealth sessions included the assessment of RA disease activity and inflammatory status, both of which are fundamental to the management of RA and are frequently included as outcome measures in rheumatology clinical research studies. However, the inclusion of patient-reported outcomes (PROs) can greatly enhance a telehealth assessment. The use of PROs has this far been a positive experience in the PIPPRA and MEDRA projects and is easily conducted via telephone and telehealth assessments. PROs are a form of clinical outcome assessment method that complement biomarkers, measures of morbidity (e.g. stroke, myocardial infarction), burden (e.g. hospitalisation), and survival that are used and reported in clinical trials and non-randomised studies (FDA, 2018). The use of PROs in clinical research has the potential to benefit patients and the wider society (Rivera et al., 2019). The use of PROs is a positive element of virtual healthcare delivery that was highlighted by a recent review, which reported structured questionnaires and wearable activity trackers could have a greater role in patient care in the future (Solomon & Rudin, 2020). In the case of PIPPRA, the use of PROs and the ability to provide wearable physical activity trackers has proved easy to facilitate both face-to-face and through telehealth/phone assessments. Observations from the MEDRA participants include that the telehealth method is flexible, more convenient and a resource-saving solution for dietary clinical research. It should be noted that current MEDRA participants are largely comfortable with the use of online platforms. It should be considered that a particular subset of patients who have RA may not be familiar with online platforms and may find completing study questionnaires online a burden and very time consuming. For the PIPPRA study, intervention delivery via telehealth sessions is yet to be evaluated but for the MEDRA study this mode of delivery has been operating effectively. This aligns with the Australian position paper which states that videoconference‐delivered nutrition care is as effective as similar programs conducted in-person (Kelly et al., 2020). A final consideration is that although the PIPPRA and MEDRA trial staff did not complete additional training to conduct assessment and deliver intervention via telehealth, there may be a need for the provision of training or upskilling opportunities for research staff and clinicians to effectively deliver telehealth.