Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05688761 |
| Other study ID # |
NordGETS |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2019 |
| Est. completion date |
December 28, 2022 |
Study information
| Verified date |
January 2023 |
| Source |
Karolinska Institutet |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
This is a population-based case-control study in all 5 Nordic countries from 1994 onwards.
All cases with an esophageal or gastric tumor will be compared with 10 times as many
population controls, frequency-matched by age, sex, and calendar year, country. This design
offers excellent statistical power, length and completeness of follow-up, quality of data on
exposures, outcomes and confounders, and control for confounding.
The project will include a specific study entitled "Long-term medication with proton pump
inhibitors and risk of gastric cancer", which is summarized here:
Research question: Medication with proton pump inhibitors (PPI) (e.g., omeprazole and
esomeprazole) is one of the most common long-term therapies globally, prompted by its high
anti-acidic efficacy and good short-term safety profile. Gastric cancer is the 3rd leading
cause of cancer-related mortality globally, responsible for 770,000 deaths each year. There
are clear biological mechanisms linking long-term PPI-use with an increased risk of gastric
cancer. However, existing research has not been able to provide a definite answer to whether
long-term PPI-use is associated with an increased risk of gastric cancer. The reasons are
that the literature is hampered by too short follow-up time to assess cancer development, and
also insufficient statistical power, lack of population-based design and confounding.
With the availability of nationwide complete medication registries in the Nordic countries,
the firsts two starting already in 1994 (Denmark and Finland), we can now, by adding registry
data from all Nordic countries together, conduct the first study providing a robust and valid
answer to this research question.
Overarching aim This project aims to clarify if (and if so to what extent) long-term
PPI-therapy influences the risk of developing gastric adenocarcinoma.
For validation reasons, we will also examine how long-term use of histamine-2-receptor
blockers (H2RB) influences the risk of developing gastric adenocarcinoma. These analyses will
validate that the findings are specific for PPIs. H2RB are used for the same indications as
PPIs, but with a different biological mechanism.
Hypothesis We plan to test the hypothesis that long-term use of PPI (but not H2RB) increases
the risk of gastric adenocarcinoma.
Prerequisites
This will be the first project with all prerequisites to provide conclusive answers to the
hypotheses above, i.e.:
- Long follow-up (up to 28 years)
- Complete follow-up (by virtue of the nationwide complete Nordic registries)
- Population-based design (which rules out biased selection of cases or controls)
- Superior statistical power (all five Nordic countries participate with nationwide data)
- High-quality data on exposures, outcomes and confounders (thanks to well-maintained and
complete nationwide Nordic health data registries)
- Control for confounding factors (available for all participants, both cases and
controls)
Description:
PROJECT DESCRIPTION
Theory and method
Study design We will conduct a nationwide and population-based multi-national case-control
study in the five Nordic countries during the total study period from 1994 through 2022, thus
allowing up to 28 years of follow-up. The start of the study period will vary between
countries depending on when their national drug registries started, i.e. in 1994 (Denmark),
1994 (Finland), 2002 (Iceland), 2004 (Norway) and 2005 (Sweden).
Participants The study will include all adult residents in Sweden, Denmark, Finland, Iceland
and Norway with a first gastric adenocarcinoma diagnosed during the study period according to
the national cancer registries. The control participants are selected from the general
populations of the five countries and frequency-matched for age, sex, calendar year, and
country. The index date for matching is the date of gastric adenocarcinoma diagnosis. For
each case of gastric cancer, 10 control participants will be included. Because the controls
are matched within each country by age and calendar year, the time-window used to ascertain
the exposure will be the same in cases and controls. We will have the same detailed
information on all study variables in cases and controls.
Exposure The exposure is long-term PPI-use. Two definitions will be used. The first, high
PPI-consumption, is defined as >180 defined daily doses (DDD) of PPI per year during the time
from start of the drug registry or entry in the cohort until the index date. The second
definition is cumulative exposure to PPI, defined by the total number of DDDs consumption
during the time window of exposure. The DDDs are retrieved from the prescribed drug
registries. From a Swedish cohort of 8,276,316 adult individuals of the general population
that we use for research purposes, 496,579 (6.0%) were exposed to long-term PPI-use (>180
DDDs).
The comparison exposure is long-term use of an H2RB (>180 DDDs), measured using the same two
definitions described for PPI, i.e., high H2RB consumption and cumulative exposure. DDDs for
H2RB are also retrieved from the prescribed drug registries.
Outcome The study outcome will be gastric adenocarcinoma. Adenocarcinoma represents >95% of
all gastric malignancies. We will not assess rare histologies of gastric malignancy because
these have different aetiology, including the potential association with PPI-use. We will
also conduct separately sub-analyses of cardia adenocarcinoma and non-cardia adenocarcinoma.
Confounders A confounder is by definition associated with both the exposure and the outcome
(and is not in the causal pathway between these).29 The main risk factor for gastric
adenocarcinoma is 1) Helicobacter pylori-infection, but also other less strong risk factors
might also have some confounding effects in this project, i.e., 2) age (as for most cancer
types), 3) sex (a majority of patients with gastric adenocarcinoma are men), 4) calendar year
(there have been changes in diagnostic ability of gastric adenocarcinoma), 5) country (there
are some variations in incidence rates of gastric adenocarcinoma between the Nordic
countries), 6) comorbidity (some severe diseases included in the Charlson comorbidity index
might increase the risk of gastric adenocarcinoma), 7) long-term medication with aspirin or
non-steroidal anti-inflammatory drugs (such medication may decrease the risk of gastric
adenocarcinoma) and 8) long-term medication with statins (could also decrease this risk).
All these 8 variables will be controlled for. Age, sex, calendar year, and country will be
controlled for by matching. Helicobacter pylori, comorbidity, long-term medication (>180
defined DDDs per year) with aspirin or non-steroidal anti-inflammatory drugs and statins will
be adjusted for using multivariable logistic regression. Regarding Helicobacter pylori, we
will use treatment of this infection as a marker of infection, which is the most complete and
valid way to assess presence of this infection in the dataset. For comorbidity we will use
the most recent version of the well-validated Charlson comorbidity index.30 We have excellent
data of both medication variables from the drug registries.
Data sources For each participant, both cases and all controls, we will collect data from the
following nationwide registries in all five countries: 1) Prescribed drug registries, 2)
cancer registries, 3) patient registries, 4) cause of death registries and 5) registries of
the total population. This will allow data on demographic characteristics (age, sex, calendar
year, country), use of all relevant medications (including PPI, H2RB, Helicobacter pylori
treatment, aspirin or non-steroidal anti-inflammatory drugs and statins with substance, brand
name, ATC-code, formulation, package size, amount, dosage and dates for prescription and
dispensation), comorbidity (all diagnoses and surgical procedures), and mortality.
Project organisation
Research team Ten people are directly involved in this project. The project originates and is
organised from our research group at Karolinska Institutet (KI). The local team includes 7
people: The chief investigator Jesper Lagergren (main applicant), the biostatistician Giola
Santoni, the statistician Jacinth Yan, the postdoctoral researcher Cecilia Radkiewicz, the
PhD candidate we hope to recruit, and the administrator Giulia Marras. In addition, we have
representatives of each of the four non-Swedish countries included in the project, i.e.,
associate professor My von Euler-Chelpin (Denmark), professor Joonas Kauppila (Finland),
associate professor Helgi Birgisson (Iceland) and associate professor Eivind Ness-Jensen
(Norway).
The main roles of these team members are outlined here:
1. Jesper Lagergren will lead the work and the team conducting the work, be responsible for
the progress of the project, and be supervisor of the postdoc and PhD candidate.
2. Giola Santoni will guide and supervise in the data complex data management and
statistical analyses and co-supervise the PhD candidate.
3. Jacinth Yan will conduct complex data management and analyses.
4. Cecilia Radkiewicz will help with the planning and co-supervise the PhD candidate.
5. The PhD candidate will draft the detailed study protocol, do data management and
statistical analyses with support of Giola Santoni, and draft the paper.
6. My von Euler-Chelpin is responsible for the Danish data collection.
7. Joonas Kauppila is responsible for the Finnish data collection.
8. Helgi Birgisson is responsible for the Icelandic data collection.
9. Eivind Ness-Jensen is responsible for the Norwegian data collection.
10. Giulia Marras will help organise the collaboration and administer the project.
Data storage and management Because Danish law does not allow their data to leave the
country, data will be stored at a safe server at the governmental agency Statistics Denmark,
and managed by remote access. Giola Santoni is responsible for the data management and
statistical analyses.
Main applicant The main applicant, Jesper Lagergren, will spend approximately 10% of his
work-time for this specific project. He is the chief investigator of this multi-national
project.
DATA ANALYSIS AND STATISTICS
Design This will be a population-based case-control study with prospectively collected data
on all variables for all cases and controls in the five Nordic countries. The data collection
is prospective, which avoids recall bias and selection bias. For each case of gastric
adenocarcinoma, 10 control participants from the general populations will be recruited. The
control participants will be frequency-matched to the cases regarding age, sex, calendar year
and country of residence. The additional possible confounders, i.e., Helicobacter pylori,
comorbidity and medication with aspirin or non-steroidal anti-inflammatory drugs as well as
statins will be adjusted for by modelling.
Statistical analysis Conditional logistic regression will be used to estimate the relative
risk of gastric adenocarcinoma comparing long-term PPI-users with non-users, providing odds
ratios with 95% confidence intervals. Three models will be applied: 1) A crude model where
only the matching variables are controlled for; 2) an adjusted model additionally adjusted
for Helicobacter pylori, comorbidity and medication with aspirin or non-steroidal
anti-inflammatory drugs as well as statins, and 3) a model with multivariable adjustment for
all 8 confounders listed under 'Confounders' above, which will guarantee that these variables
are completely adjusted for. We will also do stratified analyses for each of these 8
confounders. In addition, we will assess whether increased length of PPI-use (>10 years)
among long-term users is associated with higher risk estimates, which would argue in favour
of causality. Except for conventional confounding, confounding by indication (particularly
protopathic bias) is a special threat to the validity of many pharmaco-epidemiological
studies. However, long-term PPI-use is not an indication for gastric adenocarcinoma. Thus,
this should not be a problem in the present project.
Statistical power One of the advantages of the project is the excellent statistical power,
which is due to inclusion of cases from five entire countries, long and complete follow-up
and relatively high prevalence of long-term PPI-users. In order to further optimise the
power, we include 10 controls per case, after which further controls will not improve
power.31 The main analysis will include all approximately 47,000 cases and 470,000 controls,
and sub-analyses of non-cardia adenocarcinoma will include 35,300 cases and 353,000 controls,
while the sub-analysis of cardia adenocarcinoma will include 11,700 cases and 117,000
controls. The exposure prevalence of long-term PPI-use is 6% (and 2% for H2RB use). The main
analysis has 100% power to verity an odds ratio already of 1.10, and we expect a much
stronger association. For the analysis of cardia adenocarcinoma, the study has 94% power to
verify an odds ratio of 1.15.
