Ignite Creation Date:
2025-12-24 @ 10:23 PM
Ignite Modification Date:
2025-12-28 @ 7:38 AM
Study NCT ID:
NCT04236635
Status:
COMPLETED
Last Update Posted:
2022-04-12
First Post:
2020-01-02
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Histopathology Following CCH Injection
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24', 'submissionTracking': {'firstMcpInfo': {'postDateStruct': {'date': '2021-10-25', 'type': 'ACTUAL'}}}}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'clinicaltrials@endo.com', 'phone': '800-462-3636', 'title': 'Saji Vijayan, MBBS', 'organization': 'Endo Pharmaceuticals'}, 'certainAgreement': {'piSponsorEmployee': False, 'restrictiveAgreement': False}, 'limitationsAndCaveats': {'description': 'This was considered an exploratory study by the Sponsor. No formal sample size calculations were performed. Completion of 8 participants provided minimal data to meet the primary objective in the evaluable population.'}}, 'adverseEventsModule': {'timeFrame': 'From first injection (earliest dosing visit at Day -43) up to collection of the excised abdominal tissue on Day 0 (day of abdominoplasty) for CCH injection treatment and up to end of study (Day 28 post-abdominoplasty surgery follow-up visit)', 'description': 'Adverse events were collected throughout the study (up to Day 28 post-abdominoplasty surgery follow-up visit). Adverse events associated with local tolerability in treatment areas injected with CCH were collected up to the day abdominal tissue was excised.', 'eventGroups': [{'id': 'EG000', 'title': 'Group 1: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.', 'otherNumAtRisk': 2, 'deathsNumAtRisk': 2, 'otherNumAffected': 2, 'seriousNumAtRisk': 2, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG001', 'title': 'Group 2: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.', 'otherNumAtRisk': 1, 'deathsNumAtRisk': 1, 'otherNumAffected': 1, 'seriousNumAtRisk': 1, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG002', 'title': 'Group 3: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.', 'otherNumAtRisk': 1, 'deathsNumAtRisk': 1, 'otherNumAffected': 1, 'seriousNumAtRisk': 1, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG003', 'title': 'Group 4: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked (Area 1 and Area 2) areas of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.', 'otherNumAtRisk': 4, 'deathsNumAtRisk': 4, 'otherNumAffected': 4, 'seriousNumAtRisk': 4, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG004', 'title': 'Group 5: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.', 'otherNumAtRisk': 1, 'deathsNumAtRisk': 1, 'otherNumAffected': 1, 'seriousNumAtRisk': 1, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG005', 'title': 'Group 6: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.', 'otherNumAtRisk': 1, 'deathsNumAtRisk': 1, 'otherNumAffected': 1, 'seriousNumAtRisk': 1, 'deathsNumAffected': 0, 'seriousNumAffected': 0}], 'otherEvents': [{'term': 'Injection site oedema', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 2}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'General disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Injection site bruising', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 3}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'General disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Injection site pain', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 2}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 4}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'General disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Injection site haemorrhage', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 2}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 1}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'General disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Hypertension', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 0}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Vascular disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Abdominal hernia', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 1}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Gastrointestinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Hypoaesthesia', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 4}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Nervous system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Post procedural swelling', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 0}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Procedural pain', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 2}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 4}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Ecchymosis', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 2}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 3}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Skin and subcutaneous tissue disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Postoperative wound infection', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 0}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Post procedural erythema', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 0}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Post procedural oedema', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 1}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 4}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 1}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Urinary tract infection', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 0}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Infections and infestations', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Abdominal wound dehiscence', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 1}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 1}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Umbilical erythema', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 1}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Skin and subcutaneous tissue disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}, {'term': 'Post procedural contusion', 'stats': [{'groupId': 'EG000', 'numAtRisk': 2, 'numAffected': 0}, {'groupId': 'EG001', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG002', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG003', 'numAtRisk': 4, 'numAffected': 1}, {'groupId': 'EG004', 'numAtRisk': 1, 'numAffected': 0}, {'groupId': 'EG005', 'numAtRisk': 1, 'numAffected': 0}], 'organSystem': 'Injury, poisoning and procedural complications', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'MedDRA 22.1'}], 'frequencyThreshold': '0'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Number of Participants With a Histologic Change in a Tissue Specimen That Was Injected With CCH', 'denoms': [{'units': 'Participants', 'counts': [{'value': '2', 'groupId': 'OG000'}, {'value': '1', 'groupId': 'OG001'}, {'value': '1', 'groupId': 'OG002'}, {'value': '2', 'groupId': 'OG003'}, {'value': '1', 'groupId': 'OG004'}, {'value': '1', 'groupId': 'OG005'}]}], 'groups': [{'id': 'OG000', 'title': 'Group 1: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'OG001', 'title': 'Group 2: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'OG002', 'title': 'Group 3: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}, {'id': 'OG003', 'title': 'Group 4: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'OG004', 'title': 'Group 5: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'OG005', 'title': 'Group 6: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}], 'classes': [{'categories': [{'measurements': [{'value': '2', 'groupId': 'OG000'}, {'value': '1', 'groupId': 'OG001'}, {'value': '1', 'groupId': 'OG002'}, {'value': '2', 'groupId': 'OG003'}, {'value': '1', 'groupId': 'OG004'}, {'value': '1', 'groupId': 'OG005'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'timeFrame': 'Up to collection of the excised abdominal tissue on Day 0 (day of abdominoplasty)', 'description': 'Tissue specimens isolated from participants undergoing an abdominoplasty procedure were observed for histopathological structure changes of tissues post treatment with CCH. The number of participants with a histologic change (as determined by the pathologist) in tissue dosed with CCH relative to control tissue (tissue not dosed with CCH) is reported.', 'unitOfMeasure': 'Participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Evaluable Population: All participants who received at least 1 injection of study drug, underwent abdominoplasty within the protocol specified timelines, and had a histopathology and immunohistochemistry report.'}, {'type': 'SECONDARY', 'title': 'Number of Participants With a Histologic Change in a Tissue Specimen After 2 CCH Dose Injections Relative to a Tissue Specimen After 1 CCH Dose Injection', 'denoms': [{'units': 'Participants', 'counts': [{'value': '2', 'groupId': 'OG000'}, {'value': '1', 'groupId': 'OG001'}, {'value': '1', 'groupId': 'OG002'}, {'value': '2', 'groupId': 'OG003'}, {'value': '1', 'groupId': 'OG004'}, {'value': '1', 'groupId': 'OG005'}]}], 'groups': [{'id': 'OG000', 'title': 'Group 1: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'OG001', 'title': 'Group 2: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'OG002', 'title': 'Group 3: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}, {'id': 'OG003', 'title': 'Group 4: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'OG004', 'title': 'Group 5: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'OG005', 'title': 'Group 6: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}], 'classes': [{'categories': [{'measurements': [{'value': '2', 'groupId': 'OG000'}, {'value': '1', 'groupId': 'OG001'}, {'value': '1', 'groupId': 'OG002'}, {'value': '2', 'groupId': 'OG003'}, {'value': '1', 'groupId': 'OG004'}, {'value': '1', 'groupId': 'OG005'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'timeFrame': 'Up to collection of the excised abdominal tissue on Day 0 (day of abdominoplasty)', 'description': 'Tissue specimens isolated from participants undergoing an abdominoplasty procedure were observed for histopathological structure changes of tissues post treatment with CCH. The number of participants with a histologic change (as determined by the pathologist) in a tissue specimen injected with 2 CCH dose injections (Treatment Area 1) relative to 1 CCH dose injection (Treatment Area 2) is reported.', 'unitOfMeasure': 'Participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Evaluable Population: All participants who received at least 1 injection of study drug, underwent abdominoplasty within the protocol specified timelines, and had a histopathology and immunohistochemistry report.'}, {'type': 'SECONDARY', 'title': 'Number of Participants With Anti-AUX-I and Anti-AUX-II Anti-Drug Antibodies (ADAs) After CCH Treatment', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'CCH Subcutaneous Injection', 'description': 'Participants were administered 0.07 mg CCH using a single injection technique or 0.0653 mg CCH using a multiple injection technique.'}], 'classes': [{'title': 'Anti-AUX-I ADAs', 'categories': [{'measurements': [{'value': '9', 'groupId': 'OG000'}]}]}, {'title': 'Anti-AUX-II ADAs', 'categories': [{'measurements': [{'value': '5', 'groupId': 'OG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'timeFrame': 'End of Study (Day 28)', 'description': 'Serum samples were analyzed for anti-AUX-I clostridial class I collagenase of ADAs and anti-AUX-II Clostridial class II collagenase of ADAs. The number of participants who developed anti-AUX-I and anti-AUX-II ADAs (positive ADA result) are reported.', 'unitOfMeasure': 'Participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Safety Population: All participants who received at least 1 injection of study drug irrespective of the timing window of abdominoplasty. ADA data is reported as overall population instead of individual groups due to the small number of participants per arm and to protect PII of the participants.'}, {'type': 'SECONDARY', 'title': 'Number of Participants With Anti-AUX-I and Anti-AUX-II Neutralizing Antibodies (NAbs) After CCH Treatment', 'denoms': [{'units': 'Participants', 'counts': [{'value': '9', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'CCH Subcutaneous Injection', 'description': 'Participants were administered 0.07 mg CCH using a single injection technique or 0.0653 mg CCH using a multiple injection technique.'}], 'classes': [{'title': 'Anti-AUX-I NAbs', 'denoms': [{'units': 'Participants', 'counts': [{'value': '9', 'groupId': 'OG000'}]}], 'categories': [{'measurements': [{'value': '7', 'groupId': 'OG000'}]}]}, {'title': 'Anti-AUX-II NAbs', 'denoms': [{'units': 'Participants', 'counts': [{'value': '5', 'groupId': 'OG000'}]}], 'categories': [{'measurements': [{'value': '3', 'groupId': 'OG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'timeFrame': 'End of Study (Day 28)', 'description': 'Serum samples were analyzed for anti-AUX-I and Anti-AUX-II Nabs. The number of participants who developed anti-AUX-I and Anti-AUX-II NAbs (positive NAb results) are reported. Neutralizing antibodies were only tested from ADA positive participants.', 'unitOfMeasure': 'Participants', 'reportingStatus': 'POSTED', 'populationDescription': 'All participants who received at least 1 injection of study drug and were positive for ADAs. NAb data is reported as overall analysis population instead of individual groups due to the small number of participants per arm and to protect PII of the participants.'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Group 1: Collagenase Clostridium Histolyticum (CCH) Single Injection Technique', 'description': 'Participants were administered 0.07 milligrams (mg) CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas of the abdomen (Area 1 and Area 2) selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'FG001', 'title': 'Group 2: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'FG002', 'title': 'Group 3: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}, {'id': 'FG003', 'title': 'Group 4: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.'}, {'id': 'FG004', 'title': 'Group 5: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.'}, {'id': 'FG005', 'title': 'Group 6: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.'}], 'periods': [{'title': 'Overall Study', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '2'}, {'groupId': 'FG001', 'numSubjects': '1'}, {'groupId': 'FG002', 'numSubjects': '1'}, {'groupId': 'FG003', 'numSubjects': '4'}, {'groupId': 'FG004', 'numSubjects': '1'}, {'groupId': 'FG005', 'numSubjects': '1'}]}, {'type': 'Safety Population', 'comment': 'All participants who received at least 1 injection of study drug irrespective of the timing window of abdominoplasty.', 'achievements': [{'groupId': 'FG000', 'numSubjects': '2'}, {'groupId': 'FG001', 'numSubjects': '1'}, {'groupId': 'FG002', 'numSubjects': '1'}, {'groupId': 'FG003', 'numSubjects': '4'}, {'groupId': 'FG004', 'numSubjects': '1'}, {'groupId': 'FG005', 'numSubjects': '1'}]}, {'type': 'Evaluable Population', 'comment': 'All participants who received at least 1 injection of study drug, underwent abdominoplasty within the protocol specified timelines, and had a histopathology and immunohistochemistry report.', 'achievements': [{'groupId': 'FG000', 'numSubjects': '2'}, {'groupId': 'FG001', 'numSubjects': '1'}, {'groupId': 'FG002', 'numSubjects': '1'}, {'groupId': 'FG003', 'numSubjects': '2'}, {'groupId': 'FG004', 'numSubjects': '1'}, {'groupId': 'FG005', 'numSubjects': '1'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '2'}, {'groupId': 'FG001', 'numSubjects': '1'}, {'groupId': 'FG002', 'numSubjects': '1'}, {'groupId': 'FG003', 'numSubjects': '4'}, {'groupId': 'FG004', 'numSubjects': '1'}, {'groupId': 'FG005', 'numSubjects': '1'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}, {'groupId': 'FG001', 'numSubjects': '0'}, {'groupId': 'FG002', 'numSubjects': '0'}, {'groupId': 'FG003', 'numSubjects': '0'}, {'groupId': 'FG004', 'numSubjects': '0'}, {'groupId': 'FG005', 'numSubjects': '0'}]}]}], 'preAssignmentDetails': 'Participants were divided among 6 different cohorts based on injection technique and respective dosing days. Two participants (Group 4 multiple injection technique) were not included in the Evaluable Population when their surgeries were delayed due to the effects of COVID-19 restrictions.'}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'groups': [{'id': 'BG000', 'title': 'CCH Subcutaneous Injection', 'description': 'Participants were administered 0.07 mg CCH using a single injection technique or 0.0653 mg CCH using a multiple injection technique.'}], 'measures': [{'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '44.1', 'spread': '10.55', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'years', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '10', 'groupId': 'BG000'}]}, {'title': 'Male', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Ethnicity (NIH/OMB)', 'classes': [{'categories': [{'title': 'Hispanic or Latino', 'measurements': [{'value': '2', 'groupId': 'BG000'}]}, {'title': 'Not Hispanic or Latino', 'measurements': [{'value': '8', 'groupId': 'BG000'}]}, {'title': 'Unknown or Not Reported', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Race (NIH/OMB)', 'classes': [{'categories': [{'title': 'American Indian or Alaska Native', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Asian', 'measurements': [{'value': '4', 'groupId': 'BG000'}]}, {'title': 'Native Hawaiian or Other Pacific Islander', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Black or African American', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'White', 'measurements': [{'value': '5', 'groupId': 'BG000'}]}, {'title': 'More than one race', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Unknown or Not Reported', 'measurements': [{'value': '1', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Weight', 'classes': [{'categories': [{'measurements': [{'value': '71.31', 'spread': '16.275', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'Kg', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Height', 'classes': [{'categories': [{'measurements': [{'value': '164.47', 'spread': '7.265', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'cm', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'BMI', 'classes': [{'categories': [{'measurements': [{'value': '26.24', 'spread': '4.460', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'kg/m^2', 'dispersionType': 'STANDARD_DEVIATION'}], 'populationDescription': 'Safety Population: All participants who received at least 1 injection of study drug irrespective of the timing window of abdominoplasty. Baseline characteristics (demographic) data were combined for all participants to protect personally identifiable information (PII) of the participant and to reduce risk of participant identification in the small population size of the 2 arms/groups.'}}, 'documentSection': {'largeDocumentModule': {'largeDocs': [{'date': '2020-05-01', 'size': 11616855, 'label': 'Study Protocol', 'hasIcf': False, 'hasSap': False, 'filename': 'Prot_000.pdf', 'typeAbbrev': 'Prot', 'uploadDate': '2021-09-23T14:43', 'hasProtocol': True}, {'date': '2020-06-26', 'size': 5848669, 'label': 'Statistical Analysis Plan', 'hasIcf': False, 'hasSap': True, 'filename': 'SAP_001.pdf', 'typeAbbrev': 'SAP', 'uploadDate': '2021-09-23T14:44', 'hasProtocol': False}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NON_RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'BASIC_SCIENCE', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 10}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2019-12-20', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2022-03', 'completionDateStruct': {'date': '2020-10-26', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2022-03-17', 'studyFirstSubmitDate': '2020-01-02', 'resultsFirstSubmitDate': '2021-09-23', 'studyFirstSubmitQcDate': '2020-01-17', 'lastUpdatePostDateStruct': {'date': '2022-04-12', 'type': 'ACTUAL'}, 'resultsFirstSubmitQcDate': '2022-03-17', 'studyFirstPostDateStruct': {'date': '2020-01-22', 'type': 'ACTUAL'}, 'resultsFirstPostDateStruct': {'date': '2022-04-12', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2020-09-23', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Number of Participants With a Histologic Change in a Tissue Specimen That Was Injected With CCH', 'timeFrame': 'Up to collection of the excised abdominal tissue on Day 0 (day of abdominoplasty)', 'description': 'Tissue specimens isolated from participants undergoing an abdominoplasty procedure were observed for histopathological structure changes of tissues post treatment with CCH. The number of participants with a histologic change (as determined by the pathologist) in tissue dosed with CCH relative to control tissue (tissue not dosed with CCH) is reported.'}], 'secondaryOutcomes': [{'measure': 'Number of Participants With a Histologic Change in a Tissue Specimen After 2 CCH Dose Injections Relative to a Tissue Specimen After 1 CCH Dose Injection', 'timeFrame': 'Up to collection of the excised abdominal tissue on Day 0 (day of abdominoplasty)', 'description': 'Tissue specimens isolated from participants undergoing an abdominoplasty procedure were observed for histopathological structure changes of tissues post treatment with CCH. The number of participants with a histologic change (as determined by the pathologist) in a tissue specimen injected with 2 CCH dose injections (Treatment Area 1) relative to 1 CCH dose injection (Treatment Area 2) is reported.'}, {'measure': 'Number of Participants With Anti-AUX-I and Anti-AUX-II Anti-Drug Antibodies (ADAs) After CCH Treatment', 'timeFrame': 'End of Study (Day 28)', 'description': 'Serum samples were analyzed for anti-AUX-I clostridial class I collagenase of ADAs and anti-AUX-II Clostridial class II collagenase of ADAs. The number of participants who developed anti-AUX-I and anti-AUX-II ADAs (positive ADA result) are reported.'}, {'measure': 'Number of Participants With Anti-AUX-I and Anti-AUX-II Neutralizing Antibodies (NAbs) After CCH Treatment', 'timeFrame': 'End of Study (Day 28)', 'description': 'Serum samples were analyzed for anti-AUX-I and Anti-AUX-II Nabs. The number of participants who developed anti-AUX-I and Anti-AUX-II NAbs (positive NAb results) are reported. Neutralizing antibodies were only tested from ADA positive participants.'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': True, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'conditions': ['Characteristics of Subcutaneous Tissue']}, 'descriptionModule': {'briefSummary': 'To evaluate the histopathology of subcutaneous tissue isolated after single or multiple Collagenase Clostridium Histolyticum (CCH) injection techniques in adult female participants undergoing abdominoplasty.'}, 'eligibilityModule': {'sex': 'FEMALE', 'stdAges': ['ADULT'], 'maximumAge': '55 Years', 'minimumAge': '18 Years', 'genderBased': True, 'healthyVolunteers': True, 'eligibilityCriteria': "Inclusion Criteria:\n\n1. Be adequately informed and understand the nature and risks of the study and be able to provide consent.\n2. Be undergoing planned elective abdominoplasty.\n3. Be willing to have their tissue donated for evaluation.\n4. Be judged to be in good health.\n5. Have a negative pregnancy test.\n6. Be willing and able to cooperate with the requirements of the study.\n\nExclusion Criteria:\n\n1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) Title 45, Part 46, Section 46.111(b) and other local and national regulations, including but not limited to, employees (temporary, part-time, full time, etc) or a family member of the research staff conducting the study, or of the sponsor, or of the contract research organization, or of the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).\n2. Has systemic conditions (coagulation disorders, malignancy, keloidal scar, abnormal wound healing) that restricts study participation.\n3. Has local (in the areas to be treated) conditions (thrombosis, vascular disorder, active infection/inflammation, active cutaneous alteration, tattoo/mole) that restricts study participation.\n4. Required use of anticoagulant or antiplatelet medication (except ≤ 150 mg aspirin daily) before or during participation in the trial.\n5. Past history of any abdominal surgery, including but not limited to: liposuction, caesarean section, appendectomy, cholecystectomy, or umbilical hernia repair.\n6. Has used or intends to use any local applications/therapies/injections/procedures that restricts study participation.\n7. Is presently nursing or providing breast milk in any manner.\n8. Intends to become pregnant during the study.\n9. Intends to initiate an intensive sport or exercise program regimen during the study.\n10. Intends to use any tanning spray or tanning booths during the study.\n11. Has received any investigational drug or treatment within 30 days prior to first injection of study drug.\n12. Has a known systemic allergy to collagenase or any other excipient of study drug.\n13. Has received any collagenase treatment at any time prior to treatment in this study.\n14. Any other condition(s) that, in the investigator's opinion, might indicate the subject to be unsuitable for the study."}, 'identificationModule': {'nctId': 'NCT04236635', 'briefTitle': 'Histopathology Following CCH Injection', 'organization': {'class': 'INDUSTRY', 'fullName': 'Endo Pharmaceuticals'}, 'officialTitle': 'A Phase 2B, Open-Label Study to Explore Tissue Histopathology Following Subcutaneous Injection of Collagenase Clostridium Histolyticum Using An Abdominoplasty Model', 'orgStudyIdInfo': {'id': 'EN3835-213'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Group 1: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 milligrams (mg) CCH subcutaneously using a single injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Single Injection Technique']}, {'type': 'EXPERIMENTAL', 'label': 'Group 2: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Single Injection Technique']}, {'type': 'EXPERIMENTAL', 'label': 'Group 3: CCH Single Injection Technique', 'description': 'Participants were administered 0.07 mg CCH subcutaneously using a single injection technique. Each participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Single Injection Technique']}, {'type': 'EXPERIMENTAL', 'label': 'Group 4: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -43 and -22. Area 2 was administered CCH on Day -14.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Multiple Injection Technique']}, {'type': 'EXPERIMENTAL', 'label': 'Group 5: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -24 and -3. Area 2 was administered CCH on Day -3.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Multiple Injection Technique']}, {'type': 'EXPERIMENTAL', 'label': 'Group 6: CCH Multiple Injection Technique', 'description': 'Participants were administered 0.0653 mg CCH subcutaneously using a multiple injection technique.\n\nEach participant had 2 marked areas (Area 1 and Area 2) of the abdomen selected for injection. Area 1 was administered CCH on Days -22 and -1. Area 2 was administered CCH on Day -1.', 'interventionNames': ['Drug: Collagenase Clostridium Histolyticum Multiple Injection Technique']}], 'interventions': [{'name': 'Collagenase Clostridium Histolyticum Single Injection Technique', 'type': 'DRUG', 'otherNames': ['EN3835', 'CCH'], 'description': 'CCH was injected subcutaneously using a single injection technique. Dose per each administration was 0.07 mg.', 'armGroupLabels': ['Group 1: CCH Single Injection Technique', 'Group 2: CCH Single Injection Technique', 'Group 3: CCH Single Injection Technique']}, {'name': 'Collagenase Clostridium Histolyticum Multiple Injection Technique', 'type': 'DRUG', 'otherNames': ['EN3835', 'CCH'], 'description': 'CCH was injected subcutaneously using a multiple injection technique. Dose per each administration was 0.0653 mg.', 'armGroupLabels': ['Group 4: CCH Multiple Injection Technique', 'Group 5: CCH Multiple Injection Technique', 'Group 6: CCH Multiple Injection Technique']}]}, 'contactsLocationsModule': {'locations': [{'zip': '07042', 'city': 'Montclair', 'state': 'New Jersey', 'country': 'United States', 'facility': 'Endo Clinical Trial Site #1', 'geoPoint': {'lat': 40.82593, 'lon': -74.20903}}, {'zip': '10021', 'city': 'New York', 'state': 'New York', 'country': 'United States', 'facility': 'Endo Clinical Trial Site #2', 'geoPoint': {'lat': 40.71427, 'lon': -74.00597}}], 'overallOfficials': [{'name': 'Karen Chajko', 'role': 'STUDY_DIRECTOR', 'affiliation': 'Endo Pharmaceuticals'}]}, 'ipdSharingStatementModule': {'infoTypes': ['STUDY_PROTOCOL', 'SAP'], 'ipdSharing': 'YES'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Endo Pharmaceuticals', 'class': 'INDUSTRY'}, 'responsibleParty': {'type': 'SPONSOR'}}}}