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protocol_id stringclasses 263 values	section_number stringlengths 1 12	title stringlengths 1 1.88k	content stringlengths 0 866k	merged_titles listlengths 0 491
NCT02125461	6.4.5	Laboratory safety assessment	6.4.5 Laboratory safety assessment Blood and urine samples for determination of clinical chemistry, haematology, urinalysis, thyroid function tests, amylase, and lipase will be taken at the times indicated in Table 1 (Screening and the Treatment Period), Table 2 (follow-up for patients achieving disease control or who ...	[ "Table 6 Clinical chemistry (serum or plasma)", "Table 6 Clinical chemistry (serum or plasma)" ]
NCT02125461	6.4.6	Physical examination	6.4.6 Physical examination For timing of individual measurements refer to the study schedules (Table 1 [Screening and the Treatment Period], Table 2 [for follow-up of patients achieving disease control or who are discontinued due to toxicity or a reason other than confirmed PD] and Table 3 [for follow-up of patients di...	[]
NCT02125461	6.4.7	Electrocardiogram	6.4.7 Electrocardiogram Clinical interpretation and management of patients for all ECGs will be done locally. The same method of assessment should be used throughout. Electrocardiograms will be recorded at 25 mm/sec. Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study. EC...	[]
NCT02125461	6.4.8	Vital signs	6.4.8 Vital signs For timings of assessments refer to the study plans in Table 1 (Screening and the Treatment Period), Table 2 (for follow-up of patients achieving disease control or who are discontinued due to toxicity or a reason other than confirmed PD) and Table 3 (for follow-up of patients discontinuing due to con...	[ "Pulse and blood pressure", "Temperature, respiratory rate and oxygen saturation" ]
NCT02125461	6.4.9	Other safety assessments	6.4.9 Other safety assessments Pregnancy tests on either blood (VHUXPȕ-hCG) or urine (hCG) samples will be performed for pre-menopausal women of childbearing potential at the times specified in Table 1. Tests will be performed by the hospital's local laboratory. If results are positive the patient is ineligible/must be...	[]
NCT02125461	6.5	Patient reported outcomes	6.5 Patient reported outcomes Timings of the assessments for PRO are presented in Table 1 (Screening and the Treatment Period), Table 2 (for follow-up of patients achieving disease control or who are discontinued due to toxicity or a reason other than confirmed PD) and Table 3 (for follow-up of patients discontinuing d...	[]
NCT02125461	6.5.1	EORTC QLQ-C30	6.5.1 EORTC QLQ-C30 The EORTC QLQ-C30 is a 30-item self-administered questionnaire (Appendix G). There are 9 multiple item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health status/Quality...	[]
NCT02125461	6.5.2	Lung Cancer Module (LC13)	6.5.2 Lung Cancer Module (LC13) For NSCLC patients, a disease-specific 13-item self-administered questionnaire for lung cancer was developed (LC13; Appendix G) to be used in conjunction with the EORTC QLQ-C30 (Bergman et al 1994). It comprises both multi-item and single-item measures of lung cancer-associated symptoms ...	[]
NCT02125461	6.5.3	EuroQoL 5-dimension, 5-level health state utility index (EQ-5D-5L)	6.5.3 EuroQoL 5-dimension, 5-level health state utility index (EQ-5D-5L) The EuroQoL 5-dimension utility index (EQ-5D) is a standardised measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal (EuroQoL 1990). Applicable to a wid...	[]
NCT02125461	6.5.4	Administration of patient reported outcomes questionnaires	6.5.4 Administration of patient reported outcomes questionnaires Each centre must allocate the responsibility for the administration of the PRO instruments to a specific individual (eg, a research nurse, study coordinator) and if possible, assign a back-up person to cover if that individual is absent. The AstraZeneca/M...	[]
NCT02125461	6.6	Pharmacokinetics and ADA	6.6 Pharmacokinetics and ADA	[]
NCT02125461	6.6.1	Collection of PK samples and determination of drug concentration	6.6.1 Collection of PK samples and determination of drug concentration Blood samples (3.5 mL) for determination of MEDI4736 in serum will be taken at the times presented in the study plans in Table 1 (Screening and the Treatment Period), Table 2 (for follow-up of patients achieving disease control or who are discontinu...	[]
NCT02125461	6.6.2	Collection of samples to measure for the presence of ADA and ADA neutralising antibodies	6.6.2 Collection of samples to measure for the presence of ADA and ADA neutralising antibodies Presence of ADA will be assessed in samples taken according to the schedule presented in Table 1 (Screening and the Treatment Period), Table 2 (for follow-up of patients achieving disease control or who are discontinued due t...	[]
NCT02125461	6.7	Biomarker analysis	6.7 Biomarker analysis Mandatory tumour and blood biomarkers to be evaluated to support the exploratory objectives of the study are described in Section 6.7.1 through Section 6.7.4. Alternative biomarkers may be evaluated as determined by additional data associated with disease progression or response to MEDI4736. Biom...	[]
NCT02125461	6.7.1	Collection of patient selection biomarker data	6.7.1 Collection of patient selection biomarker data At Screening, an unstained, archived tumour tissue sample (formalin fixed paraffin embedded [FFPE]) in a quantity sufficient to allow for analysis (see the Laboratory Manual) must be deemed to be available. If an archived tumour block cannot be shipped for this study...	[]
NCT02125461	6.7.2	Blood borne biomarkers	6.7.2 Blood borne biomarkers Blood or tissue samples will be analysed to evaluate protein, nucleic acid, and cellular biomarkers that relate to MEDI4736 treatment. Blood and tissue collected for analysis of immune cell gene expression profiles within the peripheral and tumoural compartments will be evaluated for any re...	[]
NCT02125461	6.7.3	Tumour samples (immune-related or response-related markers)	6.7.3 Tumour samples (immune-related or response-related markers) The expression and spatial distribution of immune-related or response-related markers by immunohistochemistry may also include, but may not be limited to, PD-L1, CTLA-4, CD3, CD4, CD8, CD45RO, forkhead box P3, granzyme B, OX40, PD1, cleaved caspase 3 and...	[]
NCT02125461	6.7.4	Genomic analysis	6.7.4 Genomic analysis Whole blood and tumour samples will be collected for RNA and/or micro RNA/messenger RNA sample preparation. Ribonucleic acid may be used in the analyses of transcript and/or micro RNA expression and stored for future analyses. Ribonucleic acid analyses will be conducted to evaluate its utility to...	[]
NCT02125461	6.7.5	Management of biomarker data	6.7.5 Management of biomarker data The biomarker data will have unknown clinical significance. AstraZeneca/MedImmune will not provide biomarker research results to patients, their family members, any insurance company, an employer, clinical study Investigator, general physician or any other third party, unless required...	[]
NCT02125461	6.8	Pharmacogenetics	6.8 Pharmacogenetics	[]
NCT02125461	6.8.1	Collection of pharmacogenetic samples	6.8.1 Collection of pharmacogenetic samples Refer to Appendix D for details of the genetic research (optional DNA component). For blood volume see Section 7.1.	[]
NCT02125461	6.9	Health economics	6.9 Health economics For the purposes of economic evaluation it is necessary to capture healthcare resource use related to the treatment and the underlying disease. Within the study the following will be captured: - x Hospital episodes including the type of contact (hospitalisations, outpatient, day case), reason, leng...	[]
NCT02125461	7	BIOLOGICAL SAMPLING PROCEDURES	7. BIOLOGICAL SAMPLING PROCEDURES	[]
NCT02125461	7.1	Volume of blood	7.1 Volume of blood The total volume of blood that will be drawn from each patient in this study depends on the length of time that the patient receives study drug. Table 8 is a guide to the approximate volume of blood that will be drawn from each patient, based on the assumption that each patient remains in the study ...	[]
NCT02125461	7.2	Handling, storage and destruction of biological samples	7.2 Handling, storage and destruction of biological samples The samples will be used up or disposed of after analyses or retained for further use as described here. Biological samples for future research will be retained at AstraZeneca/MedImmune R&D or an appropriate vendor selected by AstraZeneca/MedImmune, on behalf ...	[]
NCT02125461	7.2.1	Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble PD-L1) samples	7.2.1 Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble PD-L1) samples Samples will be disposed of after the CSR has been finalised. For sample processing, handling and shipment refer to the Investigators Laboratory Manual.	[]
NCT02125461	7.2.2	Pharmacogenetic samples	7.2.2 Pharmacogenetic samples The processes adopted for the coding and storage of samples for genetic analysis are important to maintain patient confidentiality. Samples will be stored for a maximum of 15 years, from the date of the Last Patient's Last Visit, after which they will be destroyed. DNA is a finite resource...	[]
NCT02125461	7.3	Labelling and shipment of biohazard samples	7.3 Labelling and shipment of biohazard samples The Principal Investigator ensures that samples are labelled and shipped in accordance with the Laboratory Manual and the Biological Substance, Category B Regulations (materials containing or suspected to contain infectious substances that do not meet Category A criteria)...	[]
NCT02125461	7.4	Chain of custody of biological samples	7.4 Chain of custody of biological samples A full chain of custody is maintained for all samples throughout their lifecycle. The Principal Investigator, at each centre, keeps full traceability of collected biological samples from the patients while in storage at the centre until shipment or disposal (where appropriate)...	[]
NCT02125461	7.5	Withdrawal of informed consent for donated biological samples	7.5 Withdrawal of informed consent for donated biological samples If a patient withdraws consent to the use of donated biological samples, the samples will be disposed of/destroyed, and the action documented. If samples are already analysed, AstraZeneca/MedImmune is not obliged to destroy the results of this research. ...	[]
NCT02125461	8	ETHICAL AND REGULATORY REQUIREMENTS	8. ETHICAL AND REGULATORY REQUIREMENTS	[]
NCT02125461	8.1	Ethical conduct of the study	8.1 Ethical conduct of the study The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bi...	[]
NCT02125461	8.2	Patient data protection	8.2 Patient data protection The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate document incorporating) wording that complies with relevant data protection and privacy legislation. AstraZeneca/MedImmune will not provide individual genotype results to patients, any insurance compa...	[]
NCT02125461	8.3	Ethics and regulatory review	8.3 Ethics and regulatory review An Ethics Committee (Independent Ethics Committee or Institutional Review Board [IRB], as applicable) should approve the final study protocol, including the final version of the Informed Consent Form and any other written information and/or materials to be provided to the patients. The ...	[]
NCT02125461	8.4	Informed consent	8.4 Informed consent The Principal Investigator(s) at each centre will: - x Ensure each patient is given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study - x Ensure each patient is notified that they are free to discontinue from the study at any time - x E...	[]
NCT02125461	8.5	Changes to the protocol and informed consent form	8.5 Changes to the protocol and informed consent form Study procedures will not be changed without the mutual agreement of the International Co-ordinating Investigator and AstraZeneca. If there are any substantial changes to the study protocol, then these changes will be documented in a study protocol amendment and whe...	[]
NCT02125461	8.6	Audits and inspections	8.6 Audits and inspections Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee may perform audits or inspections at the centre, including source data verification. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and ...	[]
NCT02125461	9	STUDY MANAGEMENT BY ASTRAZENECA	9. STUDY MANAGEMENT BY ASTRAZENECA IQVIA is responsible for the management of this study and thus throughout this section IQVIA is considered the representative of AstraZeneca.	[]
NCT02125461	9.1	Pre-study activities	9.1 Pre-study activities Before the first patient is entered into the study, it is necessary for a representative of AstraZeneca to visit the investigational study site to: - x Determine the adequacy of the facilities - x Determine availability of appropriate patients for the study - x Discuss with the Investigator(s) ...	[]
NCT02125461	9.2	Training of study site personnel	9.2 Training of study site personnel Before the first patient is entered into the study, an AstraZeneca representative will review and discuss the requirements of the Clinical Study Protocol and related documents with the investigational staff and also train them in any study specific procedures (including those listed...	[]
NCT02125461	9.3	Monitoring of the study	9.3 Monitoring of the study During the study, an AstraZeneca representative will have regular contacts with the study site, including visits to: - x Provide information and support to the Investigator(s) - x Confirm that facilities remain acceptable - x Confirm that the investigational team is adhering to the protocol,...	[]
NCT02125461	9.3.1	Source data	9.3.1 Source data Refer to the Clinical Study Agreement for location of source data.	[]
NCT02125461	9.4	Study agreements	9.4 Study agreements The Principal Investigator at each/the centre should comply with all the terms, conditions, and obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the terms of Clinical ...	[]
NCT02125461	9.4.1	Archiving of study documents	9.4.1 Archiving of study documents The Investigator follows the principles outlined in the Clinical Study Agreement.	[]
NCT02125461	9.5	Study timetable and end of study	9.5 Study timetable and end of study If the study reaches statistical significance for PFS/OS at the interim or final analyses, additional follow-up for that particular endpoint may occur based on the needs for long term follow up with more mature data in order to estimate the long-term benefit for MEDI4736. The study ...	[]
NCT02125461	9.5.1	Data collection after the primary analysis of PFS and OS	9.5.1 Data collection after the primary analysis of PFS and OS If the study achieves statistical significance for the co-primary endpoints of PFS and/or OS at one of the planned interim analyses, then that will be considered the final analysis for that endpoint. Further analyses for that particular endpoint may still o...	[ "Eligibility criteria for re-treatment:", "The patient should not enter re-treatment if any of the following exclusion criteria are fulfilled:", "Table 10 Concomitant medications/Supportive Care therapy of interest during safety follow up", "Table 11 Schedule of study procedures: Long-term follow-up and retre...
NCT02125461	9.5.2	Data collection after the final DCO for the study	9.5.2 Data collection after the final DCO for the study The last DCO of the study will be the last assessment of long-term benefit. After the final DCO, patients in OS and PFS follow-up will be considered to have completed the study. Patients who are receiving treatment at time of final DCO may continue receiving inves...	[]
NCT02125461	10	DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE	10. DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE Data management will be performed by IQVIA. The data collected through third party sources will be obtained and reconciled against study data. Adverse events and medical/surgical history will be classified according to the terminology of the latest version the Medical Dict...	[]
NCT02125461	11	EVALUATION AND CALCULATION OF VARIABLES BY ASTRAZENECA, OR DELEGATE	11. EVALUATION AND CALCULATION OF VARIABLES BY ASTRAZENECA, OR DELEGATE A comprehensive Statistical Analysis Plan (SAP) will be prepared.	[]
NCT02125461	11.1	Calculation or derivation of efficacy variable(s)	11.1 Calculation or derivation of efficacy variable(s)	[]
NCT02125461	11.1.1	RECIST 1.1 based endpoints	11.1.1 RECIST 1.1 based endpoints Blinded Independent Central Review of RECIST 1.1-based assessments The BICR of all radiological imaging data will be carried out using RECIST version 1.1. All radiological scans for all patients (including those at unscheduled visits, or outside visit windows) will be provided to the ...	[ "Blinded Independent Central Review of RECIST 1.1-based assessments", "Investigator RECIST 1.1-based assessments" ]
NCT02125461	11.1.2	Blinded Independent Central Review of irRC-based assessments	11.1.2 Blinded Independent Central Review of irRC-based assessments The definitions of CR, PR, SD and PD according to irRECIST 1.1, as outlined by Wolchok et al 2009, Nishino et al 2013, will be outlined clearly in the Imaging Charter.	[]
NCT02125461	11.1.3	Co-primary endpoints	11.1.3 Co-primary endpoints The co-primary endpoints are OS and PFS. Overall survival OS is defined as the time from the date of randomisation until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be a...	[ "Overall survival", "Progression free survival" ]
NCT02125461	11.1.4	Proportion of patients alive at 24 months	11.1.4 Proportion of patients alive at 24 months The proportion of patients alive at 24 months (ie, OS24) will be defined as the Kaplan-Meier estimate of OS at 24 months.	[]
NCT02125461	11.1.5	Objective response rate	11.1.5 Objective response rate ORR (per RECIST 1.1 as assessed by BICR) is defined as the number (%) of patients with at least 1 visit response of CR or PR and will be based on all randomised patients who have measurable disease. If the BICR finds any patients do not have measurable disease at baseline then the analysi...	[]
NCT02125461	11.1.6	Duration of response	11.1.6 Duration of response DoR (per RECIST 1.1 as assessed by BICR) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The end of response should coincide with the date of progression or death from any ca...	[]
NCT02125461	11.1.7	Proportion of patients alive and progression free at 12 months	11.1.7 Proportion of patients alive and progression free at 12 months The proportion of patients alive and progression free at 12 months (ie, APF12) will be defined as the Kaplan-Meier estimate of PFS at 12 months.	[]
NCT02125461	11.1.8	Proportion of patients alive and progression free at 18 months	11.1.8 Proportion of patients alive and progression free at 18 months The proportion of patients alive and progression free at 18 months (ie, APF18) will be defined as the Kaplan-Meier estimate of PFS at 18 months.	[]
NCT02125461	11.1.9	Time from randomisation to second progression (PFS2)	11.1.9 Time from randomisation to second progression (PFS2) PFS2 will be defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the PFS endpoint or death. The date of second progression will be recorded by the Investigator and defined according to local s...	[]
NCT02125461	11.1.10	Time to death or distant metastasis	11.1.10 Time to death or distant metastasis TTDM will be defined as the time from the date of randomisation until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the radiation field according to RECIST 1.1 or proven b...	[]
NCT02125461	11.2	Calculation or derivation of safety variable(s)	11.2 Calculation or derivation of safety variable(s)	[]
NCT02125461	11.2.1	Adverse events	11.2.1 Adverse events Data from all cycles of randomised treatment will be combined in the presentation of safety data. AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient and treatment arm. Any AE occurring before treatment with study drug will be included in the data l...	[]
NCT02125461	11.2.2	Other significant adverse events (OAEs)	11.2.2 Other significant adverse events (OAEs) During the evaluation of the AE data, an AstraZeneca/MedImmune medically qualified expert will review the list of AEs that were not reported as SAEs and AEs leading to discontinuation. Based on the expert's judgement, significant AEs of particular clinical importance may, ...	[]
NCT02125461	11.2.3	Safety assessments	11.2.3 Safety assessments For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical examination, the baseline value will be the latest result obtained prior to the start of study drug. The QT interval corrected for heart rate using Fridericia's formula (QTcF) will be derived during cre...	[]
NCT02125461	11.3	Calculation or derivation of patient reported outcome variables	11.3 Calculation or derivation of patient reported outcome variables PRO questionnaires will be assessed using the EORTC QLQ-C30 with the LC13 module (HRQoL with lung cancer specific additional concerns) and EQ-5D-5L. All items/questionnaires will be scored according to published scoring guidelines or the developer's g...	[ "EORTC QLQ-C30", "Definition of clinically meaningful changes", "Time to symptom deterioration", "Time to QoL/Function deterioration", "Symptom improvement rate", "QoL/function improvement rate", "LC13", "Definition of clinically meaningful changes", "Time to symptom deterioration", "Symptom impro...
NCT02125461	11.4	Calculation or derivation of pharmacokinetic variables	11.4 Calculation or derivation of pharmacokinetic variables	[]
NCT02125461	11.4.1	PK non-compartmental analysis	11.4.1 PK non-compartmental analysis The actual sampling times will be used in the PK calculations. MEDI4736 concentration data and summary statistics will be tabulated. Individual and mean blood MEDI4736 concentration-time profiles will be generated and included in the report. Pharmacokinetic parameters will be determ...	[]
NCT02125461	11.4.2	Population PK and exposure-response/safety analysis	11.4.2 Population PK and exposure-response/safety analysis A population PK model will be developed using a non-linear mixed-effects modelling approach in patients with NSCLC. The impact of physiologically-relevant patient characteristics (covariates) and disease on PK will be evaluated. The relationship between MEDI473...	[]
NCT02125461	11.4.3	Immunogenicity analysis	11.4.3 Immunogenicity analysis Immunogenicity results will be reported descriptively by summarizing the number and percentage of patients who develop detectable anti-MEDI4736 antibodies. The immunogenicity titre and presence of neutralizing ADA will be reported for samples confirmed positive for the presence of anti-ME...	[]
NCT02125461	11.5	Calculation or derivation of biomarker variable(s)	11.5 Calculation or derivation of biomarker variable(s) Biomarker(s) will be assessed for evaluable patients according to pre-specified criteria that will be detailed in the SAP.	[]
NCT02125461	11.6	Calculation or derivation of pharmacogenetic variables	11.6 Calculation or derivation of pharmacogenetic variables In the case of genetic data, only the date the patient gave consent to participation in the genetic research and the date the blood sample was taken from the patient will be recorded in the eCRF and database. The genetic data generated from the study will be s...	[]
NCT02125461	11.7	Calculation or derivation of health economic variables	11.7 Calculation or derivation of health economic variables Frequency and estimates of resource use, including length of stay and number of hospital admissions, will be derived from the health resource use information.	[]
NCT02125461	12	STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION BY ASTRAZENECA	12. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION BY ASTRAZENECA	[]
NCT02125461	12.1	Description of analysis sets	12.1 Description of analysis sets A comprehensive SAP will be prepared. The Full Analysis Set (FAS) and the Safety Analysis Set described below will be applied to all randomised patients. Table 14 gives a summary of outcome variables and analysis populations. Table 14 Summary of outcome variables and analysis populatio...	[]
NCT02125461	12.1.1	Full analysis set	12.1.1 Full analysis set Intent-to-treat: The primary statistical analysis of the efficacy of MEDI4736 versus placebo will include all randomised patients and will compare the treatment arms on the basis of randomised treatment, regardless of the treatment actually received. Patients who were randomised but did not sub...	[]
NCT02125461	12.1.2	Safety analysis set	12.1.2 Safety analysis set All patients who received at least one dose of randomised study drug (MEDI4736 or placebo) and for whom any post-dose data are available will be included in the safety population. Throughout the safety results sections, erroneously treated patients (eg, those randomised to Treatment A but act...	[]
NCT02125461	12.1.3	PK analysis set	12.1.3 PK analysis set All patients who receive at least 1 dose of MEDI4736 per the protocol, for whom any post-dose data are available and do not violate or deviate from the protocol in ways that would significantly affect the PK analyses will be included in the PK analysis set. The population will be defined by the S...	[]
NCT02125461	12.2	Methods of statistical analyses	12.2 Methods of statistical analyses There will be 1 treatment comparison of interest: x MEDI4736 10 mg/kg versus placebo OS and PFS are co-primary endpoints and the study has been sized to characterise the OS and PFS benefit of MEDI4736 10 mg/kg. Descriptive statistics will be used for all variables, as appropriate, a...	[ "Table 15 Formal statistical analyses to be conducted and pre-planned sensitivity analyses" ]
NCT02125461	12.2.1	Multiple testing strategy	12.2.1 Multiple testing strategy The multiple testing procedure will define which significance levels should be applied to the interpretation of the raw p-values for the 2 primary endpoints of PFS and OS and the key secondary endpoints of OS24 and ORR. There will be up to 4 DCO time points in the study. The DCO for the...	[]
NCT02125461	12.2.2	Co-primary endpoints	12.2.2 Co-primary endpoints Overall survival The primary analysis of the co-primary endpoint, OS, will occur when approximately 491 deaths have occurred (approximately 70% maturity). OS will be analysed using a stratified log-rank test adjusting for DJHDWUDQGRPLVDWLRQYHUVXV\HDUVRIDJH VH[ (male versus female), and smok...	[ "Overall survival", "Progression free survival" ]
NCT02125461	12.2.3	Proportion of patients alive at 24 months (OS24)	12.2.3 Proportion of patients alive at 24 months (OS24) The proportion of patients alive at 24 months (ie, OS24) will be summarised (using the Kaplan-Meier curve) and presented by treatment arm. It will be compared between treatments by using the Kaplan-Meier estimator of survival at 24 months for each treatment to obt...	[]
NCT02125461	12.2.4	Objective response rate	12.2.4 Objective response rate The ORR will be based on the programmatically derived RECIST using the BICR data. The ORR will be compared between MEDI4736 versus placebo using a Fisher's exact test. A binary response variable for ORR will be used for the analysis with the categories of CR and PR versus SD, PD and NE. T...	[]
NCT02125461	12.2.5	Duration of response	12.2.5 Duration of response In order to analyse the DoR between arms the Expected Duration of Response (EDoR) will be derived for each treatment arm (Ellis et al 2008) for the BICR tumour data. The EDoR is the product of the proportion of patients responding to treatment and the mean DoR in responding patients and prov...	[]
NCT02125461	12.2.6	Proportion of patients alive and progression free at 12 months (APF12)	12.2.6 Proportion of patients alive and progression free at 12 months (APF12) The proportion of patients alive and progression free at 12 months will be summarised (using the Kaplan-Meier curve) and presented by treatment arm. Each will be compared between treatments by using the Kaplan-Meier estimator of PFS at 12 mon...	[]
NCT02125461	12.2.7	Proportion of patients alive and progression free at 18 months (APF18)	12.2.7 Proportion of patients alive and progression free at 18 months (APF18) The proportion of patients alive and progression free at 18 months will be summarised (using the Kaplan-Meier curve) and presented by treatment arm. Each will be compared between treatments by using the Kaplan-Meier estimator of PFS at 18 mon...	[]
NCT02125461	12.2.8	Time from randomisation to second progression (PFS2)	12.2.8 Time from randomisation to second progression (PFS2) PFS2 will be analysed using identical methods as outlined for the analysis of PFS and adjusting for the same set of covariates, but no subgroup analysis will be performed. Medians and Kaplan-Meier plots will be presented to support the analysis. The sensitivit...	[]
NCT02125461	12.2.9	Time to death or distant metastasis	12.2.9 Time to death or distant metastasis TTDM will be analysed using identical methods as outlined for the analysis of PFS and adjusting for the same set of covariates, but no subgroup analysis will be performed. Medians and Kaplan-Meier plots will be presented to support the analysis. The sensitivity analysis outlin...	[]
NCT02125461	12.2.10	Patient reported outcomes	12.2.10 Patient reported outcomes The PRO endpoints that have been identified as primary are EORTC QLQ-C30 time to QoL deterioration of global health status and LC13 time to symptom deterioration for each of dyspnoea, cough, haemoptysis, and pain. These are not part of the main multiple testing procedure but as support...	[ "EORTC QLQ-C30", "LC13", "EuroQol-5-Dimension 5-Level questionnaire" ]
NCT02125461	12.2.11	Healthcare resource use	12.2.11 Healthcare resource use An exploratory health economic analysis of hospital episodes including type of contact (hospitalisation, outpatient, day case), reason, length of stay by ward type (including intensive care unit) and procedures and tests may be undertaken to examine the impact of disease and treatment on...	[]
NCT02125461	12.2.12	Safety data	12.2.12 Safety data Safety and tolerability data will be presented by treatment arm using the safety population. Data from all cycles of treatment will be combined in the presentation of safety data. AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. The number of pati...	[]
NCT02125461	12.2.13	PK data	12.2.13 PK data MEDI4736 concentration data will be listed for each patient and each dosing day, and a summary provided for all evaluable patients. Immunogenicity analysis Immunogenicity results will be listed by patient and a summary will be provided of the number and percentage of patients who develop detectable ant...	[ "Immunogenicity analysis" ]
NCT02125461	12.2.14	PK/PDx relationships	12.2.14 PK/PDx relationships If the data are suitable, the relationship between MEDI4736 PK exposure and efficacy/safety parameters may be investigated graphically or using appropriate data modelling approach.	[]
NCT02125461	12.2.15	Biomarker data	12.2.15 Biomarker data The relationship of PD-L1 expression and if applicable, of exploratory biomarkers to OS, PFS, ORR and DoR will be presented for a subset of patients in the ITT population who are evaluable for each biomarker. This will be assessed using similar summary and graphical representations to those that ...	[]
NCT02125461	12.2.16	Interim analysis	12.2.16 Interim analysis Up to 3 interim analyses will be performed, one for PFS and two for OS. The DCO for the interim analysis of PFS will occur when it is expected that 367 PFS events have occurred (52% maturity, approximately 30 months after the first patient is randomised). The DCO for the first interim analysis ...	[ "PFS interim analysis", "OS interim analyses" ]
NCT02125461	12.3	Determination of sample size	12.3 Determination of sample size The sample size for this study was selected to be consistent with the research hypothesis as described in Section 1.2. The two co-primary endpoints of this study are OS and PFS. To control for type-I error, a significance level of 2.5% will be used for analysis of OS and a significance...	[]
NCT02125461	12.4	Independent data monitoring committee	12.4 Independent data monitoring committee This study will use an external IDMC to assess ongoing safety analyses as well as interim efficacy analyses for superiority based on PFS and OS and the primary analysis of PFS: - x The IDMC will review the safety data from approximately the first 75 patients, or approximately ...	[ "In addition:" ]
NCT02125461	13	IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE INVESTIGATOR	13. IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE INVESTIGATOR	[]
NCT02125461	13.1	Medical emergencies, AstraZeneca/MedImmune and IQVIA contacts	13.1 Medical emergencies, AstraZeneca/MedImmune and IQVIA contacts The Principal Investigator is responsible for ensuring that procedures and expertise are available to handle medical emergencies during the study. A medical emergency usually constitutes an SAE and is to be reported as such, see Section 6.4.4 In the cas...	[]
NCT02125461	13.3	Pregnancy	13.3 Pregnancy All outcomes of pregnancy should be reported to AstraZeneca/MedImmune representative (ie, IQVIA). Following the final DCO for the study, Investigators or other site personnel shall report all pregnancy outcomes to AstraZeneca/MedImmune Patient Safety.	[]
NCT02125461	13.3.1	Maternal exposure	13.3.1 Maternal exposure If a patient becomes pregnant during the course of the study investigational product should be discontinued immediately. Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational product under study may have interfered with the effectiveness of a contracepti...	[]

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