Infections

All Conditions

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Communicable Diseases

Papillomavirus Infections

Congenital Abnormalities

Sexually Transmitted Diseases

Sexually Transmitted Diseases, Viral

Virus Diseases

DNA Virus Infections

Tumor Virus Infections

Genital Diseases

Urogenital Diseases

Disease Attributes

All Drugs and Chemicals

Vaccines

Registry, survey, and HPV status data from 2004-2006

Registry, survey, and HPV status data from 2011-2012

Medical Director

This study will assess the impact of GARDASIL™ human papillomavirus (HPV) vaccine in the general female population by utilizing nationwide registry databases in the participating Nordic countries.

Time perspective: The study will be conducted using data collected both retrospectively/concurrently from registries and prospectively by questionnaire survey.

Baseline survey data were collected during a prior study from 2004-2005.

Safety Monitoring: An expert panel on teratology consisting of one teratologist from each of the participating countries will review all available medical records related to any congenital anomalies to search for any emerging patterns that may be indicative of an association between GARDASIL™ exposure in the mother and the subsequent congenital anomalies in the babies.

GARDASIL™ Vaccine Impact in Population Study (V501-033)

GARDASIL™ Vaccine Impact in Population Study

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for women \<=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for women \>26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for women \<=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for women \>26 years of age were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for women \<=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for women \>26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related high-grade (2/3) CIN was estimated based on the proportion of HPV 6/11/16/18 in all CIN in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of high-grade (2/3) CIN related to high-risk HPV types other than 16 and 18 was analyzed. High-risk HPV types include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Incidence was age-adjusted according to Nordic Standard Population.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related cervical cancer was estimated based on the proportion of HPV 6/11/16/18 in all cervical cancers in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of cervical cancer associated with high-risk HPV types other than 16 and 18 was estimated based on the proportion of HPV 16/18 in all cervical cancer in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.

The incidence of HPV-related histologically confirmed female genital diseases, including vulvar and vaginal cancer and their high-grade precursors was to be assessed.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for HPV 6, 11, 16, or 18 was analyzed.

All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for high-risk HPV Types other than 16 or 18, and not co-infected with Types 16 or 18, was analyzed.

The percentage of live born babies with major congenital anomalies (MCA) born to women vaccinated with Gardasil during pregnancy and to women in the general population was assessed. For Denmark and Sweden diagnoses of congenital anomaly within 1 year of birth are included; for Norway diagnoses at birth are included.

The incidence of CIN by Gardasil vaccination status was to be assessed.

The incidence of other cervical cancers by Gardasil vaccination status was to be assessed.

The incidence of other HPV-related genital diseases, including vulvar and vaginal cancers, by Gardasil vaccination status was to be assessed.

The percentage of participants with liquid-based cervical cytology samples positive for HPV 6, 11, 16, and 18 was to be analyzed by Gardasil vaccination status.

Danish Cancer Society

Union for International Cancer Control

Cancer Registry of Norway

Karolinska Institutet

Merck Sharp & Dohme LLC

Per protocol, adverse events were not collected as part of the study database; therefore, none were collected and the number at risk is zero

Denmark Participants

Norway Participants

Sweden Participants

Participants in Denmark who completed the first survey (before licensure of GARDASIL)

Participants in Norway who completed the first survey (before licensure of GARDASIL)

Participants in Sweden who completed the first survey (before licensure of GARDASIL)

Total

Age, Continuous

Sex: Female, Male

Participants who took the first survey given before Gardasil licensure

Senior Vice President, Global Clinical Development

Denmark Participants 2004 to 2006 Before Gardasil Licensure

Denmark Participants 2007, After Gardasil Licensure

Denmark Participants 2008 After Gardasil Licensure

Denmark Participants 2009 After Gardasil Licensure

Denmark Participants 2010 After Gardasil Licensure

Denmark Participants 2011 After Gardasil Licensure

The analysis population was the entire population of qualifying women in Denmark and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia (CIN) for Participants of All Ages in Denmark

The analysis population was the entire population of qualifying women \<=26 years of age in Denmark and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Denmark

The analysis population was the entire population of qualifying women \>26 years of age in Denmark and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Denmark

Norway Participants 2004 to 2006 Before Gardasil Licensure

Norway Participants 2007, After Gardasil Licensure

Norway Participants 2008 After Gardasil Licensure

Norway Participants 2009 After Gardasil Licensure

Norway Participants 2010 After Gardasil Licensure

Norway Participants 2011 After Gardasil Licensure

The analysis population was the entire population of qualifying women in Norway and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants of All Ages in Norway

The analysis population was the entire population of qualifying women \<=26 years of age in Norway and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Norway

The analysis population was the entire population of women \>26 years of age in Norway and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Norway

Sweden Participants 2004 to 2006 Before Gardasil Licensure

Sweden Participants 2007, After Gardasil Licensure

Sweden Participants 2008 After Gardasil Licensure

Sweden Participants 2009 After Gardasil Licensure

Sweden Participants 2010 After Gardasil Licensure

Sweden Participants 2011 After Gardasil Licensure

The analysis population was the entire population of qualifying women in Sweden and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants of All Ages in Sweden

The analysis population was the entire population of qualifying women \<=26 years of age in Sweden and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Sweden

The analysis population was the entire population of qualifying women \>26 years of age in Sweden and thus changed throughout the analysis. The number of participants analyzed given below is an estimate calculated from the number of reported cases and the incidence data.

Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Sweden

Overall CIN

HPV 6/11/16/18-related CIN

Denmark Participants 2011 to 2012 After Gardasil Licensure

Norway Participants 2011 to 2012 After Gardasil Licensure

Sweden Participants 2011 to 2012 After Gardasil Licensure

The analysis population was participants of all ages with newly-diagnosed high-grade CIN and lesional tissue samples analyzed for HPV types

Incidence of Human Papillomavirus (HPV) 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants of All Ages

The analysis population was participants \<=26 years of age with newly-diagnosed high-grade CIN and lesional tissue samples analyzed for HPV types

Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age

The analysis population was participants \>26 years of age with newly-diagnosed high-grade CIN and lesional tissue samples analyzed for HPV types

Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants >26 Years of Age

CIN not related to HPV 16/18

Incidence of Cervical Intraepithelial Neoplasia Associated With High-risk HPV Types Other Than 16/18 in Participants <=26 Years of Age

Incidence of Cervical Intraepithelial Neoplasia Associated With High-risk HPV Types Other Than 16/18 in Participants >26 Years of Age

Overall cervical cancer

HPV 6/11/16/18-related cervical cancer

The analysis population was participants with newly-diagnosed cervical cancer and lesional tissue samples analyzed for HPV types

Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants of All Ages

The analysis population was participants \<=26 years of age with newly-diagnosed cervical cancer and lesional tissue samples analyzed for HPV types

Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants <=26 Years of Age

The analysis population was participants \>26 years of age with newly-diagnosed cervical cancer and lesional tissue samples analyzed for HPV types

Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants >26 Years of Age

Cervical cancer not related to HPV 16/18

Incidence of Cervical Cancer Associated With High-risk HPV Types Other Than 16/18 in Participants <=26 Years of Age

Incidence of Cervical Cancer Associated With High-risk HPV Types Other Than 16/18 in Participants >26 Years of Age

Analysis of this endpoint was not planned nor were the data collected. Thus, the number of participants analyzed is zero.

Incidence of HPV-related Histologically Confirmed Female Genital Diseases, Including Vulvar and Vaginal Cancer and Their High-grade Precursors

The analysis population was participants \<=26 years of age with liquid-based cytology samples analyzed for HPV types

Prevalence of HPV 6/11/16/18 Infection in Participants <=26 Years of Age

The analysis population was participants \>26 years of age with liquid-based cytology samples analyzed for HPV types

Prevalence of HPV 6/11/16/18 Infection in Participants >26 Years of Age

Prevalence of HPV Infection for High-risk Types Other Than 16/18 for Participants <=26 Years of Age

Prevalence of HPV Infection for High-risk Types Other Than 16/18 for Participants >26 Years of Age

Live babies born between 2007 and 2011 to Denmark participants who received Gardasil during pregnancy

Babies Born to Denmark Participants Who Received Gardasil

Live babies born between 2007 and 2011 to Denmark participants in the general population, including participants who did and did not receive Gardasil

Babies Born to Denmark Participants

Live babies born between 2007 and 2011 to Norway participants who received Gardasil during pregnancy

Babies Born to Norway Participants Who Received Gardasil

Live babies born between 2007 and 2011 to Norway participants in the general population, including participants who did and did not receive Gardasil

Babies Born to Norway Participants

Live babies born between 2007 and 2011 to Sweden participants who received Gardasil during pregnancy

Babies Born to Sweden Participants Who Received Gardasil

Live babies born between 2007 and 2011 to Sweden participants in the general population, including participants who did and did not received Gardasil

Babies Born to Sweden Participants

The analysis population represents the babies born to participating mothers, instead of female participants, because the number of babies represents the denominator for the percentage calculation, not female participants (i.e., mothers)

Percentage of Live Born Babies With a Major Congenital Anomaly

Denmark participants who received Gardasil on or before March 2012

Denmark Participants Who Received Gardasil

Denmark Participants Who Did Not Receive Gardasil

Norway participants who received Gardasil on or before March 2012

Norway Participants Who Received Gardasil

Norway Participants Who Did Not Receive Gardasil

Sweden participants who received Gardasil on or before March 2012

Sweden Participants Who Received Gardasil

Sweden Participants Who Did Not Receive Gardasil

The analysis population was to be women who underwent cervical screening. A joint decision was made by the study team to forgo the stratified analysis by vaccination status because there were few women who had both been vaccinated with Gardasil and undergone cervical cancer screening. Thus, the number of participants analyzed is zero.

Incidence of Cervical Intraepithelial Neoplasia by Gardasil Vaccination Status

Incidence of Cervical Cancer by Gardasil Vaccination Status

Incidence of Other HPV-related Genital Diseases by Gardasil Vaccination Status

Prevalence of HPV 6, 11, 16, and 18 Infection by Gardasil Vaccination Status

Overall Study

Neoplasms

Digestive System Diseases

Rare Diseases

Esophageal Neoplasms

Stomach Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Stomach Diseases

Esophageal Cancer

Stomach Cancer

Proton Pump Inhibitors

Enzyme Inhibitors

Long-term use of medications, particularly proton pump inhibitors

Proton pump inhibitor

Jesper Lagergren, MD, PhD

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)

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.

Nordic Gastric and Esophageal Tumor Study

This requires approvals from all institutions delivering the data.

Risk of developing gastric adenocarcinoma using logistic regression providing odds ratios

Risk of developing esophageal cancer using logistic regression providing odds ratios

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
GARDASIL™ Vaccine Impact in Population Study (V501-033)	NCT01077856	Human Papilloma...		18 Years - 45 Years	Merck Sharp & Dohme LLC
Nordic Gastric and Esophageal Tumor Study	NCT05688761	Cancer of Stoma... Cancer of the E... Drug Use	Proton pump inh...	18 Years -	Karolinska Institutet
Nordic Gastric and Esophageal Tumor Study	NCT05688761	Cancer of Stoma... Cancer of the E... Drug Use	Proton pump inh...	18 Years -	Karolinska Institutet

Spots Global Cancer Trial Database for nordic

Every month we try and update this database with for nordic cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for nordic

Every month we try and update this database with for nordic cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for nordic cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.