Singapore has one of the highest rates of myopia in the world. Short-sightedness affects 28 percent of children as young as seven years old, and the rate increases to 83 percent when they reach 18 years old.
While myopia can be corrected by optical glasses, the functional impact relating to both occupational and lifestyle restrictions should not be underestimated.
Most importantly, studies have shown that persons with higher myopia are at higher risks of developing complications such as degenerative retinal changes, early-onset cataracts (in the thirties to forties) and open-angle glaucoma that can be sight-threatening later in life. Children who start developing myopia at a younger age are more likely to ultimately develop high myopia later in life, and high myopia currently occurs in at least 15 percent of our 18-year-olds in Singapore.
Based on previous ATOM trials and epidemiological studies, the ATOM3 trial continues to investigate the use of low dose Atropine to prevent and control myopia in the younger population. The study is sponsored by National Medical Research Council (NMRC) and Asia Cornea Foundation (ACF).
As a result of previous trials, we now know that Atropine can reduce or slow down myopia progression in children, at least above the age of six years. The ATOM3 study, supported by SCRI, will be performed at the Singapore Eye Research Institute (SERI) and the Singapore National Eye Centre (SNEC). This new study hopes to determine if Atropine eye drops can prevent or slow the onset of myopia in young children (with myopic parents) who have a high risk of developing myopia, or reduce myopia progression in those with low myopia at a younger age.
SCRI’s project manager provides advice to both the study and internal teams, clinical research associates for site initiation and monitoring, as well as biostatistics and pharmacovigilance support. SCRI’s Research Informatics department developed the Randomisation platform (RAND) for the project by working with the biostatistician. In addition, a data manager will be working closely with the Principal Investigator (PI) and biostatistician to customise the Oracle Clinical as well as provide data analysis and query management.
At present, there are no proven neuroprotective pharmacological treatments for ICH or other forms of acute brain injuries. A novel therapeutic approach was developed based on the known biological function of endogenous apolipoprotein. In a Phase 1 trial evaluating the safety, tolerability, and pharmacokinetics of single escalating and repeated doses of the IP in healthy human adults, the compound was found to be safe and well tolerated, with no serious drug-related adverse events (AEs) reported.
The S-CATCH study evaluates the safety and potential efficacy of repeated doses of the investigational product administered to participants with acute supratentorial ICH.
SCRI supported the study as collaborator providing clinical operations support as well as scientific support. Clinical operation team supports project management, research monitoring, pharmacovigilance and data management. The biostatistician team from SCRI also led the development of CDISC compatible data for FDA submission.
CPPL-DSO-2018 is the first clinical study to investigate the efficacy and safety of thawed cryopreserved pooled buffy coat-derived platelet transfusion in comparison to normal liquid platelet transfusion in patients with hypoproliferative thrombocytopenia.
Platelets have a particularly short shelf-life of only 5 days, which gives rise to significant logistical challenges in the supply of platelets for routine medical treatment and emergencies. To lengthen the shelf-life of platelets significantly, DSO National Laboratories has explored cryopreservation of pooled buffy-coat derived platelets, which Singapore relies more on. In addition, the prophylactic transfusion of patients with hypoproliferative thrombocytopenia is a more common indication than therapeutic platelet transfusion in bleeding patients during routine clinical practice. Once this niche study is validated, it will be important for peacetime use during low blood collection months or when there is sudden surge in platelet demand.
The study is sponsored by DSO and is a multidisciplinary collaboration involving researchers from DSO National Laboratories; Blood Services Group, Health Sciences Authority; Department of Haematology, Singapore General Hospital and the variety of research supports from SCRI.
SCRI’s coordination efforts range from protocol development, randomization, site monitoring, data cleaning, safety monitoring, medical writing to overall project management. With the able support from SCRI, CPPL-DSO-2018 successfully achieved the recruitment target, completed the final analysis in 1 month after last patient last visit and completed the study closure within the tight timeline.
As the first point of contact in the healthcare system, the emergency department (ED) is particularly important for providing appropriate end-of-life (EOL) care, primarily when most EOL patients use emergency services in the last month of their lives. This highlights the need for more specialised training for emergency physicians to adequately manage the increasing number of patients towards the end of their lives.
EMPOWER (End-of-Life management protocol offered within emergency room) is a novel multicentre study aiming to improve the quality of end-of-life care for actively dying patients in ED via a multi-prong approach, from clinical charts and perceptions of family members at the bedside. The study employs a quasi-experimental interrupted time-series design using qualitative and quantitative methods, involving the three EDs of tertiary hospitals in Singapore over 3 years. There are five phases in this study: (1) retrospective chart reviews of patients who died within 5 days of ED attendance; (2) pilot phase to validate the CODE questionnaire in the local context; (3) pre-implementation phase; (4) focus group discussions (FGDs); and (5) post implementation phase. Post-implementation processes include quality assessment of the new care protocol and cost-effectiveness analysis.
The SCRI Epidemiologists provided pre-grant support to the PIs and clinical team by advising on the study protocol’s key study concepts and methodological aspects for the NMRC Health Services Research Grant application in 2017. With its high scientific merit, the team won then the largest grant award for the ED department. Epidemiology team members also provided streamlined post-grant support for IRB approval, the operational logistics by the Project Management, as well as designing and maintaining the Redcap database system by the Research Informatics in SCRI. Our Epidemiologists were invited to be Co-Investigators of this project as a recognition of their significant contribution.
Two manuscripts have been published for the study protocol and pilot phase.
Chua MT, Sen Kuan W, Zheng CQ, Tiah L, Kumar R, Wong YKY, Lin J, Liang S, Mayland CR, Shi L, Ibrahim I, Pal RY. Validation of "Care of the Dying Evaluation" in Emergency Medicine (CODE-EM): pilot phase of end-of-life management protocol offered within emergency room (EMPOWER) study. Ann Palliat Med. 2021 Jun;10(6):6145-6155. doi: 10.21037/apm-21-380. Epub 2021 May 25. PubMed PMID: 34118856.
Yash Pal R, Kuan WS, Tiah L, Kumar R, Wong YKY, Shi L, Zheng CQ, Lin J, Liang S, Segara UC, Yong WC, Chan NGC, Chua MT, Ibrahim I. End-of-life management protocol offered within emergency room (EMPOWER): study protocol for a multicentre study. BMJ Open. 2020 Apr 28;10(4):e036598. doi: 10.1136/bmjopen-2019-036598. PubMed PMID: 32350018; PubMed Central PMCID: PMC7213875.
Adaptive COVID-19 Treatment Trial (ACTT) is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults with COVID-19. It is initiated by the National Institutes of Health (NIH) in the United States with Singapore as one of the participating countries. Each new intervention, which is introduced according to scientific and public health needs, represents a new stage of ACTT.
COVID-19 situation was evolving rapidly in early 2020 and the main focus was to initiate the ACTT as soon as possible to enable access to new treatment for patients in Singapore. To support this urgent national needs, Singapore Clinical Research Institute (SCRI) was engaged to help with the local initiation of the study, which was instrumental to accelerate the trial start-up. The study activation was eventually accomplished in one month. The 1st Singapore patient was successfully enrolled in ACTT-1 on 25 March 2020. With the continuous support from SCRI project management, the study has achieved the stage target for ACTT-1, ACTT-2, ACTT-3 and ACTT-4 successively.
In addition, SCRI project management facilitated the ACTT network local expansion. The involvement of Singapore has been expanded from the initial 1 site to 6 hospitals as of today. Being part of ACTT network enabled young hospitals like NTFGH, AH and SKH to develop the required manpower and operation workflow for ID research.
The efforts from the Singapore sites in supporting ACTT were credited by the authorship offered by NIH in NEJM publications (impact factor 74.699). Given the preliminary results about remdesivir from ACTT-1, the Food and Drug Administration issued an Emergency Use Authorization on May 1, 2020 (modified on August 28, 2020), to permit the use of remdesivir for treatment in adults and children hospitalized with suspected or laboratory- confirmed Covid-19. Remdesivir has also received conditional approval in Singapore by HSA since 10 Jun 2020.
Participating ACTT enriched the local experience of initiating treatment trials in urgent needs in expeditious manner. The collaborations with NIH also helped the local team to gain knowledge on how a multi-site, global clinical trial platform is efficiently managed to ensure the high-quality study conduct in meeting FDA standards. In addition, being part of ACTT network enabled young local site like NTFGH, AH and SKH to develop the required manpower and operation workflow for ID research. All these positive experiences are instrumental for Singapore to be better armed for future needs in pandemic circumstances.
PRIBIVAC is an adaptive, randomised, subject-blinded, controlled trial to assess a heterologous prime-boost-boost strategy in comparison with a homologous regimen in order to compare short and long-term immunogenicity of different COVID-19 vaccine combinations. It will help to address the following fundamental questions for the COVID-19 vaccination programs: Who needs a booster vaccination? How long after the primary series should it be administered? And, which vaccine should be used?
Compared with other COVID-19 vaccination trials, PRIBIVAC is unique as
- All participants have mRNA primary vaccines series;
- Multiple heterologous boost COVID-19 vaccine regimens have involved;
- Comprehensive immune evaluation
The comprehensive immunogenicity evaluation is carried out through a collaboration between A*STAR Infectious Diseases Labs, Singapore Immunology Network, Duke-NUS Medical School, National Public Health Laboratory and KK Women’s and Children’s Hospital, which showcases the capabilities and strong partnerships between Singapore research teams.
The study team also comprised
- A clinical site at The National Centre for Infectious Diseases (NCID) Research Clinic
- A vaccination site at P.H Feng Research Centre located at NCID
- An academic CRO at Singapore Clinical Research Institute (SCRI)
SCRI is proud to support NCID in initiating the study in just two weeks by preparing the site, training project teams, drawing up research monitoring and data collection plans and facilitating ethics submissions. In addition, the study database was managed to go-live within 1 month with the efforts to speed up the work which usually takes 3 months. The first data safety monitoring board meeting was achieved within 1 week upon the availability of the immunogenicity data. As the study is in an adaptive design, new intervention groups will be added depending on what COVID-19 vaccines are authorised for use in Singapore as the study progress. With the able support from SCRI, the implementation of each new intervention group so far has been achieved efficiently.
Our team will also continue to provide services in project management, site and data safety monitoring as well as data management and analysis for the study.
The Asian Myeloma Network (AMN) studies are a series of clinical trials on Asian patients with myeloma, plasma cell cancer. The Asian Myeloma Network was established by the International Myeloma Foundation (IMF) in 2011 to carry out clinical trials to bring promising new treatment to Asian Myeloma patients and help IMF in its physician education and patient support outreach in Asia. AMN members are mainly myeloma experts from several Asian countries and regions including Singapore, Japan, Korea, China, Hong Kong SAR, Taiwan, Malaysia and Thailand.
Myeloma, a plasma cell cancer is known to vary with ethnicity. While myeloma incidence for Asians used be relatively lower than for Caucasians, in recent years, Asian myeloma incidence has been fast approaching that for Caucasians, with myeloma becoming a growing health concern in Asia. As myeloma is one of the most common hematologic malignancies, there is a need to better understand the disease and identify effective treatments.
In the last eight years, AMN has successfully launched 5 clinical trials, and there will be a few new AMN studies to be initiated in the next 1-2 years. The AMN001 clinical trial, supported by Celgene Asia Pacific (Merged to BMS), was launched in December 2014 to study the efficacy of novel drug combinations with a new immunomodulatory in relapsed MM Asian patients. Following successful operation of AMN001 study, the AMN002 and AMN003 trials were launched in September 2017 to identify more new study treatment for relapsed MM patients. The AMN002 study was supported by Amgen Inc. in collaboration with the Australian Leukemia and Lymphoma Group (ALLG) with participation by study centres from Australia while the AMN003 project was supported again by Celgene Asia Pacific. Both of the AMN004 and AMN006 were phase II studies supported by Janssen Biotech, these two trials aim to study the efficacy and toxicity of daratumumab in different drug combination in Asian patients with relapsed myeloma or in Newly Diagnosed Transplant Ineligible Multiple Myeloma Patients.
Since the first AMN001 Study, SCRI has provided tremendous assistance to the AMN research team with quality and reliable clinical study support ranging from project and data management, safety management, statistical analysis to research informatics. The AMN decided in 2017 to appoint SCRI as the academic research organisation responsible for all its studies, including new studies that are in planning and preparation.
With SCRI’s able support, the AMN project team can focus on identifying promising new therapies for the Asian MM patients from more than 20 AMN sites from different countries or regions.
Cancers of the breast, lung, colon, prostate and ovary remain a highly significant cause of morbidity and mortality worldwide. One potentially promising avenue for the development of new anti-cancer agents is stimulating the immune system to specifically recognise and eradicate targeted cancer cells.
The MUC-1 Study is a single-site, First-in-Human clinical trial in oncology which aims to assess the safety and benefit of the MUC-1 vector vaccine in patients with epithelial cancers and to identify a tolerable, immunologically active dose level. This unique MUC-1 vector vaccine is provided by MicroVAX, LLC, a biotechnology company located in Manassas, Virginia, USA, the study was conducted at National Cancer Center, Singapore. SCRI was invited by the PI and MicroVAX to participate in this First-in-Human trial as the Study Sponsor.
As Study Sponsor, SCRI is responsible for ensuring sufficient resources to initiate, manage and deliver the research as proposed. SCRI also worked with the PI and MicroVAX to develop the study protocol and to prepare the site for the study initiation.
SCRI provided oversight of safety monitoring, quality control and quality assurance throughout the study to ensure the data collected was accurate and of quality standard. SCRI also provided CRO management via close supervision to ensure that overall conduct of the study was in compliance with the approved study protocol, regulatory requirements and good clinical practice.
As Sponsor, SCRI proactively identified potential study risks and provided mitigation actions. Moreover, SCRI ensured that any protocol deviations were reported promptly to the Ethics and Regulatory authorities with appropriate corrective and preventive actions. SCRI also undertook regulatory submissions to the Health Sciences Authority, obtained regulatory approvals, acted as the IP importer to ensure the appropriate delivery and storage conditions for the IP on site.
With able support from SCRI, the study has been successfully completed, data has been analysed and the results are promising. The manuscript was successfully published with promising results.
Tan, T.J., Ang, W.X.G., Wang, WW. et al. A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma. Nat Commun 13, 6453 (2022). https://doi.org/10.1038/s41467-022-33834-4
ACTIV-3, part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership is a master protocol designed to allow for the study of multiple investigational agents compared to placebo in adults hospitalized with COVID-19. This adaptive design allows investigational agents to be added and dropped during the study for efficient testing of new agents against placebo within the same trial infrastructure and maximizes efficiency in identifying a safe and efficacious therapeutic agent for COVID-19. This study is funded by NIAID, NIH in the United States.
In 2020, there was an urgent public health need for rapid development of therapeutic interventions to help combat the COVID-19 pandemic and SCRI was engaged in Aug 2020 to assist TTSH/NCID in grant application, Institutional Review Board (IRB) and Health Sciences Authority (HSA) submission. Main focus was to activate main site (TTSH/NCID) the soonest possible and import study drug in for usage. All of these were achieved within a month and the 1st Singapore patient was successfully enrolled in early Oct 2020. Till date, SCRI has assisted in IRB & HSA submission for 5 protocols and study has progressed to the 4th investigational agent with a total recruitment of 43 subjects.
Every time a study investigational drug is added, SCRI’s Project Management and Research Monitoring team would be fast on the trails of gathering required information for IRB and HSA submission. The team has built an extensive knowledge bank of submission requirements and was able to anticipate the questions that the regulatory have and provide information in an efficient manner to facilitate each protocol approval. Considering how dynamic the pandemic situation is, the team was also able to catch on to new requirements and incorporate the information based on the latest local COVID-19 situations into the submission documents for a shorter review turnaround time.
The standard management strategy for drug-sensitive (DS) pulmonary tuberculosis (TB) is to treat with multiple drugs for 6 months. Patients often fail to adhere to the long treatment, leading to poor clinical outcomes including drug resistance, which is expensive and difficult to treat.
This trial evaluates an alternative strategy of treating patients with DS-TB for 2 months with combinations including new drugs or optimised doses of currently available drugs, chosen for their sterilising efficacy. The secondary aim is to assess the possible advantages of the TRUNCATE-TB management strategy compared to the standard management strategy from the patient perspective, the programme perspective and to assess cost-effectiveness. This trial also looks into evaluating the pharmacokinetics, microbiological efficacy and toxicity of a number of boosted 8-week regimens in comparison to the standard treatment regimen; and to explore the relationship between various biomarkers and sterilisation/cure.
Sponsored by the University College London and supported by The International Union Against TB and Lung Disease, the trial is managed as a partnership between National University Hospital (Singapore) and the Medical Research Council Clinical Trials Unit at University College London. SCRI Biostatistics, Data Management, Research Informatics and Project Management departments took part in the trial.
The Data Management department was responsible for the database design and managed the data collection and data transfer processes. Due to the use of novel approaches outlined in the TRUNCATE-TB management strategy, the Trial Coordinating Centre (TCC) recognised the need for close monitoring of the sites to ensure all personnel followed the respective trial SOPs meticulously. To achieve the desired level of central monitoring, different kinds of customised reports of varying complexities were required periodically.
For example, all expected central laboratory test samples must be submitted and their results collected into the EDC system. Through the use of a customised report, the TCC is able to identify lapses in sample submission or data entry of test results, and could rectify these findings with the respective sites immediately.
The generation of such customised reports, along with the routine data reports, which are provided on monthly and quarterly basis, was supported by the SCRI Data Management with the use of wizard-driven analytics tool like the SAS Enterprise Guide.
CEA PsyEdu is a randomised controlled trial in Singapore. The trial aims to (1) develop a web-based postnatal psycho-educational programme for first-time mothers, (2) examine its effectiveness on maternal self-efficacy in newborn care (primary outcome), as well as social support, psychological well-being and maternal satisfaction with the postnatal support (secondary outcomes) and (3) evaluate its cost-effectiveness as compared to home-based psycho-educational programme and routine postnatal care.
Supported by the NMRC Health Services Research Competitive Research Grant (HSR CRG), this project shows novelty in designing and promoting a psycho-educational programme for first-time mothers. The study leverages on information technology to provide innovative and high quality nursing care that is efficient, potentially cost effective and evidence-based. This trial shows great potential of having a big impact on women going through childbirth.
SCRI’s Epidemiology Department harnesses its expertise to provide the project with cost-effectiveness analysis and economic evaluation. Playing a key role for this project in the design of CRFs, development of cost-effectiveness analysis plan, construction of Markov models, and support of manuscript drafting. The department hopes this study will pave the way for greater development of research projects to promote cost effective health services in the nursing field.
The manuscript of CEA PSYEDU has been accepted for publication by the Journal of Medical Internet Research.
Zheng, Q.S.,# Shi, L.M.,# Zhu, L.X.,# Jiao, N.N., Chong, Y.S., Chan, W.C.S., Chan, Y.H., Luo, N., Wang, W., & He, H.G.* (2021). The cost-effectiveness of web-based and home-based postnatal psychoeducational interventions for first-time mothers: An economic evaluation alongside randomized controlled trial. Journal of Medical Internet Research. DOI: 10.2196/25821