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NCT05412004
9.3.5.1
Adverse Events
9.3.5.1. Adverse Events Adverse events will be classified by system organ class and preferred term as defined by the Medical Dictionary for Regulatory Activities. All conditions existing prior to randomization at Visit 2 will be used as baseline. The postbaseline visits during the placebo-controlled phase will be inclu...
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NCT05412004
9.3.5.2
Hypoglycemic Events
9.3.5.2. Hypoglycemic Events Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia will be summarized and compared between tirzepatide at the MTD (10 mg or 15 mg) and placebo. Rate of hypoglycemic episodes will also be analyzed. Some analyses may be conducted excluding data after introducing a...
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NCT05412004
9.3.5.3
Gastrointestinal Events
9.3.5.3. Gastrointestinal Events Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be provided by each treatment.
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NCT05412004
9.3.5.4
Adjudicated Cardiovascular Events
9.3.5.4. Adjudicated Cardiovascular Events Listings of deaths, myocardial infarctions, strokes, and hospitalizations for unstable angina or heart failure confirmed by an independent Clinical Endpoint Committee (CEC) will be provided.
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NCT05412004
9.3.5.5
Central Laboratory Measures and Vital Signs
9.3.5.5. Central Laboratory Measures and Vital Signs Values and change from baseline to postbaseline values of central laboratory measures and vital signs will be summarized and compared between tirzepatide at the MTD (10 mg or 15 mg) and placebo at each scheduled visit.
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NCT05412004
9.3.5.6
Analysis of C-SSRS Data
9.3.5.6. Analysis of C-SSRS Data Suicide-related thoughts and behaviors occurring during treatment will be summarized based on responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide (The Columbia Lighthouse Project, 2013).
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NCT05412004
9.3.6
Evaluation of Immunogenicity
9.3.6. Evaluation of Immunogenicity The frequency and percentage of participants with preexisting ADA and with TE ADA+ to tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution (1:10) of the ADA assay if no ADAs were detect...
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NCT05412004
9.3.7
Other Analyses
9.3.7. Other Analyses
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NCT05412004
9.3.7.1
Health Economics
9.3.7.1. Health Economics Analyses of actual and change from baseline in PRO scores will be conducted using linear models with baseline PRO scores, treatment, stratification factors and other factors that may be considered relevant. These variables will be specified in the SAP.
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NCT05412004
9.3.7.2
Subgroup Analyses
9.3.7.2. Subgroup Analyses The following subgroups will be analyzed using the "efficacy" estimand on percent change in AHI values from baseline to 52 week visit if there are sufficient numbers of participants in each treatment by subgroup (for example, 10%): - Age (50 years, 50 years), - Baseline OSA severity (Moderate...
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NCT05412004
9.4
Interim Analysis
9.4. Interim Analysis Based on the projected enrollment, approximately 3 interim analyses of safety will be conducted. The first interim analysis is planned to occur when approximately 20% of the anticipated number of participants are randomly assigned to study intervention or 6 months after the first participant is ra...
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NCT05412004
9.5
Sample Size Determination
9.5. Sample Size Determination Approximately 206 participants per ISA will be randomly assigned to either tirzepatide or placebo in a 1:1 ratio (approximately 103 participants per treatment arm), and the statistical power is evaluated for the primary efficacy endpoint and key secondary combination PRO endpoint at a 2-s...
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NCT05412004
10
Supporting Documentation and Operational Considerations
10. Supporting Documentation and Operational Considerations
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NCT05412004
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
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NCT05412004
10.1.1
Regulatory and Ethical Considerations
10.1.1. Regulatory and Ethical Considerations This study will be conducted in accordance with the protocol and with the following: - Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethi...
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NCT05412004
10.1.2
Financial Disclosure
10.1.2. Financial Disclosure Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial information as requested to allow the sponsor to submit complete and accurate financial certification or disclosure statements to the appropriate regulatory authorities. Investigators are respon...
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NCT05412004
10.1.3
Informed Consent Process
10.1.3. Informed Consent Process The investigator or the investigator's representative will explain the nature of the study, including the risks and benefits, to the participant or the participant's legally authorized representative and answer all questions regarding the study. Participants must be informed that their ...
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NCT05412004
10.1.4
Data Protection
10.1.4. Data Protection Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets or tissue samples that are transferred to the sponsor will contain the identifier only; participant names or any information which would make the participant identifiable will not be transferred. ...
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NCT05412004
10.1.5
Committees Structure
10.1.5. Committees Structure Prospective adjudication of major adverse CV events and pancreatic AEs will be performed by the independent adjudication committees for this study. Sections [10.1.5.1](#page-71-1) and [10.1.5.2](#page-71-2), Appendix 1 outline additional information on pancreatic and CV adjudication. An ind...
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NCT05412004
10.1.5.1
Cardiovascular Adjudicated Events
10.1.5.1. Cardiovascular Adjudicated Events Deaths and nonfatal CV AEs will be adjudicated by a committee blinded to treatment assignment. The nonfatal CV AEs to be adjudicated include: - myocardial infarction - hospitalization for unstable angina - hospitalization for heart failure - coronary interventions (such as co...
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NCT05412004
10.1.5.2
Pancreatitis Adjudicated Event
10.1.5.2. Pancreatitis Adjudicated Event Acute pancreatitis is defined as an AE of special interest in this trial (Section [8.3.3\)](#page-58-0). The diagnosis of acute pancreatitis requires 2 of the following 3 features: - abdominal pain, characteristic of acute pancreatitis (generally located in the epigastrium and r...
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NCT05412004
10.1.6
Dissemination of Clinical Study Data
10.1.6. Dissemination of Clinical Study Data Reports The sponsor will disclose a summary of study information, including tabular study results, on publicly available websites where required by local law or regulation. The summary of results will be posted within the time frame specified by local law or regulation. If ...
[ "Reports", "Data" ]
NCT05412004
10.1.7
Data Quality Assurance
10.1.7. Data Quality Assurance All participant data relating to the study will be recorded on printed or electronic CRFs unless transmitted to the sponsor or designee electronically (for example, laboratory data). The investigator is responsible for verifying that data entries are accurate and correct by physically or ...
[ "Data Capture System" ]
NCT05412004
10.1.8
Source Documents
10.1.8. Source Documents Source documents provide evidence for the existence of the participant and substantiate the integrity of the data collected. Source documents are filed at the investigator's site. Data reported on or entered in the CRF and are transcribed from source documents must be consistent with the source...
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NCT05412004
10.1.9
Study and Site Start and Closure
10.1.9. Study and Site Start and Closure First Act of Recruitment The study start date is the date on which the clinical study will be open for recruitment of participants. The first act of recruitment is the first site open and will be the study start date. Study or Site Termination The sponsor or sponsor's designee...
[ "First Act of Recruitment", "Study or Site Termination" ]
NCT05412004
10.1.10
Publication Policy
10.1.10. Publication Policy In accordance with the sponsor's publication policy, the results of this study will be submitted for publication by a peer-reviewed journal.
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NCT05412004
10.1.11
Investigator Information
10.1.11. Investigator Information Researchers with appropriate education, training, and experience, as determined by the sponsor, will participate as investigators in this clinical trial.
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NCT05412004
10.1.12
Sample Retention
10.1.12. Sample Retention Sample retention enables use of new technologies, response to regulatory questions, and investigation of variable response that may not be observed until later in the development of tirzepatide or after tirzepatide becomes commercially available. | Sample Type | Custodian | Retention Period Af...
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NCT05412004
10.2
Appendix 2: Clinical Laboratory Tests
10.2. Appendix 2: Clinical Laboratory Tests The tests detailed in the table below will be performed by the central laboratory. Local laboratory results are only required in the event that the central laboratory results are not available in time for either study intervention administration and/or response evaluation. If...
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NCT05412004
10.2.1
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity Event
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity Event Purpose of collecting samples after a systemic hypersensitivity event The samples listed in this appendix are not collected for acute study participant management. The sponsor will use the laboratory tests results from these sam...
[ "Purpose of collecting samples after a systemic hypersensitivity event", "When to collect samples after a systemic hypersensitivity event occurs", "What information to record", "Allowed additional testing for participant management" ]
NCT05412004
10.3
Appendix 3: Adverse Events and Serious Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting
10.3. Appendix 3: Adverse Events and Serious Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting - The definitions and procedures detailed in this appendix are in accordance with International Organization for Standardization (ISO) 14155. - Both the investigator and the sponso...
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NCT05412004
10.3.1
Definition of AE
10.3.1. Definition of AE AE Definition - An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory fi...
[ "AE Definition", "Events Meeting the AE Definition", "Events NOT Meeting the AE Definition" ]
NCT05412004
10.3.2
Definition of SAE
10.3.2. Definition of SAE An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: a. Results in death b. Is life-threatening The term life-threatening in the definition of serious refers to an event in which the participant was at risk of death at the time of ...
[ "a. Results in death", "b. Is life-threatening", "c. Requires inpatient hospitalization or prolongation of existing hospitalization", "d. Results in persistent disability/incapacity", "e. Is a congenital anomaly/birth defect", "f. Other situations:" ]
NCT05412004
10.3.3
Definition of Product Complaints
10.3.3. Definition of Product Complaints Product Complaint - A PC is any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or performance of a study intervention. When the ability to use the study intervention safely is...
[ "Product Complaint" ]
NCT05412004
10.3.4
Recording and Follow-Up of AE and/or SAE and Product Complaints
10.3.4. Recording and Follow-Up of AE and/or SAE and Product Complaints AE, SAE, and PC Recording - When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all documentation (for example, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. - The investig...
[ "AE, SAE, and PC Recording", "Assessment of Intensity", "Assessment of Causality", "Follow-Up of AEs and SAEs" ]
NCT05412004
10.3.5
Reporting of SAEs
10.3.5. Reporting of SAEs SAE Reporting via an Electronic Data Collection Tool - The primary mechanism for reporting an SAE will be the electronic data collection tool. - If the electronic system is unavailable, then the site will use the SAE paper form (see next section) in order to report the event within 24 hours. ...
[ "SAE Reporting via an Electronic Data Collection Tool", "SAE Reporting via Paper Form" ]
NCT05412004
10.3.6
Regulatory Reporting Requirements
10.3.6. Regulatory Reporting Requirements SAE Regulatory Reporting - Prompt notification by the investigator to the sponsor of an SAE is essential so that legal obligations and ethical responsibilities toward the safety of participants and the safety of a study intervention under clinical investigation are met. - The ...
[ "SAE Regulatory Reporting" ]
NCT05412004
10.3.7
Special Safety Topics
10.3.7. Special Safety Topics
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NCT05412004
10.3.7.1
Hypoglycemia
10.3.7.1. Hypoglycemia Participants will be trained by authorized study personnel about signs and symptoms of hypoglycemia and how to treat hypoglycemia, and how to collect appropriate information for each episode of hypoglycemia. Hypoglycemia may be identified by spontaneous reporting of symptoms from participants (wh...
[ "Level 1 hypoglycemia:", "Level 2 hypoglycemia:", "Level 3 hypoglycemia:", "Nocturnal hypoglycemia:" ]
NCT05412004
10.3.7.2
Hypersensitivity Reactions
10.3.7.2. Hypersensitivity Reactions Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity reactions. If such a reaction occurs, additional data should be provided to the sponsor in the designated CRFs. Sites should have appropriately trained medical staff and appropriate me...
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NCT05412004
10.3.7.3
Injection-Site Reactions
10.3.7.3. Injection-Site Reactions Symptoms and signs of a local ISR may include erythema, induration, pain, pruritus, and edema. If an ISR is reported by a participant or parent or guardian or site staff, the ISR CRF will be used to capture additional information about this reaction, for example, injection site pain, ...
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NCT05412004
10.4
Appendix 4: Contraceptive and Barrier Guidance
10.4. Appendix 4: Contraceptive and Barrier Guidance
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NCT05412004
10.4.1
Definitions
10.4.1. Definitions | Word/Phrase | Definition | | |--------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------...
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NCT05412004
10.4.2
Contraception Guidance
10.4.2. Contraception Guidance
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NCT05412004
10.4.2.1
Females
10.4.2.1. Females WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same sex relationship, as part of their preferred and usual lifestyle | Must… | Must not… | |------------------------------------------------------------------------------------------------------------------------------...
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NCT05412004
10.4.2.2
Males
10.4.2.2. Males The table below describes contraception guidance for all men. | Topic | Guidance | |-----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------...
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NCT05412004
10.5
Appendix 5: Genetics
10.5. Appendix 5: Genetics Use/Analysis of DNA Genetic variation may impact a participant's response to study intervention, susceptibility to, and severity and progression of disease. Variable response to study intervention may be due to genetic determinants that impact drug absorption, distribution, metabolism, and e...
[ "Use/Analysis of DNA" ]
NCT05412004
10.6
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
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NCT05412004
10.6.1
Hepatic Evaluation Testing
10.6.1. Hepatic Evaluation Testing See Sections [10.6.2](#page-94-0) and [10.6.3,](#page-94-1) Appendix 6 for guidance on appropriate test selection. The Lilly-designated central laboratory must complete the analysis of all selected testing except for microbiology testing. Local testing may be performed in addition to ...
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NCT05412004
10.6.2
Close Hepatic Monitoring
10.6.2. Close Hepatic Monitoring Laboratory tests (Section [10.2,](#page-76-0) Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if one or m...
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NCT05412004
10.6.3
Comprehensive Hepatic Evaluation
10.6.3. Comprehensive Hepatic Evaluation A comprehensive evaluation should be performed to search for possible causes of liver injury if one or more of these conditions occur: | If a participant with baseline results of | develops the following elevations: | | |-------------------------------------------|--------------...
[ "Additional hepatic data collection (hepatic safety CRF) in study participants who have abnormal liver tests during the study" ]
NCT05412004
10.8
Appendix 8: Protocol GPIF Standardized Protocols for the Measurement of Height, Weight, Neck Circumference, Waist Circumference, Vital Signs, and Electrocardiogram
10.8. Appendix 8: Protocol GPIF Standardized Protocols for the Measurement of Height, Weight, Neck Circumference, Waist Circumference, Vital Signs, and Electrocardiogram The following information has been adapted from standardized physical measurement protocols for the World Health Organization's STEPwise approach to S...
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NCT05412004
10.8.1
Measuring Height
10.8.1. Measuring Height - Step 1.Ask the participant to remove their footwear and any headgear (light headgear worn for religious reasons can remain, but this should be worn by the participant at every clinic visit when their height is measured). - Step 2.Ask the participant to stand on the calibrated height measuring...
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NCT05412004
10.8.2
Measuring Weight
10.8.2. Measuring Weight - Body weight measurements should be done in a consistent manner using a calibrated electronic scale capable of measuring weight in kilograms to 1 decimal place. - All weights for a given participant should be measured using the same scale, whenever possible, at approximately the same time in t...
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NCT05412004
10.8.3
Measuring Hip and Waist Circumference
10.8.3. Measuring Hip and Waist Circumference Hip circumference measurements should be obtained with the participant in the standing position. The hip circumference should be measured at the maximal circumference of the buttocks. - Waist circumference should be measured in the horizontal plane and at the midpoint betwe...
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NCT05412004
10.8.4
Measuring Neck Circumference
10.8.4. Measuring Neck Circumference - Participants should look straight ahead during the measurement, with shoulders down (not hunched). - Measure the neck circumference at a point just below the larynx (Adam's Apple) and perpendicular to the long axis of the neck. - Do not place the tape measure over the Adam's Apple...
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NCT05412004
10.8.5
Vital Sign Measurements (Blood Pressure and Heart Rate)
10.8.5. Vital Sign Measurements (Blood Pressure and Heart Rate) - Vital sign measurements (BP and heart rate, measured by pulse) should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing - The participant should sit quietly for at least 5 minutes before vital signs me...
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NCT05412004
10.8.6
Electrocardiogram
10.8.6. Electrocardiogram - All digital ECGs will be obtained using local ECG machines. - 12-lead ECGs should be obtained after the participant has rested in a supine position for at least 5 minutes. - Electrocardiograms should be collected prior to collection of blood samples for laboratory testing, including PK sampl...
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NCT05412004
10.9
Appendix 9: Provisions for Changes in Study Conduct Due to the COVID-19 Pandemic
10.9. Appendix 9: Provisions for Changes in Study Conduct Due to the COVID-19 Pandemic Implementation of this appendix The changes to procedures described in this appendix are temporary measures intended to be used only during specific time periods as directed by the sponsor in partnership with the investigator. Stud...
[ "Implementation of this appendix", "Study disruptions due to the COVID-19 pandemic", "Implementing changes due to the COVID-19 pandemic", "Considerations for making a change", "Informed consent", "Changes in study conduct due to the COVID-19 pandemic", "Remote visits", "Telephone/Telemedicine", "Mob...
NCT05412004
10.11
Appendix 11: Country-Specific Requirements
10.11. Appendix 11: Country-Specific Requirements
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NCT05412004
10.11.1
Germany
10.11.1. Germany This section describes protocol changes applicable for adult participants in study sites in Germany. This table describes the changes and provides a rationale for the changes. | Name | Protocol Section Number and | Description of theChange | Brief Rationale | |--------------|---------------------------...
[ "7.2. Participant Discontinuation/Withdrawal from the Study", "8.3. Adverse Events, Serious Adverse Events, and Product Complaints" ]
NCT05412004
10.1.3
Informed Consent Process
10.1.3 Informed Consent Process The investigator or the investigator's representative will explain the nature of the study, including the risks and benefits, to the participant or the participant's legally authorized representative and answer all questions regarding the study. Participants must be informed that their p...
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NCT05412004
10.10
Appendix 10: Abbreviations and Definitions
10.10. Appendix 10: Abbreviations and Definitions enter Participants entered into a study are those who sign the informed consent form directly or through their legally acceptable representatives.
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NCT05412004
10.12
Appendix 12: Protocol Amendment History
10.12. Appendix 12: Protocol Amendment History The Protocol Amendment Summary of Changes Table for the current amendment is located directly before the Table of Contents (TOC). Amendment [b]: 30-Sep-2022 This amendment is considered to be substantial. The amendment is considered to be substantial because it is likely ...
[ "Amendment [b]: 30-Sep-2022", "Overall Rationale for the Amendment:", "Amendment a: 10-Feb-2022", "Overall Rationale for the Amendment:" ]
NCT05412004
11
References
11. References - [ADA] American Diabetes Association Glycemic targets: Standards of medical care in diabetes-2020. Diabetes Care. 2020:43(Suppl 1):S66–S76. https://doi.org/10.2337/dc20-S006 - [AHRQ] Agency for Healthcare Research and Quality. Continuous positive airway pressure treatment for obstructive sleep apnea. Ac...
[ "Signature Page for VV-CLIN-116270 v1.0" ]
NCT05416164
1
INTRODUCTION AND RATIONALE
1. INTRODUCTION AND RATIONALE NST is increasingly used in breast cancer treatment(1), resulting in tumour downsizing and increase in breast conserving surgery(BCS) rates without compromising local recurrence or overall survival.(2-6) The extent of tumour downsizing is largely dependent on breast cancer molecular subtyp...
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NCT05416164
2
OBJECTIVES
2. OBJECTIVES Primary Objective: To show that omitting radiotherapy in patients with a pathologic complete response to NST results in a 5-year local control rate of >94%. Secondary Objective: To show that omitting radiotherapy in patients with a pathologic complete response to NST results in good quality of life with...
[ "Primary Objective:", "Secondary Objective:" ]
NCT05416164
3
STUDY DESIGN
3. STUDY DESIGN The DESCARTES trial is a prospective single arm study investigating the effects on local control and quality of life of omitting radiotherapy after NST in cT1-2N0 patients who achieve breast and axillary pCR after NST. Eligibility of patients will be assessed at multi-disciplinary meetings. Women with a...
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NCT05416164
4
STUDY POPULATION
4. STUDY POPULATION
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NCT05416164
4.1
Population (base)
4.1 Population (base) Eligible patients are women with cT1-2, N0 HR+HER2-, HER2+(HR+/-) or TN breast cancer who achieve pathologic complete response after NST. Concurrent DCIS in pre-NST biopsy is allowed if there is no suspicion of an extensive component; patients are excluded if they have the combination of concurren...
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NCT05416164
4.2
Inclusion criteria
4.2 Inclusion criteria In order to be eligible to participate in this study, a subject must meet all of the following criteria: - Women, aged ≥ 18 years - Invasive HR positive/Her2 negative, Her2+ (ER/PR +/-) or TN breast cancer - Concurrent DCIS in pre-NST biopsy is allowed if there is no suspicion of extensive compon...
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NCT05416164
4.3
Exclusion criteria
4.3 Exclusion criteria A potential subject who meets any of the following criteria will be excluded from participation in this study: - Primary tumour (T) clinical stage cT3-4 - Pre- or post-NST diagnosis of nodal disease including isolated tumour cells - Concurrent LCIS of any type in either pre-NST biopsy or surgical...
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NCT05416164
4.4
Sample size calculation
4.4 Sample size calculation Reported 5 year local and locoregional recurrence rates for patients with stage 2 and 3 disease (cT1-4N0-3) treated with NST, breast conserving surgery and radiotherapy who achieve pCR range from 0 to 3.5%, in which patients with DCIS (all reports) and even isolated tumour cells (one report,...
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NCT05416164
5
TREATMENT OF SUBJECTS
5. TREATMENT OF SUBJECTS
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NCT05416164
5.1
Investigational product/treatment
5.1 Investigational product/treatment Not applicable
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NCT05416164
5.2
Use of co-intervention (if applicable)
5.2 Use of co-intervention (if applicable) Not applicable
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NCT05416164
5.3
Escape medication (if applicable)
5.3 Escape medication (if applicable) Not applicable Version number: 9.0 September 2024 18 of 33
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NCT05416164
6
METHODS
6. METHODS
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NCT05416164
6.1
Study parameters/endpoints
6.1 Study parameters/endpoints
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NCT05416164
6.1.1
Main study parameter/endpoint
6.1.1 Main study parameter/endpoint The primary endpoint of the DESCARTES study is the local recurrence rate after 5 years.
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NCT05416164
6.1.2
Secondary study parameters/endpoints
6.1.2 Secondary study parameters/endpoints - Local non-salvageable recurrence free survival (i.e. an in-breast recurrence that cannot be adequately cured with breast conserving surgery with RTx) after 5 years - Quality of life at baseline and after 1 and 4 years after surgery - Cancer worry at baseline and after 1 and ...
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NCT05416164
6.2
Randomisation, blinding and treatment allocation
6.2 Randomisation, blinding and treatment allocation This is a prospective non-randomized clinical trial.
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NCT05416164
6.3
Study procedures
6.3 Study procedures - Neoadjuvant systemic therapy Patients included in the DESCARTES trial will receive neoadjuvant chemotherapy +/ antiHER2 therapy according to national and local breast cancer guidelines. - Surgery of breast and axilla Breast conserving surgery should be performed. If studies show post-NST biopsies...
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NCT05416164
6.4
Withdrawal of individual subjects
6.4 Withdrawal of individual subjects Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons.
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NCT05416164
6.4.1
Specific criteria for withdrawal (if applicable)
6.4.1 Specific criteria for withdrawal (if applicable) Not applicable.
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NCT05416164
6.5
Replacement of individual subjects after withdrawal
6.5 Replacement of individual subjects after withdrawal Not applicable.
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NCT05416164
6.6
Follow-up of subjects withdrawn from treatment
6.6 Follow-up of subjects withdrawn from treatment Not applicable.
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NCT05416164
6.7
Premature termination of the study
6.7 Premature termination of the study If the interim analysis for futility shows a higher than acceptable local recurrence rate, the study will be terminated. See statistics for detailed information. Version number: 9.0 September 2024 20 of 33
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NCT05416164
7
SAFETY REPORTING
7. SAFETY REPORTING
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NCT05416164
7.1
Temporary halt for reasons of subject safety
7.1 Temporary halt for reasons of subject safety In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardise subject health or safety. The sponsor will notify the accredited METC without undue delay of a temporary...
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NCT05416164
7.2
AEs, SAEs and SUSARs
7.2 AEs, SAEs and SUSARs
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NCT05416164
7.2.2
Serious adverse events (SAEs)
7.2.2 Serious adverse events (SAEs) A serious adverse event is any untoward medical occurrence or effect that - results in death; - is life threatening (at the time of the event); - requires hospitalisation or prolongation of existing inpatients' hospitalisation; - results in persistent or significant disability or inc...
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NCT05416164
7.5
Safety Committee
7.5 Safety Committee A data safety committee will be established to monitor the number and nature of any recurrences that may occur. The data safety committee will consist of a surgical oncologist, radiation oncologist, pathologist and statistician. Version number: 9.0 September 2024 22 of 33
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NCT05416164
8
STATISTICAL ANALYSIS
8. STATISTICAL ANALYSIS
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NCT05416164
8.1
Primary study parameter(s)
8.1 Primary study parameter(s) The primary endpoint of the study is the local recurrence rate, defined as recurrence in the ipsilateral breast. Any LR is considered as an event and is included in the analysis. Time to LR will be estimated by the Kaplan-Meier method and compared to the acceptable rate of 6% at 5 years b...
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NCT05416164
8.2
Secondary study parameter(s)
8.2 Secondary study parameter(s) Rates of distant metastasis free survival, overall survival and disease specific free survival and local non-salvageable recurrence free survival after 5 and 10 years are calculated by the method of Kaplan-Meier and comparisons are made by log-rank test.
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NCT05416164
8.3
Other study parameters
8.3 Other study parameters Characteristics of the cohort will be described in detail using mean and standard deviation for continuous variables, and count and percentage for categorical variables. To compare distribution of clinical factors among subgroups (molecular subtypes), the Chi square test are used for categori...
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NCT05416164
8.4
Interim analysis
8.4 Interim analysis An analysis of futility will be performed after inclusion of 325 patients and a minimum median follow up time of 16.2 months. Assuming a 5 year follow up and a 5 year uniform accrual, assuming as well an exponential distribution for survival, we calculated that the expected number of events when 32...
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NCT05416164
9
ETHICAL CONSIDERATIONS
9. ETHICAL CONSIDERATIONS
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NCT05416164
9.1
Regulation statement
9.1 Regulation statement The study will be conducted according to the principles of the Declaration of Helsinki (version 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts.
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