Establishment of a Mesoamerican–Caribbean South–South Research Platform: Challenges in the Meriva (Curcuminoids) Gastric Cancer Chemoprevention Trial

Abstract

Gastric adenocarcinoma (GAC) is the fourth leading global cause of cancer mortality and leading infection-associated cancer. High-incidence regions of GAC include Latin America and Eastern Asia. Immigrants from high-incidence regions maintain their GAC risk. GAC is a major U.S. cancer disparity, and its incidence rates are 2 to 10 times higher in non-White populations. Emerging guidelines recommend 3-year surveillance endoscopy for patients with high-risk gastric premalignant conditions (GPMC). Clinical trials of GPMC chemoprevention agents are lacking. We conducted a NCI Division of Cancer Prevention–funded, phase II placebo-controlled chemoprevention trial in patients with GPMCs (atrophic gastritis and intestinal metaplasia) with a highly bioavailable preparation of curcuminoids (Meriva). The trial sites in Puerto Rico and rural Honduras had important characteristics: (i) representative Caribbean and Mesoamerican populations, linked to large U.S. immigrant populations; (ii) high prevalence of Helicobacter pylori infection and GPMCs; (iii) the absence of turmeric and curcuminoids in local diets; and (iv) proven bidirectional collaboration with U.S. academic institutions. H. pylori–negative patients with GPMCs were randomized to the study drug (500 mg po bid) or placebo for 180 days (NCT02782949), with primary outcomes based upon histologic parameters. Principal study challenges included (i) an international regulatory environment; (ii) research infrastructure strengthening, particularly in Central America; (iii) participant recruitment in Honduras, wherein only 10% to 15% are H. pylori negative; (iv) the COVID-19 pandemic; and (v) natural disasters (three hurricanes). There were no losses to follow-up related to the pandemic or natural disasters. In conclusion, the south–south partnership provides a model for chemoprevention and translational studies in Latino populations with prevalent cancers, such as GAC.

Introduction

Gastric adenocarcinoma (GAC) is the fourth leading global cause of cancer mortality and the leading infection-associated cancer (1–3). More than one million people are diagnosed with GAC annually, with the majority of the burden in the high-incidence regions of Latin America, East Asia, and Eastern Europe. GAC has one of the highest cancer burdens, as quantified by the disability-adjusted life years lost (4). Gastric premalignant conditions (GPMC), such as atrophic gastritis and gastric intestinal metaplasia (GIM), are prevalent both in high- and low-incidence regions of the world and correlate with populations with Helicobacter pylori infection prevalence (1, 5, 6). GIM is considered the point of no return in the Correa Cascade for gastric carcinogenesis (7). Chemoprevention agents for patients with GPMCs are needed but lacking. For example, observational studies suggest that aspirin and NSAIDs may be protective, albeit balanced by the inherent risks of chemical gastropathy and peptic ulcer disease (7–9).

Study Overview and Methodology

Study overview and rationale

We conducted a randomized, double-blind, placebo-controlled trial (NCT02782949) in Latin America, specifically focusing on patients with GPMCs, using a bioavailable formulation of curcuminoids, Meriva. This intervention was chosen due to Meriva’s significantly higher curcuminoid absorption rate, which is approximately 29-fold greater than that of unformulated curcuminoid mixtures. The rationale behind using curcuminoids lies in their anti-inflammatory, antioxidant, and potentially anticarcinogenic properties, which are thought to modulate critical biomolecular pathways involved in gastric carcinogenesis (10–12). The trial was funded by the NCI Division of Cancer Prevention (DCP) via the Cancer Prevention Network, reflecting the significant potential for interventions in high-risk populations.

Trial design and methodology

The trial aimed to enroll a total of 60 evaluable subjects (Fig. 1), stratified by their baseline gastric mucosal histologic diagnosis (multifocal atrophic gastritis and GIM). Randomization was performed using a dynamic allocation method to maintain balanced marginal distributions of stratification factors. The primary outcome was the change in gastric mucosal cytokine levels, particularly IL1β, from baseline to 6 months, measured by Luminex assay. Secondary outcomes included safety and tolerability, changes in histology (measured by the Correa histopathology score), and changes in mucosal DNA damage (assessed by γ-H2AX IHC staining). Adherence was monitored through weekly phone calls and bimonthly visits, with compliance defined as taking at least 75% of the prescribed doses. The statistical analysis plan included intention-to-treat and per-protocol analyses to assess the effects of Meriva on the specified outcomes.

Figure 1.

General study schema: Latin America Meriva (curcumin) chemoprevention trial. This figure outlines the study design and participant flow from screening through post-intervention evaluation. Notes: (i) Participants were randomly assigned to either the control group or the intervention group. (ii) The specific intervention administered to the intervention group is presented in this figure.

Study progress and assessments

Enrollment began in 2017 but was paused in 2020 due to the COVID-19 pandemic, resuming briefly with attainment of target enrollment in 2021 (Fig. 2). Patients underwent assessments at months 0 and 6, which included blood tests, endoscopy with biopsies, and histological evaluations, to monitor the drug’s efficacy and safety. The final assessments were designed to capture the culmination of the 6-month intervention period, providing a robust dataset for evaluating the primary and secondary outcomes as planned in the study schema.

Figure 2.

Study timeline: Latin America Meriva (curcumin) chemoprevention trial. This figure depicts a timeline of significant milestones and events in the study from 2016 to 2021. The timeline highlights the progression of study activities, regulatory submissions, and the impacts of external events, such as natural disasters and the COVID-19 pandemic, on the study’s enrollment and operations. CIRB, Central Institutional Review Board. Note: The study events, milestones, and challenges are positioned on the timeline, from left to right.

Statistical analysis plan

The statistical analysis plan was designed to evaluate the effectiveness of Meriva in altering gastric mucosal cytokine levels, DNA damage, and histology scores. Primary analyses were conducted using an intention-to-treat approach, which included all randomized participants regardless of protocol adherence. The primary endpoint—change in IL1β cytokine levels—was analyzed using mixed-effects models to account for intraindividual correlations and adjust for potential confounders, such as age, sex, and baseline cytokine levels. Secondary outcomes, such as changes in histology scores and DNA damage, were analyzed using similar mixed-effects models and logistic regression for dichotomous outcomes. A per-protocol analysis was also conducted, including only those participants who adhered to the intervention as prescribed, to assess the effect of Meriva under optimal compliance conditions. Subgroup analyses were planned to explore the differential effects of Meriva across various strata of baseline characteristics, enhancing our understanding of who might benefit most from the intervention. All tests were two-sided, with the significance level set at 0.05.

Study sites

The study was conducted in rural western Honduras and Puerto Rico. Western Honduras is representative of the Central America Four region (CA-4; Honduras, El Salvador, Guatemala, and Nicaragua), the core low/middle-income (LMIC) region in the western hemisphere (13). The CA-4 population is >45 million, with an estimated immigrant population of >8 million, making it unique for gastric cancer control among global LMIC regions from a U.S. perspective.

The Honduras and Puerto Rico sites have a breadth of important characteristics for the study, which were built upon prior collaborations. These characteristics included (i) the representation of Mesoamerican and Caribbean populations, linked to large groups of immigrants in the United States (14–16); (ii) high prevalence of H. pylori infection and GIM (17, 18); (iii) contrasting GAC incidence rates: high in Central America and moderate in Puerto Rico, reflecting the Latin America altitude enigma (19–21); (iv) the absence of turmeric and curcuminoids in local diets; (v) established NCI-funded research platforms; and (vi) proven bidirectional collaboration with academic institutions in the United States (13, 15, 22).

Study Challenges

We describe the implementation and unique challenges related to the study execution and the potential model for ongoing south–south research collaborations. The partnership potentially provides an exceptional platform for chemoprevention and clinical translational studies in Latino populations with prevalent cancers, such as GAC. The principal challenges were classified into six categories: (i) regulatory approval and logistic challenges, (ii) infrastructure growth, (iii) participant recruitment, (iv) the COVID-19 pandemic, (v) natural disasters and humanitarian crises, and (vi) the advancement of research infrastructure for molecular analyses and pathology. Many of the above challenges were specific to the LMIC setting in rural Honduras. The effects of these unforeseen circumstances on participant accrual and delayed completion of the study were well-documented by local research staff and entered into the Accrual Quality Improvement Program reporting system developed by the NCI DCP to promote clinical trial accrual efficiency and improve study recruitment and retention (23). Table 1 provides an overviewed of the primary challenges encountered during the study.

Table 1.

Challenges in the Latin America Meriva (curcumin) gastric cancer chemoprevention trial.

	Study challenges
Regulatory environment	•NCI CIRB •Site IRBs •New pharmaceutical agencya •Bilingual study materialsa
Research infrastructure	•Reinforce cold chaina •Facilitate on-site monitoring
Participant recruitment and retention challenges	•H. pylori–negative subjectsa •Lower GIM prevalenceb •Polypharmacyb
COVID-19 pandemic	•Strict curfews and stay-at-home mandates •Travel restrictions
Natural disasters	•Hurricane Mariab •Hurricanes Eta and Iotaa
Pathology and molecular analysis infrastructureb	•Laboratory equipment and personnel identification •SOPs and protocol creation •Personnel training

^aPrimarily affecting the Honduras site.

^bPrimarily affecting the Puerto Rico site.

Abbreviations: CRIB, Central Institutional Review Board; IRB, Institutional Review Board; SOP, standard operating procedure.

Challenge #1: Regulatory environment

The initial regulatory approval process was completed between 2016 and 2017. Because the research sites were located outside the continental United States, the requirements of the local institutional review boards and regulatory institutions resulted in significant protocol changes and subsequent resubmissions to the NCI DCP and the NCI Central Institutional Review Board. Initial regulatory approvals were completed in Puerto Rico, wherein the study was activated in April 2017.

In Honduras, there were several regulatory challenges, which resulted in unanticipated delays. Although all research protocol documents may be submitted in English in Puerto Rico (with the exception of the informed consent form, which must also be submitted in Spanish), the regulatory agencies in Honduras required the Spanish versions of all documents. The initial outsourced translations were unsatisfactory, leading to a significant delay in regulatory approvals. In addition, during 2017 to 2018, Honduras changed their pharmaceutical approval mechanisms for all agents, creating a new agency (Agencias de Regulación Sanitaria, ARSA) outside of the Ministry of Health. This included review of international medications, including over the counter (OTC) agents and investigational agents. Studies now required approvals from both the Ministry of Health and ARSA. The long-term need and benefit of this new level of organization is apparent, albeit with a delay for our study as ARSA was in the startup period. Final approvals were received in March 2018, although minor administrative matters further delayed study drug arrival in-country.

Challenge #2: Research infrastructure

The cold-chain infrastructure was critical for the execution of the trial as the primary outcomes were dependent upon flawless storage and shipment of the biospecimens at −80°C. There were no issues with biospecimen preservation in this trial. The Puerto Rico cold chain was without failures during Hurricane Maria in September 2017 (24). The site in rural western Honduras is located at the Hospital de Occidente in Santa Rosa de Copán (population 50,000). There were timely improvements from 2016 to 2017 to the national power grid, thereby eliminating frequent “brownouts.” In addition, the regional hospital underwent improvement in power system stability. Backup systems with either dry ice or liquid nitrogen had been a challenge due to the limited supply in-country. Ultimately, primary and secondary −80°C freezers were positioned, with systems of voltage regulation and backup. Immediate dry ice was operationally available for an emergent system failure. The sequential hurricanes (Eta and Iota) in November 2020 did not affect the laboratory or specimens. Notably, the cold-chain infrastructure became an available resource in western Honduras during the COVID-19 pandemic (e.g., vaccine storage).

Study monitoring may present challenges. The Honduras agencies and study team requested on-site monitoring visits with a monitor familiarized with randomized controlled trials in LMIC settings, especially in Latin America, where electronic medical records are unavailable. Having a monitor proficiency in English and Spanish was necessary to have an accurate report and progress of the trial. The verification data on-site reassured the ethical boards that the trial was conducted in accordance with Honduras and international regulations. Remote monitoring was uncommon at the time in Honduras, although becoming common in other studies with the reality of the pandemic.

Challenge #3: Participant recruitment

Study recruitment was consistent and successful, without losses to follow-up, despite the hurdles outlined herein. The challenges in the Puerto Rico population included an aging population and common polypharmacy. The economy and employment opportunities had led to a migration of working-age adults to the United States. Polypharmacy, including OTC medications (e.g., NSAIDs), was notable. The H. pylori infection prevalence in Puerto Rico is 33% (17).

The principal recruitment challenge in Honduras was H. pylori status. The study was restricted to H. pylori–negative subjects to facilitate focus on the host responses. Western Honduras has an H. pylori infection prevalence of >80%, which markedly restricted patient eligibility and extended the enrollment period (25, 26). Travel in the mountainous regions, typical of the CA-4, was an important barrier, particularly in the rainy season, which also affects access to cancer care in general (27). Specific strategies were needed to ensure consistent follow-up, which proved to be useful during the pandemic. Notably, curcuminoids also have activity and effects on H. pylori, which provides an opportunity for discovery in future studies.

Challenge #4: COVID-19 pandemic

During the SARS-CoV-2 outbreak, clinical trials around the world faced multiple challenges, particularly in the Latin America setting, which accounted for approximately 40% of the global mortality burden (28). The trial was fortunate to avoid losses to follow-up during the pandemic. In Honduras, in the initial 4 to 5 months of the pandemic, a strict national policy of curfew and stay-at-home was in place. The relatively recent widespread availability of cell phones facilitated verbal telemedicine with study patients. Special permissions from governmental authorities were obtained to arrange transportation for rural patients to the study clinic. Village leaders in some villages closed all outside access, which needed to be navigated.

The Governor of Puerto Rico also declared a national curfew. Telemedicine was useful during the pandemic, and the strategies developed during Hurricane Maria (2017) to maintain communication with patients in ongoing clinical research studies were successfully deployed during COVID-19. First, the research team developed a strategic plan to facilitate communication with study personnel and participants. There were two subjects who were active in the study during this period; they were contacted, and individual follow-up calls were completed. Study procedures (upper endoscopy, phlebotomies, centrifuging samples, etc.) were completed timely following the COVID-19 protocols for subject and personnel safety.

Challenge #5: Natural disasters

Natural disasters are a constant reality in the Caribbean and Central America. In September 2017, Hurricane Maria (24) devastated many areas of Puerto Rico and the power grid in particular. In some ways, the island is still recovering in the rural areas. Neither staff nor patients suffered serious injury, and no patients were lost to follow-up. Enrollment was suspended for a month. The study infrastructure and biobank remained intact.

In November 2020, sequential hurricanes Eta and Iota struck Honduras, as well as Nicaragua and Guatemala (29). More than 4.7 million people were affected and more than 369,000 were displaced. Nearly 1,000 roads and 400 health centers were damaged, leaving 2 million people without access to health care in the initial months. The hurricanes contributed to a new COVID-19 surge. Fortunately, as in Puerto Rico, neither staff nor patients suffered serious injury, and no patients were lost to follow-up.

Challenge #6: Changes in personnel for tissue analysis

The clinical trial laboratory analyses were conducted at the University of Puerto Rico. This presented a challenge and an opportunity to build capacity as a Latin American consortium and to advance the University of Puerto Rico’s research infrastructure. First, successful identification of laboratory teams, equipment, and personnel for tissue processing and analysis was conducted. Second, the creation of standard operating procedures and protocols using published literature and manufacturer consultation. Third, training the laboratory and pathology personnel about specific assays for the study, including Luminex assay and specific biomarkers for DNA damage, not performed routinely in clinical testing. Despite the steep learning curve, this quick adaptation and capacity building provides a solid molecular analysis and pathology infrastructure for Latin American groups.

Conclusions

We describe the implementation with unique challenges and new paradigms developed during the study execution of the first gastric cancer curcumin chemoprevention trial in Latin America (30). The goals of recruitment, patient safety, and evaluable biospecimens were achieved despite significant startup and regulatory challenges, the COVID-19 pandemic, and natural disasters (three hurricanes). The Mesoamerican–Caribbean south–south partnership potentially provides an exceptional platform for chemoprevention and clinical translational studies in Latino populations with prevalent cancers, with generalizability to linked U.S. immigrant populations.