protocol_id stringclasses 263
values | section_number stringlengths 1 12 | title stringlengths 1 1.88k | content stringlengths 0 866k | merged_titles listlengths 0 491 |
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NCT03791489 | 6.3 | CONCOMITANT MEDICATIONS | 6.3 CONCOMITANT MEDICATIONS For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are concomitant prescription medications, over-the-counter medications and supplements. Me... | [] |
NCT03791489 | 7 | STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL | 7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL | [] |
NCT03791489 | 7.1 | PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY | 7.1 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY Participants are free to withdraw from participation in the study at any time upon request. An investigator may discontinue or withdraw a participant from the study for the following reasons: - Significant study non-compliance - If any clinical adverse event (AE... | [] |
NCT03791489 | 7.2 | LOST TO FOLLOW-UP | 7.2 LOST TO FOLLOW-UP A participant will be considered lost to follow-up if he or she fails to return for 2 or more scheduled visits and is unable to be contacted by the study site staff. The following actions must be taken if a participant fails to return to the clinic for a required study visit: - The site will attem... | [] |
NCT03791489 | 8 | STUDY ASSESSMENTS AND PROCEDURES | 8 STUDY ASSESSMENTS AND PROCEDURES | [] |
NCT03791489 | 8.1 | STUDY PROCEDURES | 8.1 STUDY PROCEDURES | [] |
NCT03791489 | 8.1.1 | SCREENING VISIT (VISIT 1) (DAY -30 TO 0) | 8.1.1 SCREENING VISIT (VISIT 1) (DAY -30 TO 0) Potential study subjects will be pre-screened against study eligibility criteria. Those individuals, that meet pre-screening criteria will be offered participation in the study and will be consented (see Section 10.1.1). The Screening Visit may occur in-office up to 30 day... | [] |
NCT03791489 | 8.1.2 | BASELINE VISIT (VISIT 2) (DAY -7 TO 0) | 8.1.2 BASELINE VISIT (VISIT 2) (DAY -7 TO 0) Subjects meeting eligibility criteria will return in-office for the Baseline Visit (Visit 2). The Baseline Visit may be completed the same calendar day as the Screening (Visit 1) and Treatment (Visit 3) Visits, however it must be completed no earlier than seven (7) calendar ... | [] |
NCT03791489 | 8.1.3 | TREATMENT VISIT (VISIT 3) (DAY 0) | 8.1.3 TREATMENT VISIT (VISIT 3) (DAY 0) Enrolled subjects will receive bilateral cryoablation treatment in-office. The Treatment Visit (Visit 3) may occur on the same calendar day as Visits 1 and 2 and must be completed within thirty (30) days from Visit 1 and no later than seven (7) calendar days of Visit 2. Subjects ... | [] |
NCT03791489 | 8.1.4 | 7-DAY FOLLOW-UP VISIT (VISIT 4) (DAY 7) | 8.1.4 7-DAY FOLLOW-UP VISIT (VISIT 4) (DAY 7) Subjects will return to the office at one (1) week (±3 days) from Visit 3 for the 1-Week Follow-up Visit (Visit 4). At Visit 4, the following study activities will be completed: - 1. Concomitant Medication usage will be updated. - 2. Subject will be assessed for any new Adv... | [] |
NCT03791489 | 8.1.5 | 1-MONTH FOLLOW-UP VISIT (VISIT 5) (DAY 30) | 8.1.5 1-MONTH FOLLOW-UP VISIT (VISIT 5) (DAY 30) Subjects will return to the office at thirty (30) days (±7 days) from Visit 3 for the 1-Month Follow-up Visit (Visit 5). At Visit 5, the following study activities will be completed: - 1. Subject will complete rTNSS, NOSE, SNOT-22, VAS for Nasal Symptoms and MiniRQLQ que... | [] |
NCT03791489 | 8.1.6 | 3-MONTH FOLLOW-UP VISIT (VISIT 6) (DAY 90) | 8.1.6 3-MONTH FOLLOW-UP VISIT (VISIT 6) (DAY 90) Subjects will return to the office at ninety (90) days (±14 days) from Visit 3 for the 3-Month Follow-up Visit (Visit 6). At Visit 6, the following study activities will be completed: - 1. Subject will complete rTNSS, NOSE, SNOT-22, VAS for Nasal Symptoms and MiniRQLQ qu... | [] |
NCT03791489 | 8.1.7 | UNSCHEDULED VISITS | 8.1.7 UNSCHEDULED VISITS An Unscheduled Visit (UV) may occur after Visit 3 through the end of the study participation. A UV may occur due to a study-related adverse event. The following activities will be completed as part of a UV: - Concomitant Medication usage will be updated. - Subject will be assessed for any new A... | [] |
NCT03791489 | 8.2 | EFFICACY ASSESSMENTS | 8.2 EFFICACY ASSESSMENTS | [] |
NCT03791489 | 8.2.1 | REFLECTIVE TOTAL NASAL SYMPTOM SCORE (RTNSS) | 8.2.1 REFLECTIVE TOTAL NASAL SYMPTOM SCORE (RTNSS) The primary effectiveness endpoint will be assessed based on the four-symptom reflective Total Nasal Symptom Score (rTNSS)15,16 (See Addendum: Patient Questionnaires). rTNSS is a validated symptom severity scoring system that consists of the sum of four (4) individual ... | [] |
NCT03791489 | 8.2.2 | NASAL OBSTRUCTION AND SEPTOPLASTY EFFECTIVENESS (NOSE) SURVEY | 8.2.2 NASAL OBSTRUCTION AND SEPTOPLASTY EFFECTIVENESS (NOSE) SURVEY The Nasal Obstruction and Septoplasty Effectiveness (NOSE) survey17 consists of 5 items, each scored using a 5-point Likert scale to make a total score rant of 0 to 100. The subject completes the survey by circling the response closest to describing th... | [] |
NCT03791489 | 8.2.3 | SINO-NASAL OUTCOME TEST (SNOT-22) | 8.2.3 SINO-NASAL OUTCOME TEST (SNOT-22) The Sino-Nasal Outcome Test (SNOT-22)18 is a validated patient-reported questionnaire to assess the impact of nasal symptoms on a patient's quality of life. The questionnaire consists of 22 categories, each scored using a 5-point Likert scale (0 = No Problem to 5 = Problem as bas... | [] |
NCT03791489 | 8.2.4 | MINI RHINOCONJUNCTIVITS QUALITY OF LIFE QUESTIONNAIRE (MINIRQLQ) | 8.2.4 MINI RHINOCONJUNCTIVITS QUALITY OF LIFE QUESTIONNAIRE (MINIRQLQ) The Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) 19 is a validated tool that measures the functional (physical, emotional, and social) problems associated with rhinitis (See Addendum: Patient Questionnaires). The MiniRQLQ was ad... | [] |
NCT03791489 | 8.2.5 | VISUAL ANALOG SCALE – NASAL SYMPTOMS | 8.2.5 VISUAL ANALOG SCALE – NASAL SYMPTOMS A Visual Analog Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be measured. It is often used in epidemiologic and clinical research to measure the intensity or ... | [] |
NCT03791489 | 8.2.6 | CLINICAL GLOBAL IMPRESSION – IMPROVEMENT (CGI-I) | 8.2.6 CLINICAL GLOBAL IMPRESSION – IMPROVEMENT (CGI-I) The Clinical Global Impression--Improvement (CGI-I) 21 rating scales is a clinician completed subject assessment of the changes of symptoms since time of treatment based on their clinical experience. The CGI-I is a 7-point Likert scale that ranges from a scale of 1... | [] |
NCT03791489 | 8.3 | SAFETY AND OTHER ASSESSMENTS | 8.3 SAFETY AND OTHER ASSESSMENTS | [] |
NCT03791489 | 8.3.1 | PHYSICAL NASAL EXAM | 8.3.1 PHYSICAL NASAL EXAM A physical nasal evaluation of the treatment area and nasal cavity will be performed by a licensed clinician via endoscope at the Screening (Visit 1), 1-Week (Visit 4 due to AE occurrence or monitoring), 1- Month (Visit 5) and 3-Month (Visit 6). IMPORTANT: Except for 1-Week (Visit 4), if appli... | [] |
NCT03791489 | 8.3.2 | PAIN NUMERIC RATING SCALE | 8.3.2 PAIN NUMERIC RATING SCALE A pain numeric rating scale (NRS)22 for pain function best for the patient's subjective feeling of the intensity of pain right now—present pain intensity. The NRS utilizes an 11-point scale of zero to 10. Subjects verbally report pain on the scale of 0 to 10 with zero representing "no pa... | [] |
NCT03791489 | 8.3.3 | CLINICAL EVALUATION OF NASAL CONGESTION AND TURBINATE HYPERTROPHY | 8.3.3 CLINICAL EVALUATION OF NASAL CONGESTION AND TURBINATE HYPERTROPHY Images, photographic and video, collected at the time of Physical Nasal Exam (See Section 8.3.1) may be evaluated for visible nasal congestion and turbinate hypertrophy by an independent physician reviewer. Images will be collected at the Screening... | [] |
NCT03791489 | 8.4 | ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE DEVICE EFFECTS | 8.4 ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE DEVICE EFFECTS In this study, the following types of adverse events will be collected and documented: - ClariFix Device-related Adverse Device Effects (ADE) - Cryotherapy procedure-related Adverse Events (AE) - Head, ear, nose, th... | [] |
NCT03791489 | 8.4.1 | DEFINITION OF ADVERSE EVENTS (AE) | 8.4.1 DEFINITION OF ADVERSE EVENTS (AE) An adverse event (AE) is any untoward medical occurrence in a subject who receives treatment with the study device, which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign, symptom, or d... | [] |
NCT03791489 | 8.4.2 | DEFINITION OF ADVERSE DEVICE EFFECT (ADE) | 8.4.2 DEFINITION OF ADVERSE DEVICE EFFECT (ADE) Any adverse event related to the use of the study device. An adverse event is an untoward medical occurrence, unintended disease or injury, or untoward clinical sign in subjects. | [] |
NCT03791489 | 8.4.3 | DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) | 8.4.3 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing ... | [] |
NCT03791489 | 8.4.4 | DEFINITION OF UNEXPECTED ADVERSE DEVICE EFFECT (UADE) | 8.4.4 DEFINITION OF UNEXPECTED ADVERSE DEVICE EFFECT (UADE) Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, the study device, if that effect, problem or death was not previously identified in nature, severity or degree of incidence in the investigat... | [] |
NCT03791489 | 8.4.5 | CLASSIFICATION OF AN ADVERSE EVENT | 8.4.5 CLASSIFICATION OF AN ADVERSE EVENT | [] |
NCT03791489 | 8.4.5.1 | SEVERITY OF EVENT | 8.4.5.1 SEVERITY OF EVENT For all adverse events (AEs), the following guidelines will be used to describe severity. • Mild – Events require minimal or no treatment and do not interfere with the participant's daily activities. - Moderate Events result in a low level of inconvenience or concern with the therapeutic measu... | [] |
NCT03791489 | 8.4.5.2 | RELATIONSHIP TO STUDY INTERVENTION | 8.4.5.2 RELATIONSHIP TO STUDY INTERVENTION All adverse events (AEs) must have their relationship to both the study device and study procedure assessed by the clinician who examines and evaluates the subject based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be gra... | [] |
NCT03791489 | 8.4.5.3 | EXPECTEDNESS | 8.4.5.3 EXPECTEDNESS Sponsor will be responsible for determining whether an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described for the study intervention. | [] |
NCT03791489 | 8.4.6 | TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP | 8.4.6 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP The occurrence of an adverse event (AE), adverse device effect (ADE) or serious adverse event (SAE) may come to the attention of study personnel during study visits and interviews of a study participant presenting for medical care, or upon review by a s... | [] |
NCT03791489 | 8.4.7 | ADVERSE EVENT REPORTING | 8.4.7 ADVERSE EVENT REPORTING AEs should be documented in the source documents at time of identification, and initial entry of all AEs into the EDC should be completed within 72 hours of identification. Initial EDC entry may be pending additional information, but known information should be entered. Source and EDC entr... | [] |
NCT03791489 | 8.4.8 | SERIOUS ADVERSE EVENT REPORTING | 8.4.8 SERIOUS ADVERSE EVENT REPORTING The study investigator shall complete an Adverse Event source form and email a copy of the form to sponsor within 24-hours of identification, in addition the AE reporting in section 8.4.7 should be followed. If IRB notification is required, this should be completed as soon as possi... | [] |
NCT03791489 | 9 | STATISTICAL CONSIDERATIONS | 9 STATISTICAL CONSIDERATIONS | [] |
NCT03791489 | 9.1 | STATISTICAL HYPOTHESES | 9.1 STATISTICAL HYPOTHESES Primary Efficacy Endpoints: H0: Change from Baseline (Delta) in rTNSS = 0 H1: Change from Baseline (Delta) in rTNSS ≠ 0 Secondary Efficacy Endpoints: H0: Change from Baseline (Delta) = 0 H1: Change from Baseline (Delta) ≠ 0 | [] |
NCT03791489 | 9.2 | SAMPLE SIZE DETERMINATION | 9.2 SAMPLE SIZE DETERMINATION Inasmuch as this is a feasibility study with N=30, no formal power and/or sample size estimations were performed. The proposed sample size is comparable to those in other trials of this nature in this discipline. | [] |
NCT03791489 | 9.3 | POPULATIONS FOR ANALYSES | 9.3 POPULATIONS FOR ANALYSES There are two key populations for analyses: - The Safety Population is comprised of those subjects who received treatment by the ClariFix device - The Efficacy Population is comprised of those subjects in the Safety Population who also had at least one valid follow-up assessment. | [] |
NCT03791489 | 9.4 | STATISTICAL ANALYSES | 9.4 STATISTICAL ANALYSES | [] |
NCT03791489 | 9.4.1 | GENERAL APPROACH | 9.4.1 GENERAL APPROACH All statistical analyses will be performed using a two-sided hypothesis test at the overall 5% level of significance. P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be reported as " 0.999." No adjustments for multiplicity are planned. Continuous data wil... | [] |
NCT03791489 | 9.4.2 | ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) | 9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) For the purposes of formality, rTNSS has been designated as the primary efficacy endpoint. However, since this is, in fact, a feasibility study, any of the secondary endpoints described below may be promoted in the next study to primary status. Therefore, the analytica... | [] |
NCT03791489 | 9.4.3 | ANALYSIS OF THE SECONDARY ENDPOINT(S) | 9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) The secondary endpoints are changes over time in: - NOSE Survey - SNOT-22 - MiniRQLQ - VAS nasal symptoms - CGI-I - Physician Assessment of congestion - Physician Assessment of turbinate hypertrophy The analytical approach is described in the section above for the Primary End... | [] |
NCT03791489 | 9.4.4 | SAFETY ANALYSES | 9.4.4 SAFETY ANALYSES The overall incidence (i.e., number and percent of subjects with 1 or more adverse event) of adverse events, serious adverse device events, serious adverse events, and device and/or procedure related events (e.g., possibly, probably or definitely related) will be calculated from time of treatment ... | [] |
NCT03791489 | 9.4.5 | BASELINE DESCRIPTIVE STATISTICS | 9.4.5 BASELINE DESCRIPTIVE STATISTICS Baseline characteristics, including demographic characteristics, medical history, patient-reported outcomes and physical measurements will be summarized using descriptive statistics. | [] |
NCT03791489 | 9.4.6 | TABULATION OF INDIVIDUAL PARTICIPANT DATA | 9.4.6 TABULATION OF INDIVIDUAL PARTICIPANT DATA Listings of adverse events may be produced. | [] |
NCT03791489 | 9.4.7 | EXPLORATORY ANALYSES | 9.4.7 EXPLORATORY ANALYSES Visual severity of nasal congestion and turbinate hypertrophy will be evaluated for each side of the nasal cavity separately. Screening, 1- and 3-Month timepoint scores will be cross-tabulated, and the proportion with improvement will be calculated. | [] |
NCT03791489 | 10 | SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS | 10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS | [] |
NCT03791489 | 10.1 | REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS | 10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS | [] |
NCT03791489 | 10.1.1 | INFORMED CONSENT PROCESS | 10.1.1 INFORMED CONSENT PROCESS | [] |
NCT03791489 | 10.1.1.1 | CONSENT DOCUMENTS PROVIDED TO PARTICIPANTS | 10.1.1.1 CONSENT DOCUMENTS PROVIDED TO PARTICIPANTS An Informed Consent Form (ICF) describing in detail the study treatment and study device, study procedures, and risks are to be given to each participant and written documentation of informed consent is required prior to initiating any study-related activities. | [] |
NCT03791489 | 10.1.1.2 | CONSENT PROCEDURES AND DOCUMENTATION | 10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION Informed consent is a process that is initiated prior to the individual's agreeing to participate in the study and continues throughout the individual's study participation. Consent forms will be Institutional Review Board (IRB)-approved and the participant will be asked to... | [] |
NCT03791489 | 10.1.2 | STUDY DISCONTINUATION AND CLOSURE | 10.1.2 STUDY DISCONTINUATION AND CLOSURE The sponsor may choose to temporarily suspend or prematurely terminate study or a study site with or without cause. Written notification, documenting the reason for study suspension or termination, will be provided by the sponsor, as applicable, to the investigator and IRB. If t... | [] |
NCT03791489 | 10.1.3 | CONFIDENTIALITY AND PRIVACY | 10.1.3 CONFIDENTIALITY AND PRIVACY Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover the clinical information relating to participants. Therefore, the study protocol, documentation, data, and a... | [] |
NCT03791489 | 10.1.4 | CLINICAL MONITORING | 10.1.4 CLINICAL MONITORING Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with I... | [] |
NCT03791489 | 10.1.5 | QUALITY ASSURANCE AND QUALITY CONTROL | 10.1.5 QUALITY ASSURANCE AND QUALITY CONTROL Each clinical site will perform internal quality management of study conduct, data collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management.] Quality control (QC) procedures will be implemen... | [] |
NCT03791489 | 10.1.6 | DATA HANDLING AND RECORD KEEPING | 10.1.6 DATA HANDLING AND RECORD KEEPING | [] |
NCT03791489 | 10.1.6.1 | DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES | 10.1.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. All source docu... | [] |
NCT03791489 | 10.1.6.2 | STUDY RECORDS RETENTION | 10.1.6.2 STUDY RECORDS RETENTION Study documents should be retained for a minimum of 2 years after the close-out of the study and until there are no pending or contemplated marketing applications. These documents should be retained for a longer period, however, if required by local regulations. No records will be destr... | [] |
NCT03791489 | 10.1.7 | PROTOCOL DEVIATIONS | 10.1.7 PROTOCOL DEVIATIONS A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or the study si... | [] |
NCT03791489 | 10.1.8 | FINANCIAL DISCLOSURE | 10.1.8 FINANCIAL DISCLOSURE Investigators shall provide financial disclosure according to applicable regulations. | [] |
NCT03791489 | 10.2 | ABBREVIATIONS | 10.2 ABBREVIATIONS | AE | Adverse Event | |----------|--------------------------------------------------------| | ADE | Adverse Device Effect | | CFR | Code of Federal Regulations | | CGI-I | Clinical Global ImpressionImprovement | | CMP | Clinical Monitoring Plan | | CRF | Case Report Form | | eCRF | Electronic Case R... | [] |
NCT03791489 | 11 | REFERENCES | 11 REFERENCES 1. Rao SV, M. (2013). Cryosurgery on inferior turbinate hypertrophy under topical anaesthesia - is it boon in electricity deprived places? National Journal of Otorhinolaryngology and Head & Neck Surgery, 1(10), 7-9. - 2. Hartley, C., & Willatt, D. J. (1995, August). Cryotherapy in the treatment of nasal o... | [] |
NCT03791489 | 12 | APPENDIX I | 12 APPENDIX I | [] |
NCT03827395 | A | Phase 1, Double-blinded, Placebo Controlled, Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of HEV-239 (Hecolin®) in a Healthy US Adult Population | A Phase 1, Double-blinded, Placebo Controlled, Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of HEV-239 (Hecolin®) in a Healthy US Adult Population DMID Protocol Number: 15-0108 DMID Funding Mechanism: Vaccine Treatment and Evaluation Units Pharmaceutical Support: Division of Microbiology an... | [
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"KEY ROLES",
"BACKGROUND AND SCIENTIFIC RATIONALE",
"Background",
"Vaccine Development:",
"Scie... |
NCT03853798 | 2 | SYNOPSIS | 2. SYNOPSIS
Name of Sponsor/Company: Agios Pharmaceuticals, Inc.
Name of Investigational Product: AG-348
Study Title: An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects with Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies
Study Center(s): This multicenter study will be conducte... | [
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NCT03853798 | 3 | TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES | 3. TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
TABLE OF CONTENTS | 1. | TITLE PAGE1 | | |----------|---------------------------------------------------------------------------|----| | 2. | SYNOPSIS6 | | | 3. | TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES14 | | | 4. | LIST OF ABBREVIATIONS AND DEFI... | [
"TABLE OF CONTENTS"
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NCT03853798 | 4 | LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS | 4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS | Abbreviation | Definition | |--------------|------------------------------------------------------------------------------------------------------------------| | 2,3-DPG | 2,3-diphosphoglycerate | | ADP | Adenosine diphosphate | | AE | Adverse event | | AESI | Adverse... | [] |
NCT03853798 | 5 | INTRODUCTION | 5. INTRODUCTION | [] |
NCT03853798 | 5.1 | Pyruvate Kinase Deficiency | 5.1. Pyruvate Kinase Deficiency Pyruvate kinase deficiency (PK deficiency) is a glycolytic enzymopathy that results in life-long, nonspherocytic hemolytic anemia. It is an autosomal recessive disease with a variable clinical presentation, ranging from mild to life-threatening, which can be associated with severe, debil... | [] |
NCT03853798 | 5.1.1 | Epidemiology and Prevalence | 5.1.1. Epidemiology and Prevalence Epidemiological data for PK deficiency are scarce; however, the current estimated diagnosed prevalence of patients with PK deficiency in the US and EU5 (ie, France, Germany, Italy, Spain, the United Kingdom) is approximately 2,400 cases (Carey et al, 2000; de Medicis et al, 1992). As ... | [] |
NCT03853798 | 5.1.2 | Biochemistry and Genetics | 5.1.2. Biochemistry and Genetics In normal cells, pyruvate kinase enzymatically catalyzes the metabolic conversion of phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) into pyruvate and adenosine triphosphate (ATP) as the final step in glycolysis. It is believed that PK deficiency leads to insufficient ATP prod... | [] |
NCT03853798 | 5.1.3 | Clinical Characteristics | 5.1.3. Clinical Characteristics The natural history of untreated PK deficiency is characterized by life-long hemolytic anemia and subsequent associated comorbidities, which can include a need for transfusions, susceptibility to infections after splenectomy, worsening anemia during pregnancy, and symptoms associated wit... | [] |
NCT03853798 | 5.2 | Investigational Product (AG-348) | 5.2. Investigational Product (AG-348) AG-348 (PYRUKYND) was approved by the US FDA on 17 February 2022 for the treatment of hemolytic anemia in adults with PK deficiency (PYRUKYND (mitapivat) USPI, 2022). | [] |
NCT03853798 | 5.2.1 | Proposed Mechanism of Action of AG-348 | 5.2.1. Proposed Mechanism of Action of AG-348 AG-348 is a potent, broad-spectrum activator of PKR, 1 of 4 pyruvate kinase isoenzymes expressed in human tissues from 2 separate genes. Both PKR and the liver-specific form of pyruvate kinase (PKL) are splice isoforms of the PKLR gene, while pyruvate kinase muscle isozyme ... | [] |
NCT03853798 | 5.2.2 | Summary of AG-348 Nonclinical Data With Potential Clinical Interest | 5.2.2. Summary of AG-348 Nonclinical Data With Potential Clinical Interest A series of exploratory pharmacology studies were conducted to characterize the ability of AG-348 to activate wild-type (WT) PKR and anemia-associated PKR mutants in vitro, ex vivo, and in vivo. Biochemical studies showed that AG-348 is a potent... | [] |
NCT03853798 | 5.2.3.3 | Summary of AG-348 Clinical Safety Data | 5.2.3.3. Summary of AG-348 Clinical Safety Data Overall, AG-348 has been generally well tolerated among healthy adult subjects and adult subjects with PK deficiency. Important identified risks associated with administration of AG-348 in clinical studies include 'withdrawal hemolysis, and insomnia (not clinically seriou... | [] |
NCT03853798 | 5.3.1 | Purpose of the Study | 5.3.1. Purpose of the Study This study (Study AG348-C-011) is a multicenter, open-label extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with AG-348 in subjects who were previously enrolled in Study AG348-C-006 or Study AG348-C-007. The natural history of untreated PK deficiency... | [] |
NCT03853798 | 5.3.2 | Justification of the Study Design | 5.3.2. Justification of the Study Design This is a 3-cohort, multicenter, open-label extension study in which all subjects will receive treatment with AG-348. As this study will include subjects who received AG-348 in 1 of the 2 pivotal trials (ie, AG348-C-006 or AG348-C-007) and subjects who previously received placeb... | [] |
NCT03853798 | 5.3.3 | Justification for Individual Dose Optimization for Subjects in Cohort 1 | 5.3.3. Justification for Individual Dose Optimization for Subjects in Cohort 1 This extension study will have an individual Dose Optimization Period for subjects in Cohort 1 similar to the individual dose optimization performed in Study AG348-C-006. The reason for performing individual dose optimization is based on pri... | [] |
NCT03853798 | 5.3.4 | Rationale for the Doses Selected for the Individual Dose Optimization | 5.3.4. Rationale for the Doses Selected for the Individual Dose Optimization The dose levels being used in the Dose Optimization Period for Cohort 1 (5 mg, 20 mg, and 50 mg) in this extension study are the same as those used in the antecedent studies (Study AG348-C-006 and Study AG348-C-007). To assist with dose select... | [] |
NCT03853798 | 6 | STUDY OBJECTIVES AND ENDPOINTS | 6. STUDY OBJECTIVES AND ENDPOINTS | [] |
NCT03853798 | 6.1 | Study Objectives | 6.1. Study Objectives | [] |
NCT03853798 | 6.1.1 | Primary Objective | 6.1.1. Primary Objective The primary objective of the study is to evaluate the long-term safety and tolerability of AG-348. | [] |
NCT03853798 | 6.1.2 | Secondary Objectives | 6.1.2. Secondary Objectives Secondary objectives of the study are as follows: - To evaluate the long-term efficacy of AG-348 - To evaluate the efficacy of AG-348 in increasing Hb concentrations in subjects who previously received placebo in Study AG348-C-006 (Cohort 1 only) - To determine the effect of AG-348 on health... | [] |
NCT03853798 | 6.2 | Study Endpoints | 6.2. Study Endpoints The baseline value is defined as the most recent measurement(s) before the first dose of AG-348, considering both the antecedent study and this extension study, unless otherwise specified in Section 12.2.1. | [] |
NCT03853798 | 6.2.1 | Primary Endpoint | 6.2.1. Primary Endpoint The primary endpoint is to assess the long-term safety and tolerability of AG-348 by: - Type, incidence, severity, and relationship to study drug of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs); AESIs; and TEAEs leading to dose reduction, treatment interruption, and t... | [] |
NCT03853798 | 6.2.2 | Secondary Endpoints | 6.2.2. Secondary Endpoints The secondary endpoints of the study are as follows: - Cohort 1 only: - − Proportion of subjects achieving a hemoglobin response, defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 - − Av... | [] |
NCT03853798 | 7 | STUDY DESIGN | 7. STUDY DESIGN | [] |
NCT03853798 | 7.1 | Study Design Overview | 7.1. Study Design Overview This is a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with AG-348 in subjects who were previously enrolled in Study AG348-C-006 or Study AG348-C-007. Subjects will be assigned to 1 of the following 3 cohorts, depending on ... | [] |
NCT03853798 | 7.1.1 | Cohort 1 | 7.1.1. Cohort 1 Cohort 1 will consist of subjects who received placebo in Study AG348-C-006 and meet the eligibility criteria of this extension study. The first visit of this extension study should coincide with the last visit of Study AG348-C-006. After completion of all scheduled assessments at the subject's last vis... | [] |
NCT03853798 | 7.1.2 | Cohort 2 | 7.1.2. Cohort 2 Cohort 2 will consist of subjects who received AG-348 in Study AG348-C-006 and meet the eligibility criteria of this extension study. The first visit of this extension study should coincide with the last visit of Study AG348-C-006. After completion of all scheduled assessments at the subject's last visi... | [] |
NCT03853798 | 7.1.3 | Cohort 3 | 7.1.3. Cohort 3 Cohort 3 will consist of subjects who received AG-348 in Study AG348-C-007 and meet the eligibility criteria of this extension study. The first visit of this extension study should coincide with the last visit of Study AG348-C-007. After completion of all scheduled assessments at the subject's last visi... | [] |
NCT03853798 | 7.2 | Study Description | 7.2. Study Description | [] |
NCT03853798 | 7.2.1 | Screening Period | 7.2.1. Screening Period A subject's screening during this extension study should coincide with his/her last visit of their antecedent study (ie, Study AG348-C-006 or Study AG348-C-007). Assessments that overlap between the last visit of the antecedent study and screening of this extension study only need to be performe... | [] |
NCT03853798 | 7.2.2 | Dose Optimization Period (Cohort 1 Only) | 7.2.2. Dose Optimization Period (Cohort 1 Only) The Dose Optimization and Fixed Dose Periods of Cohort 1 will replicate the Dose Optimization and Fixed Dose Periods of Study AG348-C-006 in terms of frequency of assessments (Table 4) and dosing schema (Figure 3). Figure 3: Cohort 1 Dosing Schema for the First 24 Weeks, ... | [] |
NCT03853798 | 7.2.3 | Fixed Dose Period (Cohort 1 Only) | 7.2.3. Fixed Dose Period (Cohort 1 Only) The Fixed Dose Period is a 12-week period after the Week 12 Visit through Week 24. After the Dose Optimization Period, each subject will remain on his/her individually optimized dose and enter the Fixed Dose Period. For the purposes of dosing during the Fixed Dose Period, the do... | [] |
NCT03853798 | 7.2.4 | Continued Treatment Period | 7.2.4. Continued Treatment Period After the Week 24 Visit, subjects in Cohort 1 who, in the opinion of the Investigator, have demonstrated clinical benefit from AG-348 treatment will begin the Continued Treatment Period. During this period, they will continue the AG-348 dose regimen they were receiving at the Week 24 V... | [] |
NCT03853798 | 7.2.5 | Discontinuation and Safety Follow-up | 7.2.5. Discontinuation and Safety Follow-up All subjects who interrupt or discontinue AG-348 at any time should undergo the recommended dose taper (Section 9.3), unless an emergency situation justifies discontinuing or interrupting the study drug abruptly. Whether the dose taper is performed or not, subjects discontinu... | [] |
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