Ignite Creation Date:
2024-05-06 @ 6:30 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05688761
Status:
COMPLETED
Last Update Posted:
2024-06-24
First Post:
2023-01-09
Brief Title:
Nordic Gastric and Esophageal Tumor Study
Sponsor:
Karolinska Institutet
Organization:
Karolinska Institutet
Study Overview
Official Title:
Nordic Gastric and Esophageal Tumor Study
Status:
COMPLETED
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NordGETS
Brief Summary:
This is a population-based case-control study in all 5 Nordic countries from 1994 onwards Cases with esophageal or gastric cancer will be compared with 10 times as many population controls
The project includes a specific study Long-term medication with proton pump inhibitors and risk of gastric cancer which is summarized here
Research question Medication with proton pump inhibitors PPI is a most commonly used drug prompted by its good anti-acidic efficacy and short-term safety profile Gastric cancer is the 3rd leading cause of cancer-related mortality globally responsible for 770000 deaths each year There are biological mechanisms linking long-term PPI-use with an increased risk of gastric cancer But existing research has not provided a definite answer to whether long-term PPI-use increases risk of gastric cancer The literature is hampered by short follow-up time insufficient statistical power lack of population-based design and confounding
With the availability of nationwide complete drug registries in the Nordic countries the first two starting in 1994 Denmark and Finland we can now by adding registry data from all Nordic countries conduct the first study providing a robust and valid answer to this research question
Overarching aim To clarify if and if so to what extent long-term PPI-therapy increases the risk of 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 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 ie
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
Sufficient 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
The project includes a specific study Long-term medication with proton pump inhibitors and risk of gastric cancer which is summarized here
Research question Medication with proton pump inhibitors PPI is a most commonly used drug prompted by its good anti-acidic efficacy and short-term safety profile Gastric cancer is the 3rd leading cause of cancer-related mortality globally responsible for 770000 deaths each year There are biological mechanisms linking long-term PPI-use with an increased risk of gastric cancer But existing research has not provided a definite answer to whether long-term PPI-use increases risk of gastric cancer The literature is hampered by short follow-up time insufficient statistical power lack of population-based design and confounding
With the availability of nationwide complete drug registries in the Nordic countries the first two starting in 1994 Denmark and Finland we can now by adding registry data from all Nordic countries conduct the first study providing a robust and valid answer to this research question
Overarching aim To clarify if and if so to what extent long-term PPI-therapy increases the risk of 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 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 ie
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
Sufficient 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
Detailed 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 ie 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 8276316 adult individuals of the general population that we use for research purposes 496579 60 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 ie 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 these29 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 ie 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 index30 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 ie 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 ie 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 power31 The main analysis will include all approximately 47000 cases and 470000 controls and sub-analyses of non-cardia adenocarcinoma will include 35300 cases and 353000 controls while the sub-analysis of cardia adenocarcinoma will include 11700 cases and 117000 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 110 and we expect a much stronger association For the analysis of cardia adenocarcinoma the study has 94 power to verify an odds ratio of 115
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 ie 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 8276316 adult individuals of the general population that we use for research purposes 496579 60 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 ie 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 these29 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 ie 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 index30 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 ie 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 ie 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 power31 The main analysis will include all approximately 47000 cases and 470000 controls and sub-analyses of non-cardia adenocarcinoma will include 35300 cases and 353000 controls while the sub-analysis of cardia adenocarcinoma will include 11700 cases and 117000 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 110 and we expect a much stronger association For the analysis of cardia adenocarcinoma the study has 94 power to verify an odds ratio of 115
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None