171. ウィルソン病 Wilson disease Clinical trials / Disease details
臨床試験数 : 79 / 薬物数 : 77 - (DrugBank : 17) / 標的遺伝子数 : 6 - 標的パスウェイ数 : 30
| No. | TrialID | Date_ enrollment | Date_ registration | Public_title | Scientific_title | Condition | Intervention | Primary_ sponsor | Secondary_ sponsor | Recruitment_ Status | Inclusion_ agemin | Inclusion_ agemax | Inclusion_ gender | Target_ size | Phase | Countries |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | ChiCTR2200058434 | 2022-04-01 | 2022-04-09 | Prediction of prognosis of Wilson's disease by anti-copper treatment using transfer learning-quantitative MRI intelligent model | The study of migration learning-quantitative MRI intelligent model for predicting the prognosis of neurological Wilson's disease | Wilson's disease | Neuro-WD:Penicillamine, zinc;Hep-WD:Zinc;Control group:None; | The First Affiliated Hospital, Sun Yat-Sen University | NULL | Pending | 10 | 64 | Both | Neuro-WD:60;Hep-WD:60;Control group:60; | Phase 1 | China |
| 2 | ChiCTR2100053629 | 2021-12-12 | 2021-11-26 | A multicenter, randomized controlled, double-blind and double simulated clinical evaluation of gandouling tablet in the treatment of Wilson's disease | A multicenter, randomized controlled, double-blind and double simulated clinical evaluation of gandouling tablet in the treatment of patients with hepatolenticular degeneration | Wilson's disease | A group:Gandouling tablet + zinc gluconate simulator;B group:Zinc gluconate + gandouling tablet simulator; | The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine | NULL | Pending | 15 | Both | A group:100;B group:100; | China | ||
| 3 | EUCTR2017-004135-36-NL (EUCTR) | 30/03/2020 | 16/10/2019 | Study to Evaluate the Efficacy and Safety of ALXN1840 in pPtients with Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Not Recruiting | Female: yes Male: yes | 180 | Phase 3 | United States;Portugal;Serbia;Taiwan;Hong Kong;Greece;Spain;Israel;Russian Federation;Colombia;Italy;France;Denmark;Australia;Netherlands;Korea, Republic of;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Belgium;Poland;Singapore;Croatia;Germany;Japan;New Zealand;Sweden | ||
| 4 | EUCTR2017-004135-36-PT (EUCTR) | 13/01/2020 | 26/03/2019 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Not Recruiting | Female: yes Male: yes | 180 | Phase 3 | United States;Portugal;Serbia;Hong Kong;Taiwan;Spain;Israel;Russian Federation;Colombia;France;Denmark;Australia;Netherlands;Korea, Republic of;Turkey;Austria;United Kingdom;Hungary;Czech Republic;Canada;Brazil;Belgium;Poland;Singapore;Germany;Japan;New Zealand;Sweden | ||
| 5 | EUCTR2017-004135-36-SE (EUCTR) | 29/10/2019 | 16/04/2019 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Not Recruiting | Female: yes Male: yes | 180 | Phase 3 | Serbia;United States;Portugal;Taiwan;Hong Kong;Spain;Russian Federation;Israel;Colombia;France;Australia;Denmark;Netherlands;Korea, Republic of;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Belgium;Poland;Singapore;Germany;Japan;New Zealand;Sweden | ||
| 6 | EUCTR2017-004135-36-DK (EUCTR) | 16/10/2019 | 05/08/2019 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months - ALXN1840 Efficacy Safety administered for 48 Weeks Versus SOC in patients with Wilson Disease | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: tiomolibdic acid Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE Trade Name: Penicillamine INN or Proposed INN: PENICILLAMINE Trade Name: Trientine dihydrochloride INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE Trade Name: Wilzin INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 180 | Phase 3 | Serbia;United States;Portugal;Taiwan;Hong Kong;Spain;Israel;Russian Federation;Colombia;France;Australia;Denmark;Netherlands;Korea, Republic of;Czechia;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Poland;Belgium;Singapore;Germany;New Zealand;Japan;Sweden | ||
| 7 | EUCTR2019-000905-57-DK (EUCTR) | 17/04/2019 | 14/03/2019 | Efficacy of zinc on copper uptake in the body depending on zinc type and dose regimen measured with 64CuCl2 PET/CT-scan | Efficacy of zinc on human gut copper uptake depending on zinc type and dose regimen quantified with 64CuCl2 PET/CT-scan | Healthy volunteers (Wilson's disease) MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] | Trade Name: Wilzin INN or Proposed INN: Zinc acetate Trade Name: Zink Natur-Drogeriet INN or Proposed INN: Zinc gluconate Other descriptive name: ZINC GLUCONATE Product Name: 64CuCl2 INN or Proposed INN: 64CuCl2 Other descriptive name: COPPER (64CU) CHLORIDE | The Department of Hepatology and Gastroenterology, Aarhus University Hospital | NULL | Not Recruiting | Female: yes Male: yes | 30 | Phase 4 | Denmark | ||
| 8 | NCT03957720 (ClinicalTrials.gov) | March 15, 2019 | 8/4/2019 | The Individual Therapy for Patients With Wilson's Disease | The Individual Therapy for Patients With Wilson's Disease | Wilson's Disease | Drug: DMPS;Drug: Penicillamine;Drug: DMSA;Drug: Zinc gluconate | Second Affiliated Hospital, School of Medicine, Zhejiang University | NULL | Recruiting | N/A | N/A | All | 400 | Early Phase 1 | China |
| 9 | EUCTR2017-004135-36-FR (EUCTR) | 14/09/2018 | 15/01/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of WTX101 in adult patients who suffer from Wilson Disease. | A Phase 3, Randomised, Rater-Blinded, Multi-Centre Study to Evaluate the Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects Aged 18 and Older with an Extension Phase of up to 60 Months | Wilson Disease;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: WTX101 Product Code: WTX101 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Wilson Therapeutics AB | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 102 | Human pharmacology (Phase 1): no Therapeutic exploratory (Phase 2): no Therapeutic confirmatory - (Phase 3): yes Therapeutic use (Phase 4): no | United States;Portugal;Spain;Austria;Israel;United Kingdom;Italy;France;Czech Republic;Hungary;Belgium;Poland;Denmark;Netherlands;Germany;Sweden | ||
| 10 | NCT03659331 (ClinicalTrials.gov) | September 2018 | 28/8/2018 | A Controlled Study of Potential Therapeutic Effect of Oral Zinc in Manifesting Carriers of Wilson Disease | A Controlled Study of Potential Therapeutic Effect of Oral Zinc in Manifesting Carriers of Wilson Disease | Wilson Disease | Dietary Supplement: Zinc | Prof. Elon Pras | NULL | Unknown status | 18 Years | N/A | All | 50 | N/A | NULL |
| 11 | EUCTR2017-004135-36-ES (EUCTR) | 27/04/2018 | 22/01/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of WTX101 in adult patients who suffer from Wilson Disease. | A Phase 3, Randomised, Rater-Blinded, Multi-Centre Study to Evaluate the Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects Aged 18 and Older with an Extension Phase of up to 60 Months | Wilson Disease;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: WTX101 Product Code: WTX101 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Wilson Therapeutics AB | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 102 | Phase 3 | France;United States;Hungary;Czech Republic;Poland;Spain;Austria;Israel;Germany;Italy;United Kingdom | ||
| 12 | EUCTR2017-004135-36-GB (EUCTR) | 23/03/2018 | 19/12/2017 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of WTX101 in adult patients who suffer from Wilson Disease. | A Phase 3, Randomised, Rater-Blinded, Multi-Centre Study to Evaluate the Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects Aged 18 and Older with an Extension Phase of up to 60 Months | Wilson Disease;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: WTX101 Product Code: WTX101 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE Other descriptive name: ZINC ACETATE DIHYDRATE | Wilson Therapeutics AB | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 102 | Human pharmacology (Phase 1): no Therapeutic exploratory (Phase 2): no Therapeutic confirmatory - (Phase 3): yes Therapeutic use (Phase 4): no | United States;Portugal;Spain;Austria;Israel;United Kingdom;Italy;France;Czech Republic;Hungary;Belgium;Poland;Denmark;Netherlands;Germany;Sweden | ||
| 13 | EUCTR2017-004135-36-DE (EUCTR) | 16/03/2018 | 22/12/2017 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 180 | Phase 3 | Serbia;United States;Portugal;Hong Kong;Taiwan;Greece;Spain;Russian Federation;Israel;Colombia;France;Australia;Denmark;Netherlands;Czechia;Korea, Democratic People's Republic of;Turkey;Austria;United Kingdom;Hungary;Canada;Belgium;Brazil;Poland;Singapore;Croatia;Germany;New Zealand;Japan;Sweden | ||
| 14 | EUCTR2017-004135-36-AT (EUCTR) | 27/02/2018 | 17/01/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 180 | Phase 3 | Serbia;United States;Portugal;Hong Kong;Taiwan;Greece;Spain;Russian Federation;Israel;Colombia;France;Australia;Denmark;Netherlands;Czechia;Korea, Democratic People's Republic of;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Belgium;Brazil;Poland;Singapore;Croatia;Germany;New Zealand;Japan;Sweden | ||
| 15 | EUCTR2017-004135-36-HU (EUCTR) | 12/02/2018 | 07/02/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of WTX101 in adult patients who suffer from Wilson Disease. | A Phase 3, Randomised, Rater-Blinded, Multi-Centre Study to Evaluate the Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects Aged 18 and Older with an Extension Phase of up to 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: WTX101 Product Code: WTX101 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Wilson Therapeutics AB | NULL | Authorised-recruitment may be ongoing or finished | Female: yes Male: yes | 102 | Phase 3 | France;United States;Czech Republic;Hungary;Poland;Spain;Austria;Israel;Germany;Italy;United Kingdom | ||
| 16 | NCT00212355 (ClinicalTrials.gov) | March 2005 | 13/9/2005 | Efficacy and Safety, Long-term Study of Zinc Acetate to Treat Wilson's Disease in Japan. | Phase3, Open-Label, Clinical Trial of Zinc Acetate for Treatment of Wilson's Disease in Japan. | Wilson's Disease | Drug: NPC-02 | Nobelpharma | NULL | Completed | 1 Year | N/A | All | 37 | Phase 3 | NULL |
| 17 | NCT00212368 (ClinicalTrials.gov) | October 2004 | 13/9/2005 | Efficacy and Safety Study of Zinc Acetate to Treat Wilson's Disease in Japan. | Phase3,Open-label,Clinical Trial of Zinc Acetate for Treatment of Wilson's Disease in Japan. | Wison's Disease | Drug: Zinc acetate | Nobelpharma | NULL | Completed | 1 Year | N/A | Both | Phase 3 | NULL | |
| 18 | NCT00004338 (ClinicalTrials.gov) | October 1993 | 18/10/1999 | Study of Zinc for Wilson Disease | Wilson Disease | Drug: zinc acetate | National Center for Research Resources (NCRR) | University of Michigan | Completed | N/A | N/A | Both | 300 | Phase 4 | United States | |
| 19 | EUCTR2017-004135-36-CZ (EUCTR) | 09/01/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater- Blinder, Multi-Centre Study to Evaluate the Efficacy and Safety of ALXN1840 Administered for 48 Weeks Versus Standard of Care In Patients with Wilson Disease Aged 12 Years and Older With an Extension Period of Up to 60 months | Wilson Disease;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc. | NULL | NA | Female: yes Male: yes | 180 | Phase 3 | Serbia;United States;Portugal;Hong Kong;Taiwan;Spain;Russian Federation;Israel;Colombia;France;Australia;Denmark;Netherlands;Korea, Republic of;Czechia;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Belgium;Poland;Singapore;Germany;New Zealand;Japan;Sweden | |||
| 20 | EUCTR2017-004135-36-PL (EUCTR) | 03/04/2018 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | NA | Female: yes Male: yes | 180 | Phase 3 | Portugal;Serbia;United States;Hong Kong;Taiwan;Greece;Spain;Russian Federation;Israel;Colombia;France;Australia;Denmark;Netherlands;Korea, Republic of;Czechia;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Poland;Belgium;Singapore;Croatia;Germany;New Zealand;Japan;Sweden | |||
| 21 | EUCTR2017-004135-36-BE (EUCTR) | 17/06/2019 | A Phase 3 clinical study to Evaluate the Efficacy and Safety of ALXN1840 in adult and adolescent patients who suffer from Wilson Disease. | A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate The Efficacy And Safety Of ALXN1840 Administered For 48 Weeks Versus Standard Of Care In Patients With Wilson Disease Aged 12 Years And Older With An Extension Period Of Up To 60 Months | Wilson Disease MedDRA version: 20.0;Level: LLT;Classification code 10047988;Term: Wilson's disease;System Organ Class: 100000004850;Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] | Product Name: ALXN1840 INN or Proposed INN: Not applied Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE INN or Proposed INN: PENICILLAMINE INN or Proposed INN: TRIENTINE DIHYDROCHLORIDE INN or Proposed INN: ZINC ACETATE DIHYDRATE | Alexion Pharmaceuticals, Inc | NULL | Not Recruiting | Female: yes Male: yes | 180 | Phase 3 | United States;Portugal;Serbia;Taiwan;Hong Kong;Greece;Spain;Israel;Russian Federation;Colombia;Italy;France;Denmark;Australia;Netherlands;Korea, Republic of;Turkey;Austria;United Kingdom;Czech Republic;Hungary;Canada;Brazil;Belgium;Poland;Singapore;Croatia;Germany;Japan;New Zealand;Sweden |