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The COVID-19 pandemic has presented an ongoing global challenge, marked by the emergence of multiple SARS-CoV-2 variants. Effective management of these variants necessitates a comprehensive understanding of their clinical impact and the development of targeted interventions. This study explores the landscape of clinical trials giving a better understanding of the COVID-19 variants registered on the International Clinical Trials Registry Platform (ICTRP). Leveraging data from the ICTRP, we conducted an extensive mapping to assess basic characteristic features of registered clinical trials, while also giving an overview of currently used therapeutics, vaccines, and diagnostic tools specifically tailored to combat SARS-CoV-2 variants. Our analysis also provides valuable insights into the geographical distribution, trial design, and therapeutic modalities targeted at these variants. By synthesizing and visualizing this data, we aim to facilitate global collaboration, resource allocation, and evidence-based decision-making in the ongoing fight against COVID-19 variants. This chapter underscores the significance of the ITCRP registry for understanding the evolving pandemic landscape and highlights the ongoing efforts to confront the challenges posed by SARS-CoV-2 variants. The chapter also highlights essential considerations relevant to the management of COVID-19 variants in low- and middle-income countries with limited health infrastructure.
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Musawenkosi Ndlovu
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Asanda Mayeye
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Nomahlubi Luphondo
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Ndivhuwo Muvhulawa
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Department of Biochemistry, North-West University, Mafikeng Campus, South Africa
Yonela Ntamo
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Phiwayinkosi V. Dludla
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
Department of Biochemistry and Microbiology, University of Zululand, Richards Bay, South Africa
Charles Shey Wiysonge
World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo
*Address all correspondence to: duduzile.ndwandwe@mrc.ac.za
1. Introduction
The global COVID-19 pandemic began in late 2019, where it suddenly propelled the scientific community to come up with solutions to unravel the mysteries of the SARS-CoV-2 virus [1]. Until this day, the COVID-19 pandemic continues to challenge humanity in unprecedented ways, driving a need to develop effective vaccines and treatments to combat the virus [2, 3]. The prime example is the redefining feature of long COVID, which occurs more often in people who had severe COVID-19 illness [4]. In fact, it has become essential to understand the dynamic nature of SARS-CoV-2 variants as part of an ongoing battle against this virus. This includes exploring the genetic changes that underpin the ever-evolving world of SARS-CoV-2 variants, potentially contributing to the course of the pandemic [1].
The COVID-19 pandemic has witnessed the emergence of several distinct SARS-CoV-2 variants, each characterized by unique genetic mutations [5]. Some of the most notable variants include the Alpha variant (B.1.1.7), initially identified in the United Kingdom, and known for its significantly rapid infectious rate [6]. This variant quickly spread to numerous countries, leading to concerns about its potential to drive surges in cases [6]. Following closely behind was the Beta variant (B.1.351), first discovered in South Africa [7]. This variant raised considerable alarm within the scientific community due to mutations in the spike protein that appeared to reduce the effectiveness of certain vaccines [5, 7]. The Gamma variant (P.1), also originating in Brazil, shared genetic similarities with the Beta variant [8]. Researchers noted that both variants had mutations in common, particularly within the spike protein. In late 2021, the Delta variant (B.1.617.2) emerged as a dominant force among the COVID-19 variants [8, 9]. Originating in India, Delta exhibited unprecedented transmissibility, leading to rapid and widespread infections. By now high-quality sequences of Delta (B.1.617.2) and Delta Plus (AY.1 or B.1.617.2.1) variants have been used to uncover the prevalence of mutations in the entire SARS-CoV-2 genome [10]. Lastly, the Omicron variant (B.1.1.529) surfaced, characterized by an unusually high number of genetic mutations, particularly in the spike protein [11]. Omicron’s emergence raised concerns about its potential to evade immunity generated by previous infections or vaccinations [11]. The appearance of Omicron underscored the need for ongoing vigilance and adaptability in the fight against COVID-19 and its evolving variants, especially during the fourth wave of the pandemic [5, 12].
The past few years have seen extensive research being undertaken to understand their behavior, impact on disease severity, vaccine resistance potential, as well as relevant implications for diagnostics and treatments [5, 8, 12]. Thus, it become important to monitor and study these variants as part of the ongoing efforts to combat the evolving COVID-19 pandemic. While much work has focused on the short-term effects of COVID-19 variants, a significant research gap lies in comprehending the long-term consequences of variant exposure on immunity [13, 14, 15, 16]. These studies have shown that different variants exhibit varying degrees of immune escape, potentially impacting the effectiveness of vaccines and natural immunity [13, 14, 15, 16]. However, there is limited data on how these variants may influence the duration and strength of immunity against subsequent infections or the longevity of vaccine-induced protection. Thus, there is a need to continuously reinforce efforts our understanding the durability of immunity in individuals exposed to different variants, including reinfection rates, and vaccine breakthrough cases remains crucial for informing vaccination strategies, booster campaigns, and long-term pandemic management [17, 18, 19, 20, 21, 22, 23]. This will surely enhance the capacity ability to adapt our public health measures and vaccination approaches effectively as the virus continues to evolve.
This chapter seeks to contribute to the collective knowledge to effectively monitoring the evolution of viral variants and their potential impact on public health. The International Clinical Trials Registry Platform (ICTRP) holds immense significance in the field of medical research and healthcare. It serves as a global repository for clinical trial registrations, fostering transparency, accountability, and accessibility of crucial research endeavors [24]. By providing a centralized platform for researchers to register their trials, ICTRP ensures that valuable data on clinical trials are publicly available, enabling fellow scientists, healthcare professionals, and policymakers to access comprehensive information. This transparency not only promotes ethical research practices but also facilitates collaboration and the sharing of critical findings, eventually advancing medical knowledge and improving patient care worldwide [24]. In the context of public health crises like the COVID-19 pandemic, ICTRP’s role in disseminating vital trial information is even more pronounced, allowing for informed decision-making and the rapid development of life-saving interventions. In this cross-sectional survey of the ICTRP database, we report on the trends in the clinical trials registered on COVID-19 variants, including relevant data on clinical trials reporting on the Alpha, Beta, Delta, Gamma, and Omicron variants. The chapter also highlights essential considerations relevant to the management of COVID-19 variants in low- and middle-income countries with limited health infrastructure.
This was a comprehensive analysis of the trends in clinical trials registered with the ICTRP (https://www.who.int/clinical-trials-registry-platform) [24]. This platform collects clinical data from registries across the globe, in the process becoming a one-stop portal to access clinical trial records. The study employed the World Health Organization (WHO) classification of a clinical trial: ‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes’ [25, 26]. An advanced search function of ICTRP was used to identify relevant clinical trials, registered on 20 August 2023.
2.2 An approach for data analysis and management
An independent researcher (M.N.) made use of the world WHO-ICTRP portal to download relevant data on the 20th of August 2023. During this process, data was exported into an Excel spreadsheet before other researchers (N.M. and P.V.D.) performed quality checks. For each record, some of the critical data items collected included the trial registry source, date of registration, recruitment status, retrospective flag, gender, trial phases, and intervention model. Additional information collected were the biomarkers, symptoms, recovery time, imaging findings, viral load, immune response, psychology, and other measures corresponding to each COVID-19 variant. Collected data items allowed for a comprehensive analysis of trends and patterns across COVID-19 variants within an Excel spreadsheet.
This section reports on clinical trials conducted on the five COVID-19 variants, including the Alpha, Beta, Delta, Gamma, and Omicron. Data was retrieved per individual variant from the WHO-ICTRP. Initially, the dataset included 428 studies. However, a total of 8 duplicated studies were removed, of those, 2 were eliminated due to sharing the same trial ID, while 6 were excluded for having identical titles. Additionally, 2 studies were removed as they did not meet the inclusion criteria or did not give sufficient information on COVID-19 variants. Overall, 10 studies were eliminated, leaving a total of 418 studies for further analysis (Figure 1). These 418 studies have been registered since 1999 to 2023 (Figure 1). During the year 1999 to 2004, there were very few studies registered. The lowest being in 2001 with no registered studies. Notably, the most significant changes occurred after 2020, where the highest reported studies were seen between 2021 and 2022.
Figure 1.
Flowchart illustrating the process of clinical trials (n = 418) on the five COVID-19 variants, including the alpha, Beta, Delta, gamma, and omicron. Data was retrieved per individual variant from the international clinical trials registry platform on the 20th of august 2023.
3.2 Data on the diverse clinical trial registry sources
The WHO clearly states that access to the ICTRP is necessary to safeguard a complete view of research to those involved in healthcare decision making [27]. This will surely improve research transparency and will eventually reinforce the validity and value of the scientific evidence base [27]. The ICTRP registry pools together or gives access to data from different clinical trial registries. In terms of the COIVD-19 variants, the combined data pooled from the clinical trials shows that the Alpha (n = 104) variant had the highest number of records, followed by Beta (n = 93), Delta (n = 37), Gamma (n = 68), and Omicron (n = 116) (Table 1). The ClinicalTrials.gov remains the predominant source of accessing data for clinical trials on COVID-19 variants, including the Alpha, Beta, Delta, Gamma, and Omicron (Table 1). The next registry is the Iranian Registry of Clinical Trials (IRCT), followed by the Clinical Trials Registry- India (CTRI), International Standard Randomized Controlled Trial Number (ISRCTN), EU Clinical Trials Register, Chinese Clinical Trial Registry (ChiCTR), Australian New Zealand Clinical Trials Registry (ANZCTR), and German Clinical Trials Register (DRKS), respectively (Table 1). However, very limited data and even records are missing for the other clinical trial registries, including the Pan-African Clinical Trials Registry (PANCTR), Thai Clinical Trials Registry (TCTR), and others (Table 1).
Trial characteristic
Variants
Alpha(n = 104), n (%)
Beta(n = 93) n (%)
Delta(n = 37) n (%)
Gamma(n = 68) n (%)
Omicron(n = 116) n (%)
Trial registry source
ANZCTR
8, (7.69)
N/A
1, (2.70)
3, (4.41)
2, (1.72)
ChiCTR
11, (10.58)
1, (1.08)
6, (16.22)
N/A
36, (31.03)
ClinicalTrials.gov
28, (26.92)
39, (41.93)
18, (48.65)
21, (30.88)
56, (48.28)
CTRI
12, (11.53)
5, (5.38)
2, (5.41)
14, (20.59)
5, (4.31)
DRKS
3, (2.88)
1, (1.08)
N/A
6, (8.82)
1, (0.86)
ISRCTN
9, (8.65)
4, (4.30)
1, (2.70)
4, (5.88)
3, (2.59)
PACTR
1, (0.96)
1, (1.08)
1, (2.70)
N/A
1, (0.86)
TCTR
1, (0.96)
1, (1.08)
3, (8.11)
N/A
2, (1.72)
IRCT
16, (15.38)
29, (31.18)
N/A
7, (10.29)
1, (0.86)
RPCEC
6, (5.77)
N/A
N/A
N/A
1, (0.86)
ITMCTR
N/A
N/A
4, (10.81)
N/A
8, (6.90)
REPEC
N/A
1, (1.08)
N/A
N/A
N/A
SLCTR
1, (0.96)
N/A
N/A
N/A
N/A
EU-CTR
5, (4.81)
9, (9.68)
1, (2.70)
8, (11.76)
N/A
JPRN
N/A
1, (1.08)
N/A
1, (1.47)
N/A
REBEC
2, (1.92)
N/A
N/A
N/A
N/A
LTR
N/A
N/A
N/A
3, (4.41)
N/A
Date of registration
2019
N/A
N/A
N/A
1, (1.47)
N/A
2020
60, (57.69)
56, (60.22)
1, (2.70)
25, (36.76)
1, (0.86)
2021
24, (23.08)
17, (18.28)
13, (35.14)
24, (35.29)
2, (1.72)
2022
16, (15, 38)
18, (19.35)
20, (54.05)
15, (22.06)
88, (75.86)
2023
4, (3.85)
2, (2.15)
3, (8.11)
3, (4.41)
25, (21.55)
Recruitment status
Recruiting
34, (32.69)
32, (34.41)
13, (35.14)
22, (32.35)
48, (41.38)
Not recruiting
68, (65.38)
55, (59.14)
23, (62.16)
39, (57.35)
67, (57.76)
Authorized
2, (1.92)
N/A
N/A
7, (10.29)
N/A
Not specified
N/A
6, (6.45)
1, (2.70)
N/A
1, (0.86)
Retrospective flag
Yes
76, (73.08)
64, (68.82)
25, (67.57)
52, (76.47)
84, (72.41)
No
28, (26.92)
29, (31.13)
12, (32.43)
16, (23.53)
32, (27.59)
Gender
Both gender
86, (82.69)
82, (92.47)
35, (94.59)
52, (76.47)
111, (95.69)
Female
1, (0.96)
1, (1.08)
N/A
1, (1.47)
N/A
Male
1, (0.96)
N/A
N/A
N/A
N/A
Not specified
N/A
6, (6.45)
2, (5.41)
15, (22.06)
5, (4.31)
Trial phases
Phase I
6, (5.77)
4, (4.17)
N/A
5, (7.81)
8, (6.90)
Phase II
24, (23.08)
24, (25)
11, (29, 80)
11, (17.19)
14, (12.07)
Phase III
19, (18, 27)
36, (37.5)
7, (18.92)
11, (17.19)
15, (12.93)
Phase IV
10, (9.62)
5, (5.21
N/A
3, (4.69)
6, (5.17)
Phase I-II
5, (4.81)
1, (1.04)
N/A
1, (56)
2, (1.72)
Phase II-III
5, (4.81)
9, (9.38)
N/A
2, (3.13)
4, (3.45)
Phase III-IV
1, (0.96)
N/A
N/A
N/A
1, (0.86)
Not applicable
24, (23.08)
12, (12.50)
N/A
17, (26, 56)
31, (26.72)
Intervention Model
Cross-over assignment
5, (4.81)
9, (9.67)
1, (2.70)
2, (2.94)
2, (3)
Factorial assignment
1, (0.96)
1, (1.08)
1, (2.70)
N/A
1, (1)
Parallel assignment
65, (62.5)
74, (79.57)
22, (59.46)
38, (55.88)
54, (76)
Sequential assignment
1, (0.96)
2, (2.15)
1, (2.70)
1, (1.47)
2, (3)
Single group assignment
4, (3.85)
1, (1.08)
1, (2.70)
1, (1.47)
4, (5)
Other
2, (1.92)
3, (3.22)
5, (13.51)
15, (22.06)
4, (6)
None (open labeled)
20, (19.23)
3, (3.22)
6, (16.22)
1, (1.47
4, (6)
Table 1.
Characteristics of the clinical trials registered for the five COVID-19 variants (alpha, Beta, Delta, gamma, and omicron).
ChiCTR, Chinese Clinical Trial Registry; CTRI, Clinical Trials Registry-India; IRCT, Iranian Registry of Clinical Trials; ISRCTN, International Standard Randomized Controlled Trial Number; ITMCTR, International Traditional Medicine Clinical Trial Registry; TCTR, Thai Clinical Trials Registry, RPCEC, Cuban Public Registry of Clinical Trials; PACTR, Pan African Clinical Trials Registry; ANZCTR, Australian New Zealand Clinical Trials Registry; DRKS, German Clinical Trials Register; SLCTR, Sri Lanka Clinical Trials Registry, REPEC, The Peruvian Clinical Trials Registry; LTR, Dutch Trial Registry. CAM- Complementary and Alternative Medicine.
3.3 Data on the clinical trial registration and recruitment status
Table 1 results also showed a year-dependent registration of clinical trials on different COVID-19 variants, starting from 2019 to 2023. As expected, before the first outbreak was reported towards the end of 2019 [28], limited or no information was available on the recorded clinical trials on all COVID-19 variants (Table 1). In fact, it was only in 2020 that much of the clinical trials were recorded for both the Alpha (n = 60), and Beta (n = 56) variants, because they were the first variants to emerge. The years 2021 to 2022 recorded a steady registration of clinical trials across all COVID-19 variants (Table 1). However, more clinical trials were registered for the Omicron variant (75%) by the year 2022 (Table 1) since it first emerged and became the most transmissible variant towards the end of 2022 [29]. By the year 2023, the registered trials fell significantly across the years, although the Omicron (21%) variant still showed a higher number of registered clinical trials compared to the Alpha (3%), Beta (2%), and Delta (8%) (Table 1). There was a decline in trial recruitment status for all COVID-19 variants, based on the progressing years, especially lower for the years 2023 (Table 1).
3.4 Data on the gender and type of clinical trial
Table 1 also gives information on the gender of participants included within these clinical trials and was evenly distributed across both males and females. Only a few clinical trials included males or females only. In terms of trial phases, most records showed predominant allocation to phase II and phase III, across all COVID-19 variants (Table 1). Meaning these clinical trials were likely to be conducted to uncover the safety and efficacy of interventions or vaccines [30]. Interestingly, it was also apparent that a few records did not specify the type of phase of other clinical trial, including the Alpha (23%), Beta (12%), Gamma (26%), and the Omicron (26%) variants (Table 1). Moreover, for each category, retrospective flag scored above 60% for the Alpha, Beta, and the Omicron variants (Table 1).
3.5 Data on different interventions for COVID-19 variants
Table 2 also gives information on the different interventions or approaches that have been used for each of the COVID-19 variants, including pharmacotherapy, vaccine therapy, complementary and alternative medicine, and educational therapy. Other interventions included diagnostic (devices), behavior, and dietary supplements. The intervention model was mostly parallel across all COVID-19 variants (Table 2), where the clinical study likely involved two or more groups of participants receiving different interventions [31]. Indeed, more than 50% of clinical trials registered for the Alpha, Beta, and Gamma variants focused on pharmacotherapy intervention either as mono or combination therapy (Table 2). The most common agents studied in the registered clinical trials include Lopinavir/Ritonavir, Dexamethasone, and Ribavirin. Vaccine therapy was also among the most studied interventions, for the Alpha (19%), Beta (19%), Delta (22%), Gamma (15%), and Omicron (45%) variants (Table 2). Notably, Sinocelltech (SCTV01 E&C), mRNA 1273, Comirnaty, and BNT162b2 were among the most common vaccines used for the registered trials. The complementary and alternative medicine investigated against the five COVID-19 encompasses mostly Chinese medicine such as Ayurveda and Lianhua Qingwen (Table 2). Other interventions, including those simply educational scored less in terms of clinical trials registry (Table 2).
Yoga modules, Mental health knowledge, psychological lessons.
4, (3.84)
1, (1.08))
N/A
N/A
N/A
Others
Dietary supplements, Diagnostic, Behavioral, Nitric oxide gas
16, (15.09)
9, (6.68)
2, (5.41)
15, (22.06)
12, (12.24)
None
N/A
N/A
5, (13.51)
N/A
20, (20.41)
Table 2.
An overview of interventions corresponding to different types of intervention for each COVID-19 variant.
Different herbs; mRNA vaccine (mRNA-1273), Sinocelltech (SCTV01), Interferon beta-1α (SNG001), Complementary and alternative medicine (CAM), Interferon-gamma human recombinant (IFN-G), NVX-CoV- Novavax COVID-19 (NVX-CoV2373).
4. Data on the different primary outcomes corresponding to each COVID-19 variant
The devastating impact of the different COVID-19 variants on public health and control measures underlines the need for continued vigilance and adherence to preventive measures such as mask-wearing, physical distancing, and vaccination. Additionally, ongoing research has focused on evaluating the efficacy of existing treatments, including vaccines for their targeted impact to mitigate the associated complications. The response to the interventions made in the registered trials was measured by the evaluation of some common primary outcomes. In Table 2, the primary outcomes are categorized into different groups, including biomarkers, COVID-19 symptoms, respiration rate, recovery time, image findings, viral load, geometric mean titers, and psychological effects. Notably, the most common biomarkers included measuring several pro-inflammatory markers like interleukins, lymphocytes, tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and cytokines, as well as glucose-related markers and insulin (Table 3). These biomarkers were regularly recorded for all COVID-19 variants. In terms of symptoms, optimal physical strength appeared to be predominantly assessed, including cough, fever, headache, body temperature, and fatigue across all COVID-19 variants (Table 3). However, even more clinical symptoms could be identified, including clinical symptom score, taste, social stigma, sleep, fever, sore throat, fatigue, headache, pain, cough, body temp, insomnia, and diarrhea (Table 3). Immune response appears to be one of the critical outcomes post-vaccinations, measured as geometric mean titer and determination of neutralizing antibody titers. Some trials for the Delta, Gamma, and Omicron variants studied the psychological response of individuals post-intervention, monitoring depression, social stigma, and anxiety (Table 3).
In this chapter, we examine clinical data on the ever-evolving landscape of the COVID-19 pandemic, where new variants have emerged, presenting fresh challenges to our understanding and response. The comprehensive analysis of diverse clinical trial registry sources, as highlighted in this study, underscores the crucial role of the International ICTRP in healthcare decision-making and research transparency. The registration patterns revealed that as COVID-19 variants emerged, research efforts intensified, with the Alpha and Beta variants initially garnering significant attention due to their early appearance. In contrast, the Omicron variant, with its remarkable transmissibility, attracted a surge of clinical trials, reflecting the urgency in understanding and combating this new threat. Moreover, the study provides insights into the gender distribution of participants and the phases of clinical trials conducted for various COVID-19 variants. The balanced inclusion of both males and females in trials is noteworthy, contributing to more representative findings. Most clinical trials focused on phases II and III, indicating a primary focus on the safety and efficacy of the assessed interventions.
Moreover, the study sheds light on the diverse interventions employed to address COVID-19 variants, encompassing pharmacotherapy, vaccine therapy, complementary and alternative medicine, and to a lesser extent, the educational approaches. This multifaceted intervention landscape underscores the global effort to explore various strategies to combat the pandemic [32]. Notably, the vaccine therapy garnered significant attention across variants, emphasizing the central role of vaccination in pandemic management [33]. Overall, this comprehensive examination of clinical trial registry data highlights the impact of diverse COVID-19 variants on public health and a need to establish effective control measures or preventive strategies. Literature has increasingly covered these strategies, including mask-wearing, physical distancing, and vaccination, especially their instrumental role in mitigating the spread of the virus and preventing severe outcomes [34, 35, 36]. Indeed, as the pandemic continues to evolve, research efforts have continually assessed the effectiveness of existing treatments and interventions, with a particular focus on vaccines designed to target specific variants [37].
The evaluation of interventions within the registered clinical trials has been guided by various primary outcomes, categorized into distinct groups. Biomarkers have played a crucial role in determining immune response, with an emphasis on pro-inflammatory markers, interleukins, lymphocytes, TNF-α, C-reactive protein, and cytokines, which are likely to determine the severity of COVID-19 [12, 38]. In fact, the assessed biomarkers like blood glucose levels and insulins also indicate the surveillance of relevant risk of COVID-19 in patients with diabetes mellitus [39]. Interestingly, these biomarkers have been consistently assessed across trials for all COVID-19 variants, reflecting their importance in understanding the immune response and disease progression [40, 41, 42]. Moreover, primary outcomes related to COVID-19 have been a focal point of evaluation, with a particular emphasis on assessing optimal physical strength, including clinical symptoms such as cough, fever, headache, body temperature, and fatigue. However, a wide range of clinical symptoms has been monitored, encompassing clinical symptom scores, taste, social stigma, sleep patterns, sore throat, insomnia, diarrhea, and more. This comprehensive approach to symptom assessment reflects the complex nature of COVID-19’s impact on individuals, especially in response to different COVID-19 variants [43, 44, 45].
Consistently highlighted within this chapter, is the critical role of monitoring the immune response, especially in the context of vaccinations. Evaluation has included measures such as geometric mean titers and the determination of neutralizing antibody titers, providing insights into the effectiveness of vaccines against different variants. Additionally, the psychological response of individuals post-intervention has been examined in some trials for variants like Delta, Gamma, and Omicron, with a focus on monitoring depression, social stigma, and anxiety. This holistic approach to outcome assessment is essential in comprehensively understanding the impact of interventions and treatments on individuals’ physical and mental well-being.
In summary, this chapter provides a comprehensive exploration of the ever-evolving landscape of the COVID-19 pandemic, characterized by the emergence of diverse variants that pose ongoing challenges to our understanding and response. It highlights the pivotal role of the International ICTRP in promoting healthcare decision-making and research transparency, especially as research efforts intensified in response to new variants like Alpha, Beta, and Omicron. The study emphasizes the significance of balanced gender representation in clinical trials and the predominant focus on phases II and III, reflecting a primary concern for assessing intervention safety and efficacy. Additionally, the chapter discusses the wide array of interventions employed to combat COVID-19 variants, with vaccination as a central strategy. The evaluation of interventions within clinical trials encompasses various primary outcomes, including biomarkers crucial in assessing the severity of COVID-19.
In essence, this chapter highlights ongoing research, especially from clinical trial registries, informing on the importance of assessing the effectiveness of existing treatments and interventions, particularly vaccines targeting specific variants. This in-depth analysis of clinical trial registry data significantly contributes to our evolving understanding of COVID-19 and guides evidence-based strategies for combatting the pandemic and its myriad variants.
8. Future considerations, especially for poor health infrastructure in low-and-middle-income countries
The emergence of new variants of SARS-CoV-2 raises particular concerns for low- and middle-income countries (LMICs) with limited health infrastructure. These countries often face challenges in terms of healthcare resources, testing capacity, and access to vaccines, which can further exacerbate the impact of new variants on their populations.
Increased strain on healthcare systems: The introduction of more transmissible variants can lead to a surge in COVID-19 cases, placing a significant burden on healthcare systems that are already stretched thin. LMICs may struggle to cope with the increased demand for hospital beds, oxygen supply, and medical staff, resulting in compromised care for both COVID-19 patients and those requiring other healthcare services.
Limited testing and surveillance capabilities: Rapid and widespread testing is crucial for early detection and containment of new variants. However, LMICs often face challenges in terms of limited testing capacities and access to advanced genomic sequencing technologies. This can hinder their ability to monitor the emergence and spread of new variants, potentially delaying necessary public health responses.
Vaccine inequity and limited coverage: Vaccination campaigns play a critical role in mitigating the impact of new variants. However, many LMICs face challenges in accessing and distributing vaccines due to supply shortages, logistical hurdles, and vaccine inequity. Limited vaccine coverage in these countries can leave populations vulnerable to new variants, with potential implications for disease severity and mortality rates.
Inequitable access to therapeutics and treatments: The emergence of new variants may require the development and distribution of targeted therapeutics or treatments. However, LMICs may face challenges in accessing and affording these interventions, leading to disparities in healthcare access and outcomes.
Long-term socioeconomic impact: The ongoing impact of new variants can have long-term socioeconomic consequences for LMICs. The disruption of essential services, such as education, employment, and commerce, can deepen existing inequalities and hinder economic recovery efforts, further straining already fragile health systems.
Addressing these challenges requires international collaboration and support to strengthen health infrastructure in LMICs. This includes increasing testing capacities, enhancing genomic surveillance, ensuring equitable access to vaccines and therapeutics, and providing financial and technical assistance to bolster healthcare systems. It is crucial to prioritize the needs of LMICs and ensure that they have the resources and support necessary to effectively respond to the evolving threat posed by new variants.
All authors, including Musawenkosi Ndlovu, Asanda Mayeye, Nomahlubi Luphondo, Ndivhuwo Muvhulawa, Yonela Ntamo, Phiwayinkosi V. Dludla, and Charles Shey Wiysonge - wrote the manuscript, edited the revised draft, and approved the final version.
Funding statement
This work was supported in part by baseline funding from the South African Medical Research Council (SAMRC). The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders.
Consent for publication
Not applicable. No individual person’s data has been included in this manuscript.
Ethics approval
This is a review of already published studies and thus it does not require ethical approval.
Data availability and material
Data related to search strategy, study selection, and extraction items will be made available upon request after the manuscript is published.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Abbreviations
ANZCTR
Australian New Zealand clinical trials registry
CAM
complementary and alternative medicine
CBV
change from baseline vaccination
ChiCTR
Chinese clinical trial registry
CRP-C
reactive protein
CTRI
clinical trials registry-India
CVL
change of viral load
DRKS
German clinical trials register
EU-CTR
EU clinical trials register
GMT
geometric mean titers
HAS
human serum albumin
ICTRP
international clinical trials registry platform
IFN
interferon
IgG
immunoglobulin
IL-6
interleukin 6
IRCT
Iranian registry of clinical trials
ISRCTN
international standard randomized controlled trial number
ITMCTR
international traditional medicine clinical trial registry
JPRN
Japan primary registries network
LMICs
low- and middle-income countries
LTR
Dutch trial registry
MMSE
mini- mental state examination
NaT
neutralizing antibody titers
OR
oxygen requirement
OS
oxygen saturation
PACTR
pan African clinical trials registry
PAI-1
plasminogen activator inhibitor-1
PSQI
Pittsburgh sleep quality index
QPCR
quantitative polymerase chain reaction
RC
respiratory capacity
ReBec
Brazilian clinical trials registry
REPEC
the Peruvian clinical trials registry
RPCEC
Cuban public registry of clinical trials
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SLCTR
Sri Lanka clinical trials registry
SRAS
self-rating anxiety scale
TCTR
Thai clinical trials registry
TNF-α
factor-alpha
VFD
ventilation-free days
VNCT
virus negative conversion time
WHO
world health organization
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Written By
Duduzile Ndwandwe, Musawenkosi Ndlovu, Asanda Mayeye, Nomahlubi Luphondo, Ndivhuwo Muvhulawa, Yonela Ntamo, Phiwayinkosi V. Dludla and Charles Shey Wiysonge
Submitted: 27 September 2023Reviewed: 27 September 2023Published: 27 November 2023
Open access peer-reviewed chapter
