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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NCT03948646 | 8.3 | Efficacy Measures | 8.3 Efficacy Measures The following assessment measures will be conducted to evaluate the long-term efficacy of sofpironium bromide gel, 15% as indicated in the Procedures [Section 7.1:](#page-28-0) - HDSM-Ax as measured by the subject - GSP as measured by the Investigator - DLQI as measured by the subject (for subject... | [] |
NCT03948646 | 9 | ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) | 9 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) | [] |
NCT03948646 | 9.1 | Safety Evaluations | 9.1 Safety Evaluations The Investigator is responsible for the appropriate medical care and the safety of subjects who have entered this study. The Investigator must document any AE experienced by subjects who have entered this study and report all SAEs to the CRO (see [Section](#page-43-0) 9.3.1). Contact information ... | [] |
NCT03948646 | 9.2 | Adverse Events | 9.2 Adverse Events | [] |
NCT03948646 | 9.2.1 | Definitions of Adverse Events | 9.2.1 Definitions of Adverse Events According to 21 CFR Parts 312.32 and 320.32 (IND Safety Reporting, Applicability of Requirements Regarding an "Investigational New Drug Application"), Food and Drug Administration (FDA) Guidance for Industry (Investigational New Drug Safety Reporting Requirements for Human Drug and B... | [] |
NCT03948646 | 9.2.1.1 | Documentation and Monitoring Adverse Events | 9.2.1.1 Documentation and Monitoring Adverse Events All AEs encountered during the clinical trial following subject consent through the last study drug visit will be recorded on the appropriate Adverse Events eCRF. Special considerations: Elective procedures or routinely scheduled treatments are not considered AEs. How... | [] |
NCT03948646 | 9.2.1.2 | Assessment of Adverse Events | 9.2.1.2 Assessment of Adverse Events For each AE, the start and resolution dates, intensity, seriousness (i.e., whether the event meets the definition of an SAE [\[Section 9.3.1\]](#page-43-0)), relationship of the event to the study drug, action taken regarding study drug, and outcome of the event will be documented o... | [
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NCT03948646 | 9.3 | Serious Adverse Events | 9.3 Serious Adverse Events Any AE that is serious (see definition below) and occurs after administration of study drug must be reported to the CRO Medical Monitor within 24 hours of discovery of the event. An event occurring after informed consent but before administration of study drug that is considered serious and p... | [] |
NCT03948646 | 9.3.1 | Definition and Reporting Procedures | 9.3.1 Definition and Reporting Procedures An AE should be classified as an SAE if it meets one of the following criteria: | Fatal: | The adverse event resulted in death. | |----------------------------------------|----------------------------------------------------------------------------------------------------------... | [
"Reporting Serious Adverse Events to Regulatory Agencies"
] |
NCT03948646 | 9.4 | Follow-up of Adverse Events and Laboratory Test Abnormalities | 9.4 Follow-up of Adverse Events and Laboratory Test Abnormalities AE information will be collected during the clinical trial from the time the subject signs informed consent through the final study visit. SAEs that are considered related to study drug by the Investigator or Sponsor should be followed until the events r... | [] |
NCT03948646 | 9.5 | Pregnancy Reporting | 9.5 Pregnancy Reporting Sexually active females of childbearing potential (FOCBP)\ must have a negative pregnancy test prior to study enrollment and must use an acceptable method of contraception during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, FOCBP must be... | [] |
NCT03948646 | 9.5.1 | Time Period for Collecting Pregnancy Information | 9.5.1 Time Period for Collecting Pregnancy Information FOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period). If a subject or Investigator suspects that a subject may be pregnant at any time during the study, the investigational... | [] |
NCT03948646 | 9.5.2 | Action to Be Taken If Pregnancy Occurs | 9.5.2 Action to Be Taken If Pregnancy Occurs If following initiation of investigational product, it is subsequently discovered that a trial subject was pregnant or may have been pregnant at the time of investigational product exposure, the Investigator must immediately notify the CRO Medical Monitor of this event, and ... | [] |
NCT03948646 | 9.6 | Other Safety Measures | 9.6 Other Safety Measures Safety will also be assessed by physical examinations, laboratory tests, and measurement of vital signs assessed as indicated throughout the study schedule. Clinically significant changes in these parameters may be captured as adverse events. | [] |
NCT03948646 | 10 | STATISTICAL PROCEDURES | 10 STATISTICAL PROCEDURES A detailed statistical analysis plan (SAP) will be generated prior to the final database lock. Database lock will follow completion of data entry, verification and validation, database audit, and data clarification resolution. | [] |
NCT03948646 | 10.1 | Analysis Populations | 10.1 Analysis Populations The three analysis populations for this study are defined below. Identification of the subjects to be included in each analysis population will be determined and finalized prior to database unmasking. | [] |
NCT03948646 | 10.1.1 | Intent-to-Treat Population | 10.1.1 Intent-to-Treat Population The Intent-to-Treat (ITT) Population will include all subjects who were randomized. Subjects will be analyzed according to the treatment group to which they were randomized, regardless of post-randomization protocol deviations, including no treatment or wrong treatment received. | [] |
NCT03948646 | 10.1.2 | Per-Protocol Population | 10.1.2 Per-Protocol Population The PP Population will be a subset of the ITT Population and will include subjects who meet the following criteria: - Meets all inclusion/exclusion criteria - Has not taken or applied any interfering concomitant medications - Completed the following visits: - o Visit 2 GSP 1, and the requ... | [] |
NCT03948646 | 10.1.3 | Safety Population | 10.1.3 Safety Population The Safety Population will include all subjects randomized in the study who received study drug, either vehicle or sofpironium bromide gel, 15%, at least once. If a subject received any sofpironium bromide gel, 15%, the subject will be analyzed in the sofpironium bromide gel, 15%, treatment gro... | [] |
NCT03948646 | 10.2 | Efficacy Endpoints | 10.2 Efficacy Endpoints | [] |
NCT03948646 | 10.2.1 | Definitions | 10.2.1 Definitions For the purposes of analysis, Baseline and End of Treatment (EOT) definitions for the two primary efficacy assessment measures, HDSM-Ax-7 and Gravimetric Sweat Production (GSP), are defined below.
HDSM-Ax - Baseline = Visit 4 (Day 1) assessment - EOT = Visit 12 (Day 43) assessment
GSP - Baseline = ... | [
"HDSM-Ax",
"GSP"
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NCT03948646 | 10.2.2 | Co-Primary Efficacy Endpoints | 10.2.2 Co-Primary Efficacy Endpoints The following co-primary efficacy endpoints will be analyzed to assess the efficacy of sofpironium bromide gel, 15%: - The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from baseline to EOT. - The change in GSP from baseline to EOT. Not... | [] |
NCT03948646 | 10.2.3 | Secondary Efficacy Endpoints | 10.2.3 Secondary Efficacy Endpoints The following secondary efficacy endpoints will be analyzed: - The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score from baseline to EOT. - The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score fro... | [] |
NCT03948646 | 10.2.4 | Exploratory Efficacy Endpoints | 10.2.4 Exploratory Efficacy Endpoints Exploratory efficacy endpoints to be analyzed include the following: - The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. - The proportion of subjects achieving at least... | [] |
NCT03948646 | 10.3 | Analysis Methods | 10.3 Analysis Methods The primary efficacy analysis will be performed on the ITT population with missing values imputed. The coprimary efficacy endpoints are: - The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from baseline to EOT in the sofpironium bromide gel, 15% group... | [] |
NCT03948646 | 10.3.1 | Primary and Secondary Analysis of the HDSM-Ax-7 Co-Primary Endpoint | 10.3.1 Primary and Secondary Analysis of the HDSM-Ax-7 Co-Primary Endpoint Data: HDSM-Ax-7 total scores 2-point responder status (0, 1) at EOT. Missing data will be imputed first before analysis is performed. Imputation Model: Imputation will be item-level. If a subject is missing values for any of items 1a, 1b, 2a, 2b... | [
"Hypothesis Tested:"
] |
NCT03948646 | 10.3.2 | Primary and Secondary Analyses of the GSP Co-Primary Endpoint | 10.3.2 Primary and Secondary Analyses of the GSP Co-Primary Endpoint Data: Either rank-based GSP change from baseline to EOT or continuous GSP change from baseline to EOT will be analyzed. The GSP assessment is known to be a highly variable measure, and as such, the Shapiro Wilk test of normality will be performed to d... | [
"Hypothesis Tested:"
] |
NCT03948646 | 10.3.3 | Method of Pooling Sites to Generate Analysis Centers | 10.3.3 Method of Pooling Sites to Generate Analysis Centers Subjects from low enrolling sites will be pooled in order to generate analysis centers. The minimum number of subjects per analysis center is 10. For sites with <10 enrollments, the lowest enrolling site will be combined with the largest enrolling site, and th... | [] |
NCT03948646 | 10.3.4 | Handling of Missing Data for the Co-Primary Efficacy Endpoints in the ITT Population | 10.3.4 Handling of Missing Data for the Co-Primary Efficacy Endpoints in the ITT Population For both HDSM-Ax-7 and GSP, multiple imputations for missing values in the vehicle group will be performed assuming MAR. For the sofpironium bromide gel, 15% group, multiple imputations using the CBI model will be employed as th... | [] |
NCT03948646 | 10.3.5 | Sensitivity Analyses of the Co-Primary Efficacy Endpoints | 10.3.5 Sensitivity Analyses of the Co-Primary Efficacy Endpoints To further explore the robustness of the primary analysis results to different missing data assumptions, analyses using two additional imputation methods will be performed as presented below. Furthermore, the ranked GSP and non-rank transformed GSP ANCOVA... | [
"Summary of Sensitivity Analyses of the Co-Primary Efficacy Endpoints"
] |
NCT03948646 | 10.3.6 | Analysis of the Secondary Efficacy Endpoints | 10.3.6 Analysis of the Secondary Efficacy Endpoints A gated, fixed-sequence testing procedure will be used in this protocol to control the overall familywise false positive error rate for the primary and secondary endpoints analyses. As described above, the primary analysis will be regarded as positive and the trial wi... | [] |
NCT03948646 | 10.3.7 | Analysis of Exploratory Efficacy Endpoints | 10.3.7 Analysis of Exploratory Efficacy Endpoints PGI-S and PGI-C endpoints will be analyzed using a Cochran-Mantel-Haenszel test. All other exploratory efficacy endpoints that involve a proportion of responders will be analyzed using methods similar to what was described for the HDSM-Ax-7 co-primary endpoint. All othe... | [] |
NCT03948646 | 10.3.8 | Psychometric Analysis of the HDSM-Ax-7 | 10.3.8 Psychometric Analysis of the HDSM-Ax-7 In parallel to the traditional statistical analysis, psychometric evaluation of the HDSM-Ax-7 will be carried out to confirm the most appropriate HDSM-Ax-7 scoring algorithm and to examine internal validity, construct validity (i.e., examination of the magnitude of correlat... | [] |
NCT03948646 | 10.4 | Safety Analyses | 10.4 Safety Analyses Safety assessments of interest are local tolerability assessments, AEs, laboratory evaluations, and vital signs. Safety analysis will be performed by treatment received for the Safety Population. Treatment-emergent adverse event descriptions will be mapped to standard terms, i.e., Medical Dictionar... | [] |
NCT03948646 | 10.5 | Sample Size | 10.5 Sample Size Sample size estimation was performed for the co-primary efficacy endpoints based on the results of a Phase 2b study (BBI-4000-CL-203): - HDSM-Ax-7 responder analysis: 2-point improvement response rates of 29.8% and 53.7% were assumed for the vehicle and sofpironium bromide gel, 15% arms, respectively. ... | [] |
NCT03948646 | 11 | STUDY ADMINISTRATION PROCEDURES | 11 STUDY ADMINISTRATION PROCEDURES | [] |
NCT03948646 | 11.1 | Subject Entry Procedures | 11.1 Subject Entry Procedures | [] |
NCT03948646 | 11.1.1 | Overview of Entry Procedures | 11.1.1 Overview of Entry Procedures Subjects with hyperhidrosis as defined by the criteria in [Sections 4.2](#page-20-2) and [4.3](#page-21-0) (inclusion/exclusion criteria) will be considered for entry into this study. | [] |
NCT03948646 | 11.1.2 | Informed Consent and Subject Privacy | 11.1.2 Informed Consent and Subject Privacy The study will be discussed with the subject, and a subject wishing to participate must give informed consent prior to any study-related procedures or change in treatment. The subject must also give Authorization for Use and Release of Health and Research Study Information an... | [] |
NCT03948646 | 11.1.3 | Method for Assignment to Study Product Groups | 11.1.3 Method for Assignment to Study Product Groups All subjects who have signed an ICF will receive a 8-digit subject screening number composed of a 1-digit study number (2), a 3-digit site number, followed by a 4-digit sequentially assigned number starting at 0001, at each site. For instance, the first subject from ... | [] |
NCT03948646 | 11.2 | Compliance with Protocol | 11.2 Compliance with Protocol At each post-baseline visit, the following activities will occur to ensure compliance with the protocol: - Subjects will be asked whether they have used the investigational product as instructed. - Subjects will be reminded to perform ONE FULL pump actuation and use the gel expressed per a... | [] |
NCT03948646 | 11.3 | Study Termination | 11.3 Study Termination The study may be stopped at a study site at any time by the site Investigator, after first notifying the Sponsor and discussing the reason(s) for stopping the study. Brickell Biotech, Inc. may stop the study with appropriate notification. | [] |
NCT03948646 | 12 | ADMINISTRATIVE ISSUES | 12 ADMINISTRATIVE ISSUES | [] |
NCT03948646 | 12.1 | Posting of Information on Clinicaltrials.gov | 12.1 Posting of Information on Clinicaltrials.gov Study information from this protocol will be posted on clinicaltrials.gov before enrollment of subjects begins. | [] |
NCT03948646 | 12.2 | Protection of Human Subjects | 12.2 Protection of Human Subjects | [] |
NCT03948646 | 12.2.1 | Compliance with Informed Consent Regulations (US 21 CFR Part 50) and Relevant Country Regulations | 12.2.1 Compliance with Informed Consent Regulations (US 21 CFR Part 50) and Relevant Country Regulations Written informed consent is to be obtained from each subject prior to any study-related procedures. Potential subjects will be screened within 45 days prior to Visit 4 (Rescreening/Baseline) to assess their eligibil... | [] |
NCT03948646 | 12.2.2 | Compliance with IRB Regulations | 12.2.2 Compliance with IRB Regulations This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103). The Investigator must obtain approval from a properly constituted IRB prior to initiating the study and re-approval or review at least annually. Brickell Biotech, Inc. is to be notified immed... | [] |
NCT03948646 | 12.2.3 | Compliance with Good Clinical Practice | 12.2.3 Compliance with Good Clinical Practice This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines, e.g., the ICH Guideline on GCP. | [] |
NCT03948646 | 12.3 | Changes to the Protocol | 12.3 Changes to the Protocol The Investigator should not implement any deviation from or changes to the protocol without approval by Brickell Biotech, Inc. and prior review and documented approval/favorable opinion from the IRB of a protocol amendment, except where necessary to eliminate immediate hazards to study subj... | [] |
NCT03948646 | 12.4 | Subject Confidentiality | 12.4 Subject Confidentiality A report of the results of this study may be published or sent to the appropriate health authorities in any country in which the investigational product may ultimately be marketed, but a subject's name will not be disclosed in these documents. A subject's name may be disclosed to the Sponso... | [] |
NCT03948646 | 12.4.1 | Subject Privacy | 12.4.1 Subject Privacy Written authorization and other documentation in accordance with the relevant country and local privacy requirements (where applicable) are to be obtained from each subject prior to enrollment into the study, in accordance with the applicable privacy requirements (e.g., HIPAA). | [] |
NCT03948646 | 12.5 | Documentation | 12.5 Documentation | [] |
NCT03948646 | 12.5.1 | Source Documents | 12.5.1 Source Documents Source documents may include a subject's medical records, hospital charts, clinic charts, the Investigator's subject study files, as well as the results of diagnostic tests. The Investigator's copy of the CRF serves as part of the Investigator's record of a subject's study-related data. | [] |
NCT03948646 | 12.5.2 | Electronic Case Report Form Completion | 12.5.2 Electronic Case Report Form Completion The Investigator is responsible for ensuring that data are properly recorded on each subject's eCRFs and related documents. The eCRFs are to be completed in a timely manner as defined in the clinical study agreement, or as otherwise specified by Brickell Biotech. | [] |
NCT03948646 | 12.5.3 | Retention of Documentation | 12.5.3 Retention of Documentation All study-related correspondence, subject records, consent forms, subject privacy documentation, records of the distribution and use of all investigational products, and copies of CRFs should be maintained on file. The Sponsor-specific essential documents should be retained until ≥2 ye... | [] |
NCT03948646 | 12.6 | Labelling, Packaging, Storage, and Return or Disposal of Investigational Product | 12.6 Labelling, Packaging, Storage, and Return or Disposal of Investigational Product | [] |
NCT03948646 | 12.6.1 | Labeling/Packaging | 12.6.1 Labeling/Packaging The investigational product will be packaged, labeled, and supplied by Brickell Biotech, Inc. The product will be identified as an investigational compound for external use. The study number and a unique bottle number will be identified on the unit label of the product. | [] |
NCT03948646 | 12.6.2 | Storage of Investigational Product | 12.6.2 Storage of Investigational Product The investigational product must be stored in a secure area with access limited to the Investigator and authorized site staff and administered only to subjects entered into the clinical study, at no cost to the subject, in accordance with the conditions specified in this protoc... | [] |
NCT03948646 | 12.6.3 | Clinical Supply Inventory | 12.6.3 Clinical Supply Inventory The investigational product must be prepared and dispensed only by an appropriately qualified person to subjects in the study. The investigational product is to be used in accordance with the protocol by subjects who are under the direct supervision of the Principal Investigator. The In... | [] |
NCT03948646 | 12.6.4 | Return or Disposal of Investigational Product | 12.6.4 Return or Disposal of Investigational Product All investigational product (used and unused) will be returned to Brickell Biotech, Inc. or its designee for destruction.  | [] |
NCT03948646 | 12.7 | Monitoring by the Sponsor | 12.7 Monitoring by the Sponsor A representative of the Sponsor will monitor the study on a periodic basis. The determination of the extent and nature of monitoring will be based on considerations such as the objective, purpose, design, complexity, size, and endpoints of the study. In the event of interruptions to site ... | [] |
NCT03948646 | 12.8 | Publications | 12.8 Publications Brickell Biotech, Inc. as the Sponsor has proprietary interest in this study. Authorship and manuscript composition will reflect joint cooperation between the Investigator and Brickell Biotech, Inc. personnel. Authorship will be established prior to the writing of the manuscript. No manuscripts regard... | [] |
NCT03948646 | 13 | REFERENCES | 13 REFERENCES - 1. Doolittle J, Walker P, Mills T, Thurston J. Hyperhidrosis: an update on prevalence and severity in the United States. Arch Dermatol Res. 2016;308(10):743-749. - 2. Ayele BT, Lipkovich I, Molenberghs G, Mallinckrodt CH. A Multiple-Imputation-Based Approach to Sensitivity Analyses and Effectiveness Ass... | [] |
NCT03948646 | 14 | APPENDICES | 14 APPENDICES 
APPENDIX 1: GRAVIMETRICALLY MEASURED SWEAT PRODUCTION Method: Axilla Filter Paper Gravimetric Sweat Production Measurements Set Up IMPORTANT: Make sure that you distinguish each gravimetric collection packet Right (R) from Left (L) throughout the gravimetric measurement (i.e., du... | [
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"2. Since you woke up yesterday, how severe was your experience with the following? (Please select the number that best descr... |
NCT03988023 | A | RANDOMIZED, CONTROLLED, DOUBLE‐ BLIND STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AN INTRA‐ARTICULAR INJECTION OF AMPION™ IN ADULTS WITH PAIN DUE TO SEVERE OSTEOARTHRITIS OF THE KNEE | A RANDOMIZED, CONTROLLED, DOUBLE‐ BLIND STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AN INTRA‐ARTICULAR INJECTION OF AMPION™ IN ADULTS WITH PAIN DUE TO SEVERE OSTEOARTHRITIS OF THE KNEE STUDY PROTOCOL STUDY NUMBER: AP‐013 NCT 03988023 7 JUNE 2019
CLINICAL STUDY PROTOCOL | [
"CLINICAL STUDY PROTOCOL"
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NCT03988023 | A | RANDOMIZED, CONTROLLED, DOUBLE-BLIND STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AN INTRA-ARTICULAR INJECTION OF AMPION™ IN ADULTS WITH PAIN DUE TO SEVERE OSTEOARTHRITIS OF THE KNEE | A RANDOMIZED, CONTROLLED, DOUBLE-BLIND STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AN INTRA-ARTICULAR INJECTION OF AMPION™ IN ADULTS WITH PAIN DUE TO SEVERE OSTEOARTHRITIS OF THE KNEE STUDY NUMBER: AP-013 | Drug Development Phase: | Phase 3 | |--------------------------|------------------------------------------------... | [
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NCT04065841 | 1 | Introduction | 1 Introduction | [] |
NCT04065841 | 1.1 | Background | 1.1 Background | [] |
NCT04065841 | 1.1.1 | Non Alcoholic Steatohepatitis (NASH) | 1.1.1 Non Alcoholic Steatohepatitis (NASH) Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world [\(Browning et](#page-147-0) al 2004, Ratziu et [al 2010, Szczepaniak](#page-147-0) et al 2005). The clinical histologic phenotype of the disease extends from non alcoholic ... | [] |
NCT04065841 | 1.1.2 | Farnesoid X Nuclear Receptor (FXR) | 1.1.2 Farnesoid X Nuclear Receptor (FXR) The bile acid receptor, farnesoid X receptor (FXR), is a nuclear receptor expressed in liver, intestine and kidney. FXR acts as a sensor of elevated bile acids and initiates homeostatic responses to control bile acid levels and modulate other metabolic processes such as gluconeo... | [] |
NCT04065841 | 1.1.3 | Tropifexor | 1.1.3 Tropifexor Tropifexor is a highly potent, specific and orally available non-bile acid agonist of the bile acid receptor FXR and is currently being evaluated in clinical studies. The investigator's brochure (IB) provides a detailed review of the pre-clinical and clinical information on tropifexor available to date... | [] |
NCT04065841 | 1.1.4 | Licogliflozin | 1.1.4 Licogliflozin Licogliflozin is a selective and potent inhibitor of the sodium glucose co-transporters (SGLTs) 1 and 2 that decreases absorption of glucose in the gut and reabsorption in the kidney (Chao and [Henry 2010\)](#page-147-0). In the normal state, 90% of the filtered glucose is reabsorbed by SGLT2 in the... | [] |
NCT04065841 | 1.1.5 | Biological rationale for the combination of tropifexor and licogliflozin | 1.1.5 Biological rationale for the combination of tropifexor and licogliflozin Tropifexor and licogliflozin impact distinct targets affecting different nodes of NASH pathophysiology as evidenced by the following data in the tropifexor (LJN452) and licogliflozin (LIK066) Investigator's Brochures: - Tropifexor activates ... | [] |
NCT04065841 | 1.1.6 | Drug interactions | 1.1.6 Drug interactions | [] |
NCT04065841 | 1.1.6.1 | Tropifexor | 1.1.6.1 Tropifexor Based upon in vitro investigations as well as a human absorption, distribution, metabolism, and excretion (ADME) study (CLJN452A2101), tropifexor metabolism in humans is catalyzed by multiple uridine 5'-diphosphoglucuronosyltransferases (UGTs), predominantly UGT1A1 and UGT1A3 as well as oxidative met... | [] |
NCT04065841 | 1.1.6.2 | Licogliflozin | 1.1.6.2 Licogliflozin Based on the human absorption, distribution, metabolism, and excretion (ADME) study and in vitro investigations, licogliflozin is eliminated predominantly via metabolism including direct glucuronidation (UGT1A9, UGT2B4/2B7) and oxidation (mainly by CYP3A4). Strong CYP3A4 inhibitors and inducers as... | [] |
NCT04065841 | 1.1.6.3 | Drug interaction between tropifexor and licogliflozin | 1.1.6.3 Drug interaction between tropifexor and licogliflozin The pharmacokinetic drug interaction between tropifexor (140 µg) and licogliflozin (50 mg) was investigated in study CLJN452E12101. (LJN452 IB Edition 11) Preliminary data from this study confirm the absence of a clinically relevant pharmacokinetic drug inte... | [] |
NCT04065841 | 1.1.7 | Toxicology of tropifexor | 1.1.7 Toxicology of tropifexor Single oral administration of tropifexor did not cause severe acute toxicity. Tropifexor was also evaluated in oral gavage toxicology studies up to 1 month in mice, 26 weeks in rats, and 39 weeks in dogs. Below is a summary of the major findings, their adversity and clinical relevance: - ... | [] |
NCT04065841 | 1.1.8 | Toxicology of licogliflozin | 1.1.8 Toxicology of licogliflozin The principal target organs of toxicity identified in oral studies in rats (up to 26 weeks in duration) and/or dogs (up to 39 weeks in duration) were the gastrointestinal (GI) tract, kidney, urinary tract, bone, liver and adrenal gland; effects in these systems were considered related,... | [] |
NCT04065841 | 1.1.9 | Toxicology of the combination | 1.1.9 Toxicology of the combination Licogliflozin and tropifexor were administered in combination daily via oral gavage to rats for at least 13 weeks to assess the reversibility, persistence, or delayed occurrence of any effects after an 8 week recovery phase (Study 1770788). Licogliflozin / tropifexor-related clinical... | [] |
NCT04065841 | 1.1.10 | Rationale for testing the combination of tropifexor and licogliflozin | 1.1.10 Rationale for testing the combination of tropifexor and licogliflozin The rationale for evaluating the combination of tropifexor 140 μg and licogliflozin 30 mg daily is based on the following: 1. Each of the drugs used as monotherapy has been shown to have potential benefits in treating NASH based on the data av... | [] |
NCT04065841 | 1.2 | Purpose | 1.2 Purpose The purpose of this study is to compare tropifexor and licogliflozin in combination therapy and each monotherapy to placebo for efficacy, safety, and tolerability in participants with NASH and liver fibrosis (stage 2 or 3) as per NASH clinical research network (CRN) histological score. | [] |
NCT04065841 | 2 | Objectives, endpoints and estimands | 2 Objectives, endpoints and estimands Table 2-1 Objectives and related endpoints | Objective(s) | Endpoint(s) | |---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------... | [
"Objective(s) Endpoint(s)"
] |
NCT04065841 | 2.1 | Primary estimands | 2.1 Primary estimands The primary question of interest to be answered in the trial using liver histology is: Does the combination therapy (tropifexor + licogliflozin), administered once per day in participants with NASH and stage 2 or 3 fibrosis over 48 weeks, lead to histologic improvement compared with placebo treatm... | [] |
NCT04065841 | 3 | Study design | 3 Study design This is a randomized, double-blind, parallel-group, multiple-arm study to assess the efficacy, safety and tolerability of tropifexor and licogliflozin combination therapy, and each monotherapy compared with placebo as well as the combination therapy compared to each monotherapy, in participants with NASH... | [] |
NCT04065841 | 4 | Rationale | 4 Rationale | [] |
NCT04065841 | 4.1 | Rationale for study design | 4.1 Rationale for study design NASH is a complex disease with the involvement of multiple pathways. Combination therapy with tropifexor (multimodal effect with anti-steatotic, anti-inflammatory and anti-fibrotic properties) and licogliflozin (weight loss through calorie wasting from gut and kidney, better glycemic cont... | [] |
NCT04065841 | 4.2 | Rationale for dose/regimen and duration of treatment | 4.2 Rationale for dose/regimen and duration of treatment The doses and dosing regimens of licogliflozin and tropifexor are chosen in this study to reflect doses and dosing regimens currently under consideration or evaluation in monotherapy NASH studies. (See [Section 6.7.2](#page-85-0) for instructions on taking study ... | [] |
NCT04065841 | 4.3 | Rationale for choice of control drugs (comparator/placebo) or combination drugs | 4.3 Rationale for choice of control drugs (comparator/placebo) or combination drugs Currently there is no drug established as standard of care for participants with NASH. Combination of tropifexor and licogliflozin and each of these compounds as monotherapy will be compared to placebo. Subsequently, the combination tre... | [] |
NCT04065841 | 4.4 | Purpose and timing of interim analyses/design adaptations | 4.4 Purpose and timing of interim analyses/design adaptations No interim analysis is planned for this study. | [] |
NCT04065841 | 4.5 | Risks and benefits | 4.5 Risks and benefits When used as monotherapy, tropifexor and licogliflozin have been shown to have potential benefits in treating NASH. Based on the mechanisms of action of FXR agonists and SGLT1/2 inhibitors and the fact that the biologic pathways do not overlap, it is expected that they will complement each other ... | [] |
NCT04065841 | 4.5.1 | Tropifexor | 4.5.1 Tropifexor Based on the mechanism of action of tropifexor as a highly potent and specific agonist of the Farnesoid X Receptor (FXR) and data acquired in nonclinical toxicology studies, the First-in-Human study CLJN452X2101, and the ongoing Phase 2b CLJN452A2202 study, the riskbenefit assessment of tropifexor is a... | [] |
NCT04065841 | 4.5.1.1 | Benefits | 4.5.1.1 Benefits Due to its multimodal mechanism of action, tropifexor treatment may have the anticipated benefits on biliary metabolism (reduced synthesis and increased detoxification), lipid distribution (lowering hepatic triglycerides accumulation) as well as anti-inflammatory and anti-fibrotic properties, leading t... | [] |
NCT04065841 | 4.5.1.2 | Risks | 4.5.1.2 Risks
Non-clinical Liver effects: In rats, hepatic effects (hepatocellular vacuolation periportal hepatocellular hypertrophy, and bile duct hyperplasia as well as increases in FXR target gene for alkaline phosphatase expression) occurred at tropifexor doses ≥ 0.03 mg/kg/day in toxicity studies ranging from 2 w... | [
"Non-clinical",
"Normal healthy human volunteers",
"NASH Participants"
] |
NCT04065841 | 4.5.2 | Licogliflozin | 4.5.2 Licogliflozin | [] |
NCT04065841 | 4.5.2.1 | Benefits | 4.5.2.1 Benefits Numerous lines of evidence, including data from a licogliflozin First–in-Human (FIH) clinical study CLIK066X2101, indicate that combining the effects of both SGLT1 and SGLT2 inhibition may offer more effective and safe treatment for obesity and diabetes via numerous mechanisms [\(Zambrowicz](#page-147-... | [] |
NCT04065841 | 4.5.2.2 | Risks | 4.5.2.2 Risks Risks of SGLT1/2 inhibition in human participants may include the development of diarrhea and genital and urinary tract infection (secondary to glucosuria). In study CLIK066X2204, the most common AE was diarrhea, reported by similar number of participants in the placebo and 30 mg groups but at a higher ra... | [] |
NCT04065841 | 4.5.3 | Study conduct | 4.5.3 Study conduct Women of child bearing potential must be informed that taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur during the study and must agree that in order to participate in the study they must adhere to the contraception requirements outlined in the exclusion c... | [] |
NCT04065841 | 4.6 | Rationale for Public Health Emergency mitigation procedures | 4.6 Rationale for Public Health Emergency mitigation procedures During a public health emergency as declared by Local or Regional authorities, i.e,. pandemic, epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity are listed in relevant sections. Notification of the public ... | [] |
NCT04065841 | 5 | Study Population | 5 Study Population The study population will consist of approximately 380 adult male and female participants with histologic evidence of NASH and fibrosis stage 2 or 3 as per NASH CRN histological score; see Inclusion and Exclusion criteria for details. The study will be conducted in approximately 155 centers worldwide... | [] |
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