|Year : 2021 | Volume
| Issue : 2 | Page : 205-208
Impact of the Coronavirus Disease 2019 pandemic on an ongoing pragmatic pediatric clinical trial
Abrar F Hudairi1, Fahad A Bashiri1, Lujain K AL-Sulimani2, Dimah AlSaqabi3, Mohamed A A. Mohamed4, Muddathir H Hamad1, Reem Al Khalifah2
1 Department of Pediatrics, Division of Pediatric Neurology, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
2 Department of Pediatrics, Pediatric Endocrinology Division, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
3 College of Medicine Research Center, King Saud University, Riyadh, Saudi Arabia
4 Department of Emergency Medicine, King Salman Hospital, Riyadh, Saudi Arabia
|Date of Submission||01-Oct-2020|
|Date of Acceptance||30-Nov-2020|
|Date of Web Publication||13-Apr-2021|
Reem Al Khalifah
Department of Pediatrics, College of Medicine, King Saud University, P.O. BOX 7805 Riyadh 11472
Source of Support: None, Conflict of Interest: None
Background: The coronavirus disease 2019 (COVID-19) pandemic has a significant negative impact on clinical trials. Therefore, maintaining an optimal trial conduct should be considered to minimize risks to trial integrity while ensuring the safety of trial staff and participants. In this study, we aimed to describe the impact of the COVID-19 pandemic on conducting an ongoing clinical trial, along with challenges and solutions encountered and required to continue the trial. Methods: This Phase IV pragmatic randomized superiority controlled open-label trial included children with epilepsy receiving Vitamin D supplementation at King Saud University Medical City, Riyadh, Saudi Arabia (clinicaltrials.gov registration number: NCT03536845). Children with epilepsy receiving chronic antiepileptic medications and with normal baseline 25-hydroxyvitamin D level were randomized to receive cholecalciferol 400 IU/day versus 1000 IU/day for 6 months. The primary outcome was the percentage of children with Vitamin D insufficiency at 6 months. The secondary outcomes included seizure control, bone mineral density, and safety. Results: Under COVID-19 public health emergency measures, exceptional methods were used, such as telemedicine, home visit for blood extractions, shipping of the study medication to the patient's home, using reminder text messages to follow patients' compliance, and using privacy-compliant platforms to connect the research team members. Conclusion: During the widespread pandemic, ethical dilemmas are of major concern, especially when conducting trials on vulnerable age groups. Therefore, actions should be proportionate and based on benefit-risk considerations, affecting the risk of bias from protocol deviation and overall results.
Keywords: Children, clinical trial, coronavirus disease 2019, COVID-19, epilepsy, pandemic, Vitamin D
|How to cite this article:|
Hudairi AF, Bashiri FA, AL-Sulimani LK, AlSaqabi D, A. Mohamed MA, Hamad MH, Al Khalifah R. Impact of the Coronavirus Disease 2019 pandemic on an ongoing pragmatic pediatric clinical trial. J Nat Sci Med 2021;4:205-8
|How to cite this URL:|
Hudairi AF, Bashiri FA, AL-Sulimani LK, AlSaqabi D, A. Mohamed MA, Hamad MH, Al Khalifah R. Impact of the Coronavirus Disease 2019 pandemic on an ongoing pragmatic pediatric clinical trial. J Nat Sci Med [serial online] 2021 [cited 2021 May 18];4:205-8. Available from: https://www.jnsmonline.org/text.asp?2021/4/2/205/313641
| Introduction|| |
The coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving situation. Its ultimate global impact and trajectory have yet to be discovered. On March 11, 2020, the World Health Organization declared the COVID-19 outbreak a global pandemic, making COVID-19 the third CoV outbreak recorded in human history after the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus. On March 2, 2020, Saudi Arabia confirmed its first case of COVID-19. With the increasing number of cases, the government of Saudi Arabia has announced multiple safety measures, including curfew restrictions, suspension of national and international travels, working from home, limiting large public gatherings, and strict social distancing to reduce the spread of the virus. The COVID-19 pandemic has a significant negative impact on all aspects of clinical care, including conducting research and clinical trials.,,
Clinical trials are a crucial research tool for advancing medical knowledge and patient care and are essential for discovering new treatments for diseases and new ways to detect, diagnose, and reduce the risk of developing the disease or its complications. Therefore, during this unprecedented time, maintaining an optimal trial conduct should be considered to minimize risks of trial integrity while ensuring the safety of trial staff and participants. Vitamin D supplementation to prevent Vitamin D deficiency in children with epilepsy is an ongoing randomized, pragmatic trial that started recruiting patients in December 2017 at King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia. In this study, we aimed to describe the impact of the COVID-19 pandemic on conducting a clinical trial, along with challenges and solutions encountered and required to continue the trial.
| Methods|| |
The study protocol followed the SPIRIT guidelines to report protocol items for randomized controlled trials, which was approved by the Institutional Review Board of King Saud University. Informed consent was obtained from patients and parents. The study population was recruited from the pediatric neurology clinic of KSUMC since December 2017. The KSUMC is a tertiary academic center that provides yearly care to >250 children with epilepsy. The study registration number at clinicaltrials.gov is NCT03536845. We enrolled children with epilepsy aged 2–16 years and were treated with antiepileptic medications (AEDs). We aimed to determine if 400 IU daily maintenance of Vitamin D versus 1000 IU daily would be sufficient to maintain optimal Vitamin D levels in children with epilepsy and normal baseline Vitamin D levels for >6 months of treatment and would provide clinically significant seizure reduction. The primary outcome was to compare the effect of high-dose Vitamin D (1000 IU/day) supplementation versus standard dose (400 IU/day) for >6 months to maintain the Vitamin D level at >75 nmol/L of supplementation for children with epilepsy. The secondary outcomes included determining the prevalence of Vitamin D deficiency in children with epilepsy, and the proportion of children with AED treatment failure, mean seizure frequency, mean serum parathyroid hormone, and bone mineral density (BMD). Upon children recruitment, baseline demographic data, type of epilepsy, and AEDs with dosage and drug levels were determined with the baseline serum 25-hydroxyvitamin D level. Children with normal 25-hydroxyvitamin D levels will be randomized into two groups. Group A receives 400 IU\day of cholecalciferol, whereas Group B receives 1000 IU\day of cholecalciferol for 6 months. Children with low 25-hydroxyvitamin D will be treated with cholecalciferol 5000 IU\day for 8 weeks as recommended by the endocrine society (2000–10,000 IU/day), and 30–75 mg/kg per day of elemental calcium in three divided doses for 4 weeks, and then the 25-hydroxyvitamin D level will be measured.
| Results|| |
To date, we enrolled 129 patients, randomized 88 patients, and administered treatment doses of Vitamin D deficiency in 41 patients. In March 2020 and for the period following the announcement of the COVID-19 pandemic, the research team was forced to work from home, and patients were prohibited from visiting the hospital. During the COVID-19 pandemic, all pediatric neurology clinics stopped seeing patients in person and changed to virtual visits served by the minimal number of staff. Therefore, the ability to confirm participant eligibility to study recruitment has been significantly affected, as well as parent's willingness to enroll for a trial was impacted negatively, leading to recruitment suspension. Randomization was carried out as usual, and parents were informed about treatment allocation over the phone. Meanwhile, patients randomized or receiving treatment for Vitamin D deficiency were contacted through the phone to maintain their engagement with the trial. To minimize the risks to trial integrity, we implemented measures to ensure optimal outcome measurement as planned in our protocol. Therefore, we contracted a laboratory that offered in-house visits for blood extraction since patients cannot leave home. For families living in Riyadh, 25 children did the blood workup using the services of a contracted laboratory. However, 11 parents refused the service because they were afraid of virus transmission through the laboratory personnel. Ten families had left Riyadh to the suburb area to avoid the high endemic areas and so were asked if they could get blood extracted at their local areas. Four of those families agreed to do the laboratory tests, whereas the others could not do them, and two were lost to follow-up. Other outcome measures, such as seizure control, were assessed through virtual clinics. Furthermore, hospital COVID-19 political restrictions prohibited nonurgent radiological procedures, interfering with the performance of BMD for four participants who completed all their study visits as well as weight and height measurements. [Figure 1] summarizes the way of conduction of the study before and during COVID-19.
|Figure 1: The way of conduction of the study before and during coronavirus disease 2019|
Click here to view
Prescriptions for cholecalciferol were arranged to be delivered to patients at home. Moreover, the team sent weekly broadcast messages for all patients to remind them about taking the dose to ensure compliance. No patient withdrew from the study due to fear of contracting COVID-19. Due to budget limitations, we decided to allocate the remaining budget to the contracted laboratory to optimally maintain compliance with good clinical practice (GCP) with the enrolled patients. With that, we performed sample size re-estimation and found that with the currently recruited patients, we can address at least the primary outcome. The study team held a semiweekly virtual meeting through Zoom to discuss challenges in the trial, follow up patient results, and discuss optimal solutions. Despite taking all precautionary measures, one study team member, unfortunately, contracted the virus; fortunately, he was in good health and was able to attend team meetings virtually. Moreover, no trial participant had contracted the virus.
| Discussion|| |
During the COVID-19 public health emergency, the present clinical trial, as other global trials, is facing various challenges due to quarantine, travel limitations, budget limitations, and interruptions due to personnel or trial participants becoming infected with COVID-19. These challenges are caused by restriction of health-care facility visitations, increased load on health services, and changes to trial staff availability. Consequently, these challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits such as laboratory/diagnostic testing.
Although delays with certain study procedures leading to protocol deviation may be appropriate in the context of a pragmatic trial, issues related to the risk of bias from the study conduct might arise. These deviations are unavoidable due to COVID-19 public health control measures. The major challenge of the present trial was the family's concerns about the risk of being infected with SARS-CoV-2 that leads to the refusal to comply with some of the study procedures. In addition, the ethical dilemma between the risk and benefit of participation in a low-risk clinical trial that does not provide treatment for a chronic illness can impact trial willingness to continue negatively and compliance with therapy. In our trial, some parents perceived Vitamin D as a noncritical medication for a child with seizure disorder.
We utilized several alternative methods successfully, from balancing the perspective between the maximum compliance with the protocol and the need to minimize participant and research team members' exposure to SARS-CoV-2, for example, using telemedicine, home visits for blood extractions, shipping the study medication directly to the patient's home, using text messages to follow patients' compliance, and using privacy-compliant platforms (e.g., Zoom) to connect the research team members. Merging virtual clinics within clinical trials is a rational approach to maintain patient participation in ongoing and future clinical trials. They provide participants with direct and immediate access to investigators, nurses, and other study team members from home, which not only encourages engagement and retention but also may relieve some of the patients' concerns about participating in site-based research during a public health emergency. However, limitations and risks of such methods and requirements for data protection should be considered, and such alternative arrangements need to be adequately documented.
Unfortunately, staying at home most of the time due to curfew poses an additional risk for Vitamin D deficiency from a minimal sun exposure, and it increases sedentary behavior in children and adults. This additional risk factor is important during the analysis stage to avoid systematic bias. The ability to apply alternative methods varies between clinical trials based on trial designs, participant's health, and regions where the study was conducted along with funding availability. By considering local drug agencies, such as the US Food and Drug Administration or the European Medicines Agency for the most up-to-date guidance, some of the suggestions are general considerations that may be adapted to individual locations, studies, and participants based on their unique needs following the general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with GCP, and minimizing risks to trial integrity. Ethical dilemmas are of major concern, especially when conducting trials on vulnerable groups. Therefore, actions should be proportionate and based on benefit-risk considerations, impact on the risk of bias, and overall results. Finally, thorough documentation of any pandemic-related alterations of study procedures/performance should be performed, so that their impact on study outcomes can be analyzed.
| Conclusion|| |
The COVID-19 outbreak is a rapidly evolving situation, with several unknown trajectories worldwide, ultimately affecting ongoing trials. We outlined some practical solutions for investigator-initiated trials such as the utilization of virtual visits and making every effort to sustain medication delivery and laboratory tests utilized in a similar setting. We believe that transparent reporting of challenges during a pandemic improves the understanding of the research context, interpretability of results, and future methodological developments in the area.
Financial support and sponsorship
This work was supported by Dallah Healthcare, Kingdom of Saudi Arabia, and Grant number (CMRC-DHG1/006).
Conflicts of interest
There are no conflicts of interest.
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