Ignite Creation Date:
2025-12-24 @ 3:31 PM
Ignite Modification Date:
2025-12-28 @ 2:01 PM
Study NCT ID:
NCT01770392
Status:
COMPLETED
Last Update Posted:
2014-11-27
First Post:
2013-01-15
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Relative Bioavailability of a Single Dose of Nintedanib Given Alone and in Combination With Multiple Doses of Rifampicin
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'interventionBrowseModule': {'meshes': [{'id': 'C530716', 'term': 'nintedanib'}, {'id': 'D012293', 'term': 'Rifampin'}], 'ancestors': [{'id': 'D012294', 'term': 'Rifamycins'}, {'id': 'D006576', 'term': 'Heterocyclic Compounds, 4 or More Rings'}, {'id': 'D000072471', 'term': 'Heterocyclic Compounds, Fused-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}, {'id': 'D047029', 'term': 'Lactams, Macrocyclic'}, {'id': 'D047028', 'term': 'Macrocyclic Compounds'}, {'id': 'D011083', 'term': 'Polycyclic Compounds'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'clintriage.rdg@boehringer-ingelheim.com', 'phone': '1-800-243-0127', 'title': 'Boehringer Ingelheim Call Center', 'organization': 'Boehringer Ingelheim Pharmaceuticals'}, 'certainAgreement': {'otherDetails': "Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights", 'restrictionType': 'OTHER', 'piSponsorEmployee': False, 'restrictiveAgreement': True}}, 'adverseEventsModule': {'timeFrame': 'From the first trial drug administration until up to 14 days after last trial drug administration, up to 28 days', 'eventGroups': [{'id': 'EG000', 'title': 'Nintedanib', 'description': '150 mg of nintedanib was given as a single dose on Day 1.', 'otherNumAtRisk': 26, 'otherNumAffected': 5, 'seriousNumAtRisk': 26, 'seriousNumAffected': 0}, {'id': 'EG001', 'title': 'Washout Period', 'description': 'washout period of at least 14 days between the administrations of nintedanib. During this period no trial drug was administered', 'otherNumAtRisk': 26, 'otherNumAffected': 2, 'seriousNumAtRisk': 26, 'seriousNumAffected': 0}, {'id': 'EG002', 'title': 'Rifampicin', 'description': '600 mg rifampicin was given every evening from Day -7 to Day -1', 'otherNumAtRisk': 25, 'otherNumAffected': 25, 'seriousNumAtRisk': 25, 'seriousNumAffected': 0}, {'id': 'EG003', 'title': 'Nintedanib + Rifampicin', 'description': '600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.', 'otherNumAtRisk': 25, 'otherNumAffected': 4, 'seriousNumAtRisk': 25, 'seriousNumAffected': 0}], 'otherEvents': [{'term': 'Dizziness', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 2}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 0}], 'organSystem': 'Nervous system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Headache', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 2}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 5}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 2}], 'organSystem': 'Nervous system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Diarrhoea', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 5}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 3}], 'organSystem': 'Gastrointestinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Faeces discoloured', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 3}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 0}], 'organSystem': 'Gastrointestinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Flatulence', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 2}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 0}], 'organSystem': 'Gastrointestinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Chromaturia', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 25}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 0}], 'organSystem': 'Renal and urinary disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}, {'term': 'Fatigue', 'stats': [{'groupId': 'EG000', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 26, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 25, 'numAffected': 2}, {'groupId': 'EG003', 'numAtRisk': 25, 'numAffected': 0}], 'organSystem': 'General disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MEDDRA 15.1'}], 'frequencyThreshold': '5'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)', 'denoms': [{'units': 'Participants', 'counts': [{'value': '26', 'groupId': 'OG000'}, {'value': '25', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'Nintedanib', 'description': '150 mg of nintedanib was given as a single dose on Day 1.'}, {'id': 'OG001', 'title': 'Nintedanib + Rifampicin', 'description': '600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.'}], 'classes': [{'categories': [{'measurements': [{'value': '183', 'spread': '36.1', 'groupId': 'OG000'}, {'value': '89.4', 'spread': '36.8', 'groupId': 'OG001'}]}]}], 'analyses': [{'pValue': '1.0000', 'groupIds': ['OG000', 'OG001'], 'paramType': 'Geometric Mean Ratio in percentage', 'ciNumSides': 'TWO_SIDED', 'ciPctValue': '90', 'paramValue': '50.12', 'ciLowerLimit': '47.155', 'ciUpperLimit': '53.275', 'pValueComment': 'p-value for ratio outside interval 0.8 - 1.25', 'dispersionType': 'STANDARD_DEVIATION', 'dispersionValue': '12.7', 'estimateComment': 'The standard deviation is actually the geometric coefficient of variation (in %).\n\nThe ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %)', 'statisticalMethod': 'ANOVA', 'nonInferiorityType': 'SUPERIORITY_OR_OTHER', 'statisticalComment': 'The model includes fixed effect for treatment and effect "subjects" was considered as random', 'testedNonInferiority': False}], 'paramType': 'GEOMETRIC_MEAN', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity.\n\nFor this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.', 'unitOfMeasure': 'ng*h/mL', 'dispersionType': 'Geometric Coefficient of Variation', 'reportingStatus': 'POSTED', 'populationDescription': 'TS'}, {'type': 'PRIMARY', 'title': 'Maximum Measured Concentration (Cmax)', 'denoms': [{'units': 'Participants', 'counts': [{'value': '26', 'groupId': 'OG000'}, {'value': '25', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'Nintedanib', 'description': '150 mg of Nintedanib was given as a single dose on Day 1.'}, {'id': 'OG001', 'title': 'Nintedanib + Rifampicin', 'description': '600 mg Rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.'}], 'classes': [{'categories': [{'measurements': [{'value': '22.1', 'spread': '51.8', 'groupId': 'OG000'}, {'value': '12.8', 'spread': '43.4', 'groupId': 'OG001'}]}]}], 'analyses': [{'pValue': '1.0000', 'groupIds': ['OG000', 'OG001'], 'paramType': 'Geometric Mean Ratio in percentage', 'ciNumSides': 'TWO_SIDED', 'ciPctValue': '90', 'paramValue': '59.76', 'ciLowerLimit': '53.829', 'ciUpperLimit': '66.348', 'pValueComment': 'p-value for ratio outside interval 0.8 - 1.25', 'dispersionType': 'STANDARD_DEVIATION', 'dispersionValue': '21.9', 'estimateComment': 'The standard deviation is actually the geometric coefficient of variation (in %).\n\nThe ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %).', 'statisticalMethod': 'ANOVA', 'nonInferiorityType': 'SUPERIORITY_OR_OTHER', 'statisticalComment': 'The model includes fixed effect for treatment and effect "subjects" was considered as random', 'testedNonInferiority': False}], 'paramType': 'GEOMETRIC_MEAN', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'Cmax represents the maximum concentration of nintedanib in plasma. For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.', 'unitOfMeasure': 'ng/mL', 'dispersionType': 'Geometric Coefficient of Variation', 'reportingStatus': 'POSTED', 'populationDescription': 'TS'}, {'type': 'SECONDARY', 'title': 'Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)', 'denoms': [{'units': 'Participants', 'counts': [{'value': '26', 'groupId': 'OG000'}, {'value': '25', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'Nintedanib', 'description': '150 mg of nintedanib was given as a single dose on Day 1.'}, {'id': 'OG001', 'title': 'Nintedanib + Rifampicin', 'description': '600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.'}], 'classes': [{'categories': [{'measurements': [{'value': '173', 'spread': '36.9', 'groupId': 'OG000'}, {'value': '84.1', 'spread': '38.1', 'groupId': 'OG001'}]}]}], 'analyses': [{'pValue': '1.0000', 'groupIds': ['OG000', 'OG001'], 'paramType': 'Geometric Mean Ratio in percentage', 'ciNumSides': 'TWO_SIDED', 'ciPctValue': '90', 'paramValue': '49.98', 'ciLowerLimit': '46.886', 'ciUpperLimit': '53.286', 'pValueComment': 'p-value for ratio outside interval 0.8 - 1.25', 'dispersionType': 'STANDARD_DEVIATION', 'dispersionValue': '13.3', 'estimateComment': 'The standard deviation is actually the geometric coefficient of variation (in %).\n\nThe ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %).', 'statisticalMethod': 'ANOVA', 'nonInferiorityType': 'SUPERIORITY_OR_OTHER', 'statisticalComment': 'The model includes fixed effect for treatment and effect "subjects" was considered as random', 'testedNonInferiority': False}], 'paramType': 'GEOMETRIC_MEAN', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from 0 to the last quantifiable analyte plasma concentration.\n\nFor this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.', 'unitOfMeasure': 'ng*h/mL', 'dispersionType': 'Geometric Coefficient of Variation', 'reportingStatus': 'POSTED', 'populationDescription': 'TS'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Overall Study', 'description': 'This was an open-label, two-period, fixed-sequence trial. During the first period 150 mg of nintedanib was administered orally in form of a soft gelatine capsule. In the second period, a single dose of 600 mg of rifampicin was administered orally via film-coated tablet every day for a week, then a single dose of nintedanib was administered. The administrations of nintedanib were separated by a washout period of at least 14 days.'}], 'periods': [{'title': 'Nintedanib', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '26'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '26'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}]}]}, {'title': 'Washout Period of at Least 14 Days', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '26'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '25'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '1'}]}], 'dropWithdraws': [{'type': 'Adverse Event', 'reasons': [{'groupId': 'FG000', 'numSubjects': '1'}]}]}, {'title': 'Nintedanib+ Rifampicin', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '25'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '25'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}]}]}]}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '26', 'groupId': 'BG000'}]}], 'groups': [{'id': 'BG000', 'title': 'Overall Study', 'description': 'This was an open-label, two-period, fixed-sequence trial. During the first period 150 mg of nintedanib was administered orally in form of a soft gelatine capsule. In the second period, a single dose of 600 mg of rifampicin was administered orally via film-coated tablet every day for a week, then a single dose of nintedanib was administered. The administrations of nintedanib were separated by a washout period of at least 14 days.'}], 'measures': [{'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '37.3', 'spread': '8.7', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'years', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Male', 'measurements': [{'value': '26', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}], 'populationDescription': 'The treated set (TS) consists of all subjects who took at least one dose of study medication.'}}, 'protocolSection': {'designModule': {'phases': ['PHASE1'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NON_RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'SINGLE_GROUP'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 26}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2013-01'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2014-11', 'completionDateStruct': {'date': '2013-03', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2014-11-26', 'studyFirstSubmitDate': '2013-01-15', 'resultsFirstSubmitDate': '2014-11-14', 'studyFirstSubmitQcDate': '2013-01-15', 'lastUpdatePostDateStruct': {'date': '2014-11-27', 'type': 'ESTIMATED'}, 'resultsFirstSubmitQcDate': '2014-11-26', 'studyFirstPostDateStruct': {'date': '2013-01-17', 'type': 'ESTIMATED'}, 'resultsFirstPostDateStruct': {'date': '2014-11-27', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2013-03', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity.\n\nFor this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.'}, {'measure': 'Maximum Measured Concentration (Cmax)', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'Cmax represents the maximum concentration of nintedanib in plasma. For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.'}], 'secondaryOutcomes': [{'measure': 'Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)', 'timeFrame': '1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib', 'description': 'AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from 0 to the last quantifiable analyte plasma concentration.\n\nFor this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.'}]}, 'conditionsModule': {'conditions': ['Healthy']}, 'referencesModule': {'references': [{'pmid': '29500603', 'type': 'DERIVED', 'citation': 'Luedtke D, Marzin K, Jungnik A, von Wangenheim U, Dallinger C. Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects. Eur J Drug Metab Pharmacokinet. 2018 Oct;43(5):533-541. doi: 10.1007/s13318-018-0467-9.'}]}, 'descriptionModule': {'briefSummary': 'To investigate the effect of the P-gp inducer rifampicin on the pharmacokinetic parameters of nintedanib'}, 'eligibilityModule': {'sex': 'MALE', 'stdAges': ['ADULT'], 'maximumAge': '55 Years', 'minimumAge': '18 Years', 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion criteria:\n\n1\\. Healthy male subjects\n\nExclusion criteria:\n\n1\\. Any relevant deviation from healthy conditions'}, 'identificationModule': {'nctId': 'NCT01770392', 'briefTitle': 'Relative Bioavailability of a Single Dose of Nintedanib Given Alone and in Combination With Multiple Doses of Rifampicin', 'organization': {'class': 'INDUSTRY', 'fullName': 'Boehringer Ingelheim'}, 'officialTitle': 'Relative Bioavailability of a Single Oral Dose of Nintedanib Given Alone and in Combination With Multiple Oral Doses of Rifampicin in Healthy Male Volunteers (an Open-label, Two-period, Fixed Sequence Phase I Trial)', 'orgStudyIdInfo': {'id': '1199.162'}, 'secondaryIdInfos': [{'id': '2012-002507-18', 'type': 'EUDRACT_NUMBER', 'domain': 'EudraCT'}]}, 'armsInterventionsModule': {'armGroups': [{'type': 'ACTIVE_COMPARATOR', 'label': 'Test', 'description': 'multiple doses of Rifampicin + single dose of Nintedanib', 'interventionNames': ['Drug: Rifampicin', 'Drug: Nintedanib']}, {'type': 'EXPERIMENTAL', 'label': 'Reference', 'description': 'single dose of Nintedanib', 'interventionNames': ['Drug: Nintedanib']}], 'interventions': [{'name': 'Nintedanib', 'type': 'DRUG', 'description': 'single dose administration', 'armGroupLabels': ['Reference']}, {'name': 'Rifampicin', 'type': 'DRUG', 'description': 'single dose once daily for 7 days', 'armGroupLabels': ['Test']}, {'name': 'Nintedanib', 'type': 'DRUG', 'description': 'single dose administration', 'armGroupLabels': ['Test']}]}, 'contactsLocationsModule': {'locations': [{'city': 'Biberach', 'country': 'Germany', 'facility': '1199.162.1 Boehringer Ingelheim Investigational Site', 'geoPoint': {'lat': 48.33333, 'lon': 8.03333}}], 'overallOfficials': [{'name': 'Boehringer Ingelheim', 'role': 'STUDY_CHAIR', 'affiliation': 'Boehringer Ingelheim'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Boehringer Ingelheim', 'class': 'INDUSTRY'}, 'responsibleParty': {'type': 'SPONSOR'}}}}