Trial document




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  DRKS00003252

Trial Description

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Title

Use of Acetylsalicylic Acid (ASA) for Enhanced Early Detection of Colorectal Neoplasms

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Trial Acronym

ASTER

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URL of the Trial

https://www.dkfz.de/de/klinepi/Projekte/aster-Studie.html

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Brief Summary in Lay Language

Purpose and Background:
With over 1.2 million new cases and over 600,000 deaths annually, colorectal cancer (CRC) is the third most common cancer and the fourth most common cancer cause of death worldwide. The majority of cases of this severe disease could be prevented by early detection and removal of cancer precursors and early cancer stages. There are a number of methods for early detection of colorectal cancer, such as the test for blood in stool (fecal occult blood test). However, this test is not very sensitive to early stages of cancer. This means, that it is possible that the test does not show blood in the stool sample, although the disease is present. Therefore, it is necessary to develop better tests. At the moment, the best method for early detection is a screening colonoscopy, but many people do not want to undergo this invasive test.
In a recent study, our group has shown that the sensitivity of tests for blood in stool was strongly increased in study participants that took acetylsalicylic acid on a regular basis. Acetylsalicylic acid is marketed in Germany by Bayer under the name Aspirin®. The study results suggest that the use of acetylsalicylic acid before a test for blood in stool could be a promising approach to better early detection of colorectal cancer. However, acetylsalicylic acid was only used by about 10% of the participants in our study and in almost all cases it was taken on a regular basis for a longer period of time. Although we expect that a single dose of acetylsalicylic acid will have the same effect, this has not been studied so far. In addition, most of the acetylsalicylic acid users were men and thus the effects in women are unclear.

What will be done:
In the current study, we will study two tests for blood in stool after a single low dose of acetylsalicylic acid. Acetylsalicylic acid or placebo will be given to 2400 study participants between 40 and 80 years of age at least 5 days before a planned, study-independent colonoscopy. Stool samples will be collected at the start of the study and 2, 3 and 4 days after the dose of acetylsalicylic acid/placebo. The results of the stool tests will be compared to the results of the colonoscopy.

Study question:
To evaluate diagnostic performance (sensitivity, specificity, positive and negative predictive values, likelihood ratios, area under the curve) of 2 immunochemical Fecal Occult Blood Tests (iFOBTs) for detecting advanced colorectal neoplasms after a single dose of acetylsalicylic acid as compared to placebo.
Additional questions in this study are if there are differences in effects between men and women and if the test becomes better if stool samples collected on multiple days are combined.
In the future, blood tests may also play a role in early detection of colorectal cancer. So far, no such tests are available. Therefore, an optional blood sample collection is part of this study. This blood sample will be used to study new blood markers for early detection of colorectal cancer in the future.

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Brief Summary in Scientific Language

With over 1.2 million new cases and over 600,000 deaths annually, colorectal cancer (CRC) is the third most common cancer and the fourth most common cancer cause of death worldwide. Its typically slow progression from detectable and fully curable precursors (adenomas) gives much better perspectives for prevention by early detection than for most other cancer types. Thus, the majority of CRCs could be prevented by endoscopy with detection and removal of adenomas. However, participation of patients in endoscopic screening programs is low, likely due to its invasiveness. Higher participation rates can be achieved with non-invasive stool- or blood-based screening tests. However, these tests suffer from poor sensitivity. In a recent study by our group, sensitivity for detecting advanced colorectal neoplasms by immunochemical fecal occult blood test (iFOBT) was 70.8% among users of low-dose aspirin compared with 35.9% among non-users (p=0.001), whereas there were only very small differences in specificity. In ROC analysis, the area under the curve (AUC) was much higher for users than for non-users, with particularly strong differences in men (0.87 versus 0.68, p=0.003). This finding suggests that use of low-dose aspirin before conduction of iFOBT might be a promising approach to improve non-invasive screening for CRC. In the randomised, double-blind, placebo-controlled study that we propose here, we will evaluate the diagnostic performance (sensitivity, specificity, positive and negative predictive values, likelihood ratios, area under the curve) of two iFOBTs for detecting advanced colorectal neoplasms after a single dose of low-dose aspirin compared to application of the tests without prior use of aspirin. Aspirin or placebo will be administered at least 5 days before a planned, study-independent colonoscopic screening in 2000 participants aged 40 to 80 years. Stool samples will be obtained at baseline and 2, 3, and 4 days after the single dose of aspirin/placebo. The diagnostic performance of the iFOBTs will be compared to the results of the colonoscopy as a gold standard for the diagnosis of colorectal neoplasms.
Additional study questions include gender-specific performance of the tests and gain in diagnostic performance by test application on multiple days.
In addition, an optional blood sample is taken for future biomarker studies.

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Organizational Data

  •   DRKS00003252
  •   2013/03/13
  •   [---]*
  •   yes
  •   Approved
  •   AFmu-271/2012, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  •   2011-005603-32 
  •   4038264 
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Health Condition or Problem studied

  •   C18 -  Malignant neoplasm of colon
  •   C19 -  Malignant neoplasm of rectosigmoid junction
  •   C20 -  Malignant neoplasm of rectum
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Interventions/Observational Groups

  •   Volunteers in arm 1 receive a single oral dose of acetylsalicylic acid (ASA) 300 mg, in order to evaluate the diagnostic potential of two immunochemical Fecal Occult Blood Tests (iFOBTs) for detecting advanced colorectal neoplasms.
    Only volunteers with a planned (study-independent) colonoscopy (6 days to 3 month after ASA) are included.
  •   Volunteers in arm 2 receive a single oral dose of a placebo. Other procedures are identical to arm 1.
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Placebo
  •   Screening
  •   Parallel
  •   III
  •   Yes
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Primary Outcome

To evaluate diagnostic performance (sensitivity, specificity, positive and negative predictive values, likelihood ratios, area under the curve) of 2 imunochemical Fecal Occult Blood Tests for detecting advanced colorectal neoplasms after a single dose of aspirin as compared to application of the tests without prior use of aspirin.

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Secondary Outcome

To study gender-specific performance of the 2 iFOBTs and the possible gain in diagnostic performance by stool sampling on multiple days.
To study the safety of single-dose aspirin in the selected population.

Participants will be asked to fill out a standardized questionnaire addressing potential determinants of risk of colorectal neoplasms and of test performance, including general participant characteristics, co-morbidities, and lifestyle factors.

To collect blood samples for additional biomarker analyses (optional).

Blood samples will be stored at the coordinating center without a time limit for future development and analysis of biomarkers including genetic markers potentially related to the presence of advanced adenomas and/or colorectal carcinoma and for analysis of the determinants of the effects of acetylsalicylic acid. Long-term storage of the blood samples collected in this study will allow evaluating such novel blood markers with minimal delay. As intensive research into new blood tests is ongoing, it is neither useful nor possible to explicitly state which exact markers will be tested in the future. These markers may be based upon the literature, but it is also likely, that markers will be tested that are found in one of the several observational studies into early detection of colorectal cancer that are currently ongoing in the Department of Clinical Epidemiology and Aging Research of the DKFZ. These may include genetic or epigenetic markers.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Doctor's Practice 
  • Medical Center 
  • Medical Center 
  • Doctor's Practice 
  • Medical Center 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Medical Center 
  • Doctor's Practice 
  • Doctor's Practice 
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Recruitment

  •   Actual
  •   2013/06/18
  •   2400
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   40   Years
  •   80   Years
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Additional Inclusion Criteria

• Age 40 to 80 years (both males and females; premenopausal women must have a negative pregnancy test before inclusion into the study, postmenopausal women are women who have not had menstrual bleeding for at least 12 months, or have been surgically sterilized)
• Planned screening or diagnostic colonoscopy
• Able to speak and understand German sufficiently to be able to give written informed consent and comply with the study requirements

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Exclusion Criteria

1. Factors potentially influencing the primary endpoint
a. Diseases/symptoms
a1. Chronic inflammatory bowel disease
a2. Angiodysplasia of the colon
a3. Anamnestic or observed blood loss per anum
b. Use of any of the following drugs
b1. Within 2 weeks before the study
• Anticoagulants (including, but not limited to heparin, vitamin K antagonists, e.g. phenprocoumon, warfarin, direct thrombin inhibitors)
• Antiplatelet drugs (e.g. clopidogrel, prasugrel, ticlopidin)
b2. Within 1 week before the study
• Acetylsalicylic acid
b3. Within 3 days before the study
• NSAIDs and COX-2 inhibitors

2. Factors potentially affecting the safety
a. Any current clinically relevant signs and symptoms, including
a1. Signs and symptoms suggesting acute gastrointestinal ulcer
a2. Known clinically relevant thrombocytopenia
a3. Acute infection
a4. Volume deficit (exsiccosis)
a5. Any currently present allergy with dermal reactions, pruritus, or urticaria
a6. Severe or insufficiently controlled asthma
a7. Severe kidney or liver diseases
a8. Any liver cirrhosis
a9. Severe, not sufficiently treated heart failure
a10. Severe, poorly controlled hypertension
a11. Any other unclear symptoms needing further investigation in the opinion of the investigator
b. Any of the following anamnestic findings
b1. History of severe gastrointestinal bleeding
b2. Known hemorrhagic diathesis, including, but not limited to, hypoprothrombinaemia, thrombocytopenia, hemophilia
b3. Asthma, except for patients who have used acetylsalicylsäure in the past without negative effects
b4. Hypersensitivity against salicylic acid or other ingredients of the study drugs
b5. Previous intolerance to NSAIDs, COX-2 inhibitors, or antirheumatic medication
b6. Severe gout (e.g. recurrent attacks)
b7. Hereditary oxaluria
b8. Known G6PD or glutathione peroxidase deficiency
b9. Known epilepsy with generalised seizures
b10. Severe cardiac diseases (including, but not limited to, myocardial infarction in the past 6 months)
c. Intention to use any of the following drugs during the study
c1. Anticoagulants
c2. Antiplatelet drugs
c3. NSAIDs, COX-2 inhibitors
c4. Methotrexate ≥ 15 mg/week
c5. Systemic glucocorticoids
c6. Selective serotonin reuptake inhibitors (SSRIs)
c7. Valproic acid
d. Planned surgery/dental treatment during participation in the study
e. Known pregnancy or lactation

3. Other factors
a. Known or suspected relevant alcohol abuse
b. Known or suspected illicit drug abuse
c. Suspected non-compliance with the study procedures
d. Participation in another clinical study

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Addresses

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    • Deutsches Krebsforschungszentrum Heidelberg
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    • Deutsches Krebsforschungszentrum Heidelberg
    • Mr.  Professor Dr. med.  Hermann  Brenner 
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    • Abteilung Klinische Epidemiologie und Alternsforschung Deutsches Krebsforschungsinstitut
    • Ms.  Dr.  Kaja  Tikk 
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
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Status

  •   Recruiting complete, follow-up complete
  •   2017/01/27
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.