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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
NCT03734016	7.2.1.1	Zanubrutinib	7.2.1.1. Zanubrutinib Zanubrutinib is primarily metabolized by CYP3A (Section [1.2.2.2\)](#page-20-0). Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers (refer to [Appendix](#page-97-0) 5 for a list of these medications) and grapefruit juice and Seville oranges should be used with c...	[]
NCT03734016	7.2.1.2	Ibrutinib	7.2.1.2. Ibrutinib Local prescribing guidelines should be followed for guidance on drug interactions and contraindications when using ibrutinib. An example of common local prescribing guidelines for use of ibrutinib with CYP3A Inhibitors is given in [Table](#page-55-2) 6, Section [6.5.2.3,](#page-54-1) but follow the l...	[]
NCT03734016	8	SAFETY MONITORING AND REPORTING	8. SAFETY MONITORING AND REPORTING The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE as provided in this protocol.	[]
NCT03734016	8.1	Adverse Events	8.1. Adverse Events	[]
NCT03734016	8.1.1	Definitions and Reporting	8.1.1. Definitions and Reporting An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. Examples of an AE include: - Worsening of a c...	[]
NCT03734016	8.1.1.1	Assessment of Severity	8.1.1.1. Assessment of Severity The investigator will assess the severity for each AE and SAE reported during the study. When applicable, AEs and SAEs should be assessed and graded based upon the NCI-CTCAE v4.03. Patients with CLL may have low blood counts at initiation of therapy so assessment of AE severity for hemat...	[]
NCT03734016	8.1.1.2	Assessment of Causality	8.1.1.2. Assessment of Causality The investigator is obligated to assess the relationship between the study drug and the occurrence of each AE or SAE. The investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, o...	[]
NCT03734016	8.1.1.3	Follow-up of Adverse Events and Serious Adverse Events	8.1.1.3. Follow-up of Adverse Events and Serious Adverse Events After the initial AE or SAE report, the investigator is required to proactively follow each patient and provide further information to the sponsor on the patient's condition. All AEs and SAEs documented at a previous visit/contact and designated as ongoing...	[]
NCT03734016	8.1.2	Laboratory Test Abnormalities	8.1.2. Laboratory Test Abnormalities Abnormal laboratory findings (eg, chemistry, CBC, coagulation) or other abnormal assessments (ECG, radiographical studies, and vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically significant abnormal la...	[]
NCT03734016	8.1.3	Lack of Efficacy	8.1.3. Lack of Efficacy "Lack of efficacy" will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including clarifications).	[]
NCT03734016	8.2	Serious Adverse Events	8.2. Serious Adverse Events	[]
NCT03734016	8.2.1	Definitions	8.2.1. Definitions An SAE is any untoward medical occurrence that, at any dose: - Results in death - Is life-threatening NOTE: the term "life-threatening" in the definition of "serious" refers to an AE in which the patient was at risk of death at the time of the AE; it does not refer to an AE, which hypothetically migh...	[]
NCT03734016	8.3	Suspected Unexpected Serious Adverse Reaction	8.3. Suspected Unexpected Serious Adverse Reaction A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is both unexpected (ie, not present in the product's Reference Safety Information) and meets the definition of a serious adverse drug reaction (SADR), the specificity or severity...	[]
NCT03734016	8.4	Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse Events	8.4. Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse Events	[]
NCT03734016	8.4.1	Adverse Event Reporting Period	8.4.1. Adverse Event Reporting Period After informed consent has been signed but prior to the administration of the study drug, only SAEs should be reported. After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be reported until 30 days after the last dose of study drugs. Bey...	[]
NCT03734016	8.4.2	Eliciting Adverse Events	8.4.2. Eliciting Adverse Events The investigator or designee will ask about AEs by asking the following standard questions: - How are you feeling? - Have you had any medical problems since your last visit? - Have you taken any new medicines since your last visit?	[]
NCT03734016	8.5	Specific Instructions for Recording Adverse Events and Serious Adverse Events	8.5. Specific Instructions for Recording Adverse Events and Serious Adverse Events	[]
NCT03734016	8.5.1	Disease Progression	8.5.1. Disease Progression Disease progression (including fatal disease progression), which is expected in this study population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, the symptoms, signs or clinical sequelae that result from disease progression should be reported as the AE...	[]
NCT03734016	8.5.2	Death	8.5.2. Death Death is an outcome and not usually considered an event. If the only information available is death and the cause of death is unknown, then the death is reported as an event, eg, "death," "death of unknown cause," or "death unexplained."	[]
NCT03734016	8.6	Prompt Reporting of Serious Adverse Events	8.6. Prompt Reporting of Serious Adverse Events	[]
NCT03734016	8.6.1	Time Frames for Submitting Serious Adverse Events	8.6.1. Time Frames for Submitting Serious Adverse Events SAEs will be reported promptly (within 24 hours of first knowledge of the SAE) to the sponsor or designee as described once the investigator determines that the AE meets the protocol definition of an SAE. Table 7: Time Frames and Documentation for Reporting SAEs ...	[ "Completion and Transmission of the Serious Adverse Event Report" ]
NCT03734016	8.6.2	Regulatory Reporting Requirements for Serious Adverse Events	8.6.2. Regulatory Reporting Requirements for Serious Adverse Events The investigator will promptly report all SAEs to the sponsor in accordance with the procedures detailed in Section [8.6.1](#page-65-2) The sponsor has a legal responsibility to notify, as appropriate, both the local regulatory authority and other regu...	[]
NCT03734016	8.7	Pregnancy Reporting	8.7. Pregnancy Reporting If a female patient or the partner of a male patient becomes pregnant while receiving study treatment or within 90 days of the last dose of study drug, a pregnancy report form should be completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. Information on the stat...	[]
NCT03734016	8.8	Post-Study Adverse Event	8.8. Post-Study Adverse Event A post-study AE or SAE is defined as any AE that occurs after the AE/SAE reporting period, defined in Section [8.4.1.](#page-64-2) Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the investigator learns of any SAE, including a death, at any time...	[]
NCT03734016	8.9	Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and Independent Ethics Committees	8.9. Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and Independent Ethics Committees The sponsor will promptly assess all SAEs against cumulative study drug experience to identify and expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs, a...	[]
NCT03734016	9	STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION	9. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION All statistical analyses will be performed by the sponsor or designee. Data will be listed and summarized according to sponsor -agreed reporting standards. Details of the statistical analyses will be included in a separate Statistical Analysis Plan.	[]
NCT03734016	9.1	Study Endpoints	9.1. Study Endpoints	[]
NCT03734016	9.1.1	Primary Endpoint	9.1.1. Primary Endpoint The primary endpoint is ORR (PR or higher, defined as CR/CRi + PR + nodular PR) determined by investigator assessment using the "modified" 2008 IWCLL guidelines ([Hallek M](#page-87-0) et al 2008) with modification for treatment-related lymphocytosis [\(Cheson et al 2012\)](#page-86-0) for patie...	[]
NCT03734016	9.1.2	Secondary Endpoints	9.1.2. Secondary Endpoints Key Secondary Endpoint: The key secondary endpoint is PFS, defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first, determined by the investigator. While the key secondary efficacy endpoint is per investigator assessmen...	[ "Other Secondary Endpoints:" ]
NCT03734016	9.1.3	Exploratory Endpoints	9.1.3. Exploratory Endpoints - Correlation between clinical outcomes (eg, ORR, PFS, DOR, OS) and the prognostic and predictive biomarkers - MRD - PK parameters - Self-administered Activity and Quality of Life questionnaire	[]
NCT03734016	9.2	Statistical Analysis	9.2. Statistical Analysis	[]
NCT03734016	9.2.1	Randomization Methods	9.2.1. Randomization Methods Patients will be randomized using the Interactive Response Technology system for this study by permuted block stratified randomization. The stratified randomization using age (< 65 years versus ≥ 65 years), geographic region (China versus non-China), refractory status (yes or no), and del17...	[]
NCT03734016	9.2.2	Analysis Sets	9.2.2. Analysis Sets The Intent-to-Treat Analysis Set includes all randomized patients. The Intent-to-Treat Analysis Set will be the primary analysis set for efficacy analyses. The Safety Analysis Set includes all patients who received any dose of study drug. Patients will be included in the treatment group correspondi...	[]
NCT03734016	9.2.3	Subject Disposition	9.2.3. Subject Disposition The number of patients screened, randomized, randomized but not treated, treated, discontinued from study drug, and discontinued from study will be summarized. The primary reason for study drug discontinuation and study discontinuation will be summarized according to the categories recorded i...	[]
NCT03734016	9.2.4	Demographics and Other Baseline Characteristics	9.2.4. Demographics and Other Baseline Characteristics Demographics and other baseline characteristics will be summarized in the Intent-to-Treat Analysis Set using descriptive statistics. Continuous variables include age, weight, vital signs, and time since initial CLL/SLL diagnosis; categorical variables include sex, ...	[]
NCT03734016	9.2.5	Prior and Concomitant Therapy	9.2.5. Prior and Concomitant Therapy Concomitant medications will be assigned an 11-digit code using the World Health Organization Drug Dictionary drug codes. Concomitant medications will be further coded to the appropriate Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior and concomitan...	[]
NCT03734016	9.2.6	Efficacy Analysis	9.2.6. Efficacy Analysis	[]
NCT03734016	9.2.6.1	Primary Efficacy Endpoint Analyses	9.2.6.1. Primary Efficacy Endpoint Analyses The primary hypothesis testing for the primary endpoint of ORR by investigator assessment (for the United States, by independent central review) will be to demonstrate the non-inferiority of zanubrutinib to ibrutinib. The null and alternative hypotheses for the non-inferiorit...	[ "Justification of the Non-inferiority Margin" ]
NCT03734016	9.2.6.2	Secondary Efficacy Endpoint Analyses	9.2.6.2. Secondary Efficacy Endpoint Analyses If the primary objective of demonstrating the non-inferiority of zanubrutinib to ibrutinib in ORR is met, the treatment effect of the key secondary efficacy endpoint of PFS by investigator assessment (for the United States, by independent central review) will be tested for ...	[ "Key Secondary Efficacy Endpoints", "Progression-free Survival", "Other Secondary Efficacy Endpoints", "Duration of Response", "Time to Treatment Failure", "Rate of PR-L or Higher by Independent Central Review", "Overall Survival", "Patient-Reported Outcomes" ]
NCT03734016	9.2.6.3	Exploratory Efficacy Analyses	9.2.6.3. Exploratory Efficacy Analyses Cox and/or logistic regression models, as well as descriptive comparisons, may be used to explore the association between the prognostic, predictive biomarkers, as well as MRD and the clinical outcomes. Changes in the self-administered activity and quality of life questionnaire ma...	[]
NCT03734016	9.2.6.4	Sensitivity Analyses	9.2.6.4. Sensitivity Analyses For PFS, alternative censoring rules such as censoring for new anticancer therapy will be used as sensitivity analyses. Details of sensitivity analyses will be described in the SAP.	[]
NCT03734016	9.2.7	Pharmacokinetics Analyses	9.2.7. Pharmacokinetics Analyses A population PK analysis may be performed to include plasma concentrations of zanubrutinib from this trial in an existing model. PK parameters such as apparent systemic clearance and AUC may be derived from the population PK analysis if supported by data. An exposure-response (efficacy ...	[]
NCT03734016	9.3	Safety Analyses	9.3. Safety Analyses Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v4.03. Laboratory values (CBC, serum chemistry, and coagulation), vital signs, physical exams, and ECG findings will also be used in the safety assessment. Descriptive statistics will be used to analyze all safety data ...	[]
NCT03734016	9.3.1	Extent of Exposure	9.3.1. Extent of Exposure The extent of exposure to the study drug will be summarized descriptively as the number of cycles received (number and percentage of patients), duration of exposure (days), cumulative total dose received per patient (mg), dose intensity (mg/day), and relative dose intensity (%). The number (an...	[]
NCT03734016	9.3.2	Adverse Events	9.3.2. Adverse Events The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified into standardized medical terminology using Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to MedDRA (Version 20.0 or higher) lower level term closest to the verbatim term. The l...	[]
NCT03734016	9.3.3	Laboratory Analyses	9.3.3. Laboratory Analyses Selected CBC components and serum chemistry values will be evaluated for each laboratory parameter by treatment group. Abnormal laboratory values will be flagged and identified as those outside of (above or below) the normal range. Reference (normal) ranges for laboratory parameters will be i...	[]
NCT03734016	9.3.4	Vital Signs	9.3.4. Vital Signs Descriptive statistics for the vital sign parameters (systolic and diastolic blood pressure, heart rate, temperature, and weight) and the changes from baseline will be presented by visit and treatment group for all visits. Vital signs will be listed by patient and visit.	[]
NCT03734016	9.3.5	Electrocardiogram	9.3.5. Electrocardiogram ECG assessments will be performed as described in Section [5.5.4](#page-36-4) and in [Appendix](#page-104-0) 10. Descriptive statistics for absolute and change from baseline ECG parameters will be presented.	[]
NCT03734016	9.4	Sample Size Consideration	9.4. Sample Size Consideration The sample size calculation is based on the primary efficacy analysis for the primary endpoint of ORR. Assuming a response ratio (zanubrutinib arm/ibrutinib arm) of 1.03 (72%/70%), 600 patients will provide more than 90% power to demonstrate the non-inferiority of zanubrutinib to ibrutini...	[]
NCT03734016	9.5	Interim Analysis	9.5. Interim Analysis There will be 1 interim analysis for the non-inferiority (and the superiority if the non-inferiority is met) testing of ORR. The interim analysis will be performed approximately 12 months after the randomization of 415 patients. The monitoring boundaries for the interim and the final analyses for ...	[]
NCT03734016	9.6	Final Analysis	9.6. Final Analysis If the primary objective of the ORR non-inferiority is met, the study will continue to follow up for PFS until 205 events are observed, which is estimated to be approximately 45 months from study start.	[]
NCT03734016	10	STUDY COMMITTEES AND COMMUNICATION	10. STUDY COMMITTEES AND COMMUNICATION	[]
NCT03734016	10.1	Steering Committee	10.1. Steering Committee This study will be overseen by a Steering Committee consisting of experts in CLL/SLL and members of the sponsor's staff. The Steering Committee plays a central role in the design of the study, oversees the conduct of the study, and is to agree on a plan for communication of the results.	[]
NCT03734016	10.2	Data Monitoring Committee	10.2. Data Monitoring Committee An independent DMC consisting of experts in CLL/SLL, clinical trial safety monitoring, and statistics will evaluate safety data on a periodic basis and perform the efficacy interim analysis for this study. Approximately every 6 months, the DMC will review all available safety data and al...	[]
NCT03734016	10.3	Independent Central Review	10.3. Independent Central Review The sponsor will contract with an independent central review facility to provide an independent and blinded review of imaging and clinical data necessary to assess tumor response in this study. This will be conducted by qualified, board-certified radiologists and hematologists assigned ...	[]
NCT03734016	10.4	Provision of Study Results and Information to Investigators	10.4. Provision of Study Results and Information to Investigators When the Clinical Study Report is completed, the sponsor will provide the major findings of the study to the investigator. In addition, details of the study drug assignment will be provided to the investigator to enable him/her to review the data to dete...	[]
NCT03734016	11	INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS	11. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS	[]
NCT03734016	11.1	Regulatory Authority Approval	11.1. Regulatory Authority Approval The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements or file the protocol to an appropriate regulatory agency before the study is initiated at a study center in that cou...	[]
NCT03734016	11.2	Investigator Responsibilities	11.2. Investigator Responsibilities	[]
NCT03734016	11.2.1	Good Clinical Practice	11.2.1. Good Clinical Practice The investigator will ensure that this study is conducted in accordance with the principles of the "Declaration of Helsinki" ICH guidelines and that the basic principles of "Good Clinical Practice," as outlined in 21 Code of Federal Regulations 312, Subpart D, "Responsibilities of sponsor...	[]
NCT03734016	11.2.2	Ethical Conduct of the Study and Ethics Approval	11.2.2. Ethical Conduct of the Study and Ethics Approval This study will be conducted by the investigator and the study center in accordance with GCP and all applicable regulatory requirements, including, where applicable, the current version of the Declaration of Helsinki. The sponsor's sample ICF will be provided to ...	[]
NCT03734016	11.2.2.1	Protocol Amendments	11.2.2.1. Protocol Amendments Protocol modifications, except those intended to reduce immediate risk to study patients, may be initiated only by BeiGene. All protocol modifications must be submitted by the investigator (or sponsor, where applicable) to competent authorities according to local requirements and to the IR...	[]
NCT03734016	11.2.3	Informed Consent	11.2.3. Informed Consent The investigator is responsible for obtaining written informed consent from each individual participating in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study and before undertaking any study-related procedures. The investigator must util...	[]
NCT03734016	11.2.4	Investigator Reporting Requirements	11.2.4. Investigator Reporting Requirements As indicated in Section [8.6.2,](#page-65-3) the investigator (or sponsor, where applicable) is responsible for reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. Furthermore, the investigator may be required to provide periodic safety updates on th...	[]
NCT03734016	11.2.5	Confidentiality	11.2.5. Confidentiality The investigator and sponsor will maintain confidentiality and privacy standards by following applicable data privacy laws covering the collection, storage, transmission, and processing of patients' personal and medical information. Patient medical information obtained during this study is confi...	[]
NCT03734016	11.2.6	Data Collection	11.2.6. Data Collection Data required by the protocol will be entered into an EDC system. Data collection in the eCRF should follow the instructions described in the eCRF Completion Guidelines. The investigator has ultimate responsibility for the collection and reporting of all clinical data entered in the eCRF. The in...	[]
NCT03734016	11.2.7	Data Management/Coding	11.2.7. Data Management/Coding All final patient data, both eCRF and external data (eg, laboratory data), collected according to the protocol, will be stored at BeiGene at the end of the study. Standard procedures (including following data review guidelines, computerized validation to produce queries, and maintenance o...	[]
NCT03734016	11.2.8	Data Integrity and In-house Blinding	11.2.8. Data Integrity and In-house Blinding Due to the open-label design of the study, access to the patient-level clinical data in the EDC system will only be assigned to predefined study personnel. Functions/persons with access to the EDC system shall be prohibited from using the EDC system to generate unnecessary l...	[]
NCT03734016	11.2.9	Drug Accountability at Site	11.2.9. Drug Accountability at Site The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of all used and unused study drug. This includes acknowledgment of receipt of each shipment of study product where applicable (quantity and condition), patient-drug dispensation records,...	[]
NCT03734016	11.2.10	Inspections, Audits, and Monitoring Visits	11.2.10. Inspections, Audits, and Monitoring Visits The investigator must ensure the facilities used for this trial and all the source documents for this trial should be made available to appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, or to regulatory authority or health authority ...	[]
NCT03734016	11.2.11	Protocol Adherence	11.2.11. Protocol Adherence The investigator is responsible for ensuring the study is conducted in accordance with the procedures and evaluations described in this protocol. Investigators assert they will apply due diligence to avoid protocol deviations. The investigator is to document and explain any deviations from t...	[]
NCT03734016	11.2.12	Financial Disclosure	11.2.12. Financial Disclosure Investigators are required to provide the sponsor with sufficient, accurate financial information in accordance with regulations to allow the sponsor to submit complete disclosure or certification to the absence of certain financial interest of clinical investigators and/or disclose those ...	[]
NCT03734016	11.3	Study Report and Publications	11.3. Study Report and Publications A Clinical Study Report will be prepared and provided to the regulatory agency(ies). BeiGene will ensure that the report meets the standards set out in the International Conference on Harmonisation Guideline for Structure and Content of Clinical Study Reports (International Conferenc...	[]
NCT03734016	11.4	Study and Study Center Closure	11.4. Study and Study Center Closure Upon completion of the study, the monitor will conduct the following activities in conjunction with the investigator or study center personnel, as appropriate: - Return of all study data to the sponsor - Resolve and close all data queries - Accountability, reconciliation, and arrang...	[]
NCT03734016	11.5	Records Retention and Study Files	11.5. Records Retention and Study Files The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into at least the following 2 categories: (1) investigator's study file and ...	[]
NCT03734016	11.6	Information Disclosure and Inventions	11.6. Information Disclosure and Inventions All information provided by the sponsor and all data and information generated by the study center as part of the study (other than a patient's medical records) are the sole property of the sponsor. All rights, title, and interests in any inventions, know-how or other intelle...	[]
NCT03734016	11.7	Joint Investigator/Sponsor Responsibilities	11.7. Joint Investigator/Sponsor Responsibilities	[]
NCT03734016	11.7.1	Access to Information for Monitoring	11.7.1. Access to Information for Monitoring In accordance with International Conference on Harmonisation GCP guidelines, the study monitor must have direct access to the investigator's source documentation in order to verify the data recorded in the eCRFs for consistency. The monitor is responsible for routine review ...	[]
NCT03734016	11.7.2	Access to Information for Auditing or Inspections	11.7.2. Access to Information for Auditing or Inspections Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any time during or after completion of this clinical study. If the investigator is notified of an inspection by a regulatory authority, the investigator agrees to notify th...	[]
NCT03734016	12	REFERENCES	12. REFERENCES Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibo...	[ "APPENDIX 1. SIGNATURE OF INVESTIGATOR", "APPENDIX 2. CLL RESPONSE DEFINITIONS", "APPENDIX 3. THE LUGANO CLASSIFICATION FOR CT-BASED RESPONSE FOR SLL (CHESON ET AL 2014)", "Modification from Lugano Classification for NHL [\\(Cheson et al 2014\\)](#page-86-1):", "APPENDIX 4. NEW YORK HEART ASSOCIATION CLASSI...
NCT03734016	12	General Well Being	12. General Well Being This month compared to the prior month - I feel worse than last month - I feel the same as last month - I feel better than last month	[]
NCT03734016	13	Mobile device tracking	13. Mobile device tracking How much of the time have you carried this mobile device with you when you were active since the last time you completed this questionnaire? - Close to 100% of the time - More than 50% of the time - About 50% of the time - Less than 50% of the time - Very little or not at all \| Approval with ...	[]
NCT03737812	1	SYNOPSIS	1 SYNOPSIS \| Background and Rationale:Elezanumab is an investigational product under development for thetreatment of multiple sclerosis (MS). It is a monoclonalimmunoglobulin (Ig) of the human IgG1 isotype that binds specificallyto the soluble and the membrane-bound forms of repulsive guidancemolecule A (RGMa). Elezanu...	[]
NCT03737812	2	INTRODUCTION	2 INTRODUCTION	[]
NCT03737812	2.1	Background and Rationale	2.1 Background and Rationale Why Is This Study Being Conducted Elezanumab is an investigational product under development for the treatment of multiple sclerosis (MS). It is a monoclonal immunoglobulin (Ig) of the human immunoglobulin G1 (IgG1) isotype that binds specifically to the soluble and the membrane-bound form...	[ "Why Is This Study Being Conducted", "Clinical Hypothesis" ]
NCT03737812	2.2	Benefits and Risks to Subjects	2.2 Benefits and Risks to Subjects The safety and efficacy data from the elezanumab clinical program support development of elezanumab in Phase 2 in subjects with PMS. For further details, please see findings from completed studies, including safety data in the elezanumab Investigator's Brochure.[1](#page-30-2) An inte...	[]
NCT03737812	3	STUDY OBJECTIVES AND ENDPOINTS	3 STUDY OBJECTIVES AND ENDPOINTS	[]
NCT03737812	3.1	Objective	3.1 Objective To evaluate the safety and efficacy of elezanumab in subjects with PMS.	[]
NCT03737812	3.2	Primary Endpoint	3.2 Primary Endpoint Primary endpoint: Mean Overall Response Score (ORS) at Week 52. Overall Response Score is a composite score derived from 4 components: - Expanded Disability Status Scale (EDSS) - Timed 25-Foot Walk (T25FW) - 9-Hole Peg Test in the dominant hand (9HPT-D) - 9HPT in the non-dominant hand (9HPT-ND) Th...	[ "Primary endpoint:" ]
NCT03737812	3.3	Secondary Endpoints	3.3 Secondary Endpoints - 1. Disability improvement response rate on the Expanded Disability Status Scale Plus (EDSS +) (T25FW, 9-Hole Peg test [9HPT, either hand], EDSS) at Week 52 - 2. ORS at Weeks 12, 24, and 36	[]
NCT03737812	3.4	Safety Endpoints	3.4 Safety Endpoints Safety evaluations include AE monitoring, serious adverse event (SAE) monitoring, adverse events of special interest (AESI) monitoring, physical examinations, neurologic examinations, vital sign measurements, clinically significant magnetic resonance imaging (MRI) abnormalities, electrocardiogram (...	[]
NCT03737812	3.5	Pharmacokinetic Endpoints	3.5 Pharmacokinetic Endpoints Samples will be collected for serum elezanumab concentrations, elezanumab anti-drug antibody (ADA) titers, and elezanumab neutralizing ADAs. Samples will be obtained at the visits indicated in [Figure](#page-9-0) 1 and [Appendix](#page-36-1) D. Descriptive summary statistics will be provid...	[]
NCT03737812	3.6	Biomarker Research Endpoints for Target Engagement and Neuro-restoration	3.6 Biomarker Research Endpoints for Target Engagement and Neuro-restoration Blood samples including serum and plasma will be collected at specified time points ([Appendix](#page-36-1) D) throughout the study to evaluate known and/or novel disease-related and target engagement biomarkers and their response to treatment...	[]
NCT03737812	3.7	Exploratory Endpoints	3.7 Exploratory Endpoints - 1. Disability improvement response rate on the T25FW, 9HPT, either hand, and EDSS at Weeks 12, 24, 36, and 52, and the EDSS + at Weeks 12, 24, and 36. - 2. Change from Baseline on the T25FW and 9HPT, either hand, at Weeks 12, 24, 36, and 52 - 3. Disability progression response rate on the ED...	[ "MRI Endpoints" ]
NCT03737812	4	INVESTIGATIONAL PLAN	4 INVESTIGATIONAL PLAN	[]
NCT03737812	4.1	Overall Study Design and Plan	4.1 Overall Study Design and Plan This is a 52-week, Phase 2a, proof-of concept, randomized, double-blinded, parallel-group, placebo-controlled multicenter study to evaluate the safety and efficacy of 2 doses of elezanumab in adult subjects with progressive forms of MS who have established disability. This study will i...	[]
NCT03737812	4.2	Discussion of Study Design	4.2 Discussion of Study Design Choice of Control Group The control group will be administered placebo infusion every 4 weeks. Subjects will be maintained on their MS standard of care therapy without any adjustment in their treatment so that management of their underlying MS is not compromised. In addition, no neurores...	[ "Choice of Control Group", "Appropriateness of Measurements", "Suitability of Subject Population", "Selection of Doses in the Study" ]
NCT03737812	5	STUDY ACTIVITIES	5 STUDY ACTIVITIES	[]
NCT03737812	5.1	Eligibility Criteria	5.1 Eligibility Criteria A subject will be eligible for study participation if he/she meets all of the following inclusion and none of the exclusion criteria. Inclusion Criteria Consent 1. Subjects or their legally authorized representative must voluntarily sign and date an informed consent, approved by an independen...	[ "Inclusion Criteria", "Consent", "Demographic and Laboratory Assessments", "Disease Activity", "Subject History", "Contraception", "Exclusion criteria", "Disease Activity", "Subject History", "Contraception", "Concomitant Medications" ]
NCT03737812	5.2	Contraception Recommendations	5.2 Contraception Recommendations Contraception Requirements for Females Subjects must follow the following contraceptive guidelines as specified: Females, Non-Childbearing Potential Females do not need to use birth control during or following study drug treatment if considered of non-childbearing potential due to mee...	[ "Contraception Requirements for Females" ]

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