ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair.

NCT04061798 | Terminated Phase 4 DMC

• 1 other identifier: NL-66759
• Study Type: interventional
• Target: 294
• Locations: 2 countries
• Sites: 22

Brief Summary

Aim of the ACTION-1 study is to determine whether ACT guided heparinization decreases thrombo-embolic complications (TEC) and mortality after elective open AAA surgery, without causing more bleeding complications.

Conditions

Abdominal Aortic Aneurysm; Surgery; Arterial Disease

Keywords

ACT guided heparinization in open aortic surgery

Outcome Measures

Primary Outcomes (1)

• Combined incidence of all thrombo-embolic complications (TEC) and all-cause mortality.

  TEC are any complication as caused by thrombus or embolus perioperatively, including but not exclusively: myocardial infarction, leg ischemia, deep venous thrombosis, colon ischemia, transient ischemic attack (TIA)/stroke, graft thrombosis, peroperative thrombus requiring embolectomy or redo of an anastomosis, thrombus or embolus in organs or lower limbs and other peripheral thrombosis. Incidence of bleeding complications according to European multicenter study on Coronary Artery Bypass Grafting (E-CABG) classification, grade 1 and higher: per- or postoperative transfusion of 2 or more units of red blood cells, transfusion of platelets, transfusion of fresh frozen plasma or reoperation for bleeding during hospital stay.

  Within 30 days or during the same admission in hospital

Secondary Outcomes (1)

• Complications (non-TEC).

  Within 30 days or during the same admission in hospital

Study Arms (2)

ACT guided heparinization

EXPERIMENTAL

Heparin is given to reach an ACT of 200-220 seconds. At the start of the procedure, before any heparin is given, a baseline ACT measurement is performed. 3-5 minutes before clamping of the aorta 100 IU/kg bodyweight of heparin is administrated intravenously. 5 minutes after administration of heparin, ACT measurement is performed.

Drug: ACT guided heparinization

5 000 IU of heparin

ACTIVE COMPARATOR

A single dose of 5 000 IU of heparin is given 3-5 minutes before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps. Depending on that ACT value near the end of surgery, the local protamine can be given to neutralize the effect of heparin. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report.

Drug: 5 000 IU of heparin

Interventions

ACT guided heparinization DRUG

If the ACT is \<180 sec., an additional dose of heparin of 60 IU/kg is administered. If the ACT is 180-200 sec., 30 IU/kg. If the ACT is \>200 sec., no extra heparin is given. 5 min. after every administration of heparin the ACT is measured. If the ACT is \>200 sec, the next ACT measurement is performed every 30 min., until the end of the procedure or until new heparin administration is required. After each new dose of heparin, an ACT measurement is performed after 5 min. and the above- described protocol of ACT measurements will be repeated. After re-establishing blood flow and removing all clamps, the ACT is measured. If the ACT at closure is 200-250 sec., 2500 IU of protamine should be administered. If \>250 sec., 5000 IU protamine. If 180-200 sec., 1000 IU protamine. 5 min. after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 sec. If the ACT is still more than 200 sec., protamine should be administered again.

ACT guided heparinization

5 000 IU of heparin DRUG

A single dose of 5 000 IU of heparin is given 3-5 min before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps. Only on clarified indications extra doses of heparin or protamine are permitted, at the discretion of the attending vascular surgeon. Indications could be clot formation intravascular or in a prosthesis, excessive bleeding or prolonged operation duration. Deviations from protocol should be clearly stated with reasoning in the operative report. If the ACT at closure is between 200 and 250 s, 2500 IU protamine should be administered. If the ACT is higher than 250 s, 5000 IU protamine should be administered. If the ACT is between 180 and 200 s, 1000 IU protamine should be administered. Five minutes after the administration of protamine, the ACT is measured. The ACT should preferably be below 180 s. If the ACT is still more than 200 s, protamine should be administered again.

5 000 IU of heparin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to speak and read in local language of trial hospital.
• Patients older than 18 years scheduled for elective, open repair of an iliac or abdominal aortic aneurysm distal of the Superior Mesenteric Artery (SMA) (DSAA segment C).
• Implantation of a tube or bifurcation prosthesis.
• Trans-abdominal or retroperitoneal surgical approach of aneurysm.
• Able and willing to provide written informed consent.

You may not qualify if:

• Not able to provide written informed consent.
• History of coagulation disorders, heparin induced thrombocytopenia (HIT), allergy for heparin or thrombocyte pathology.
• Impaired renal function with EGFR below 30 ml/min.
• Acute open AAA surgery.
• Hybrid interventions.
• Connective tissue disorders.
• Dual anti-platelet therapy, which cannot be discontinued.
• Life expectancy less than 2 years.
• Inflammatory, mycotic or infected aneurysms.
• Allergy for protamine or fish protein

Sponsors & Collaborators

• Dijklander Ziekenhuis: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Amsterdam UMC, location VUmc: collaborator
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator

Study Sites (22)

Universitätsklinikum Hamburg-Eppendorf

Hamburg, Germany

Location

Krankenhaus Barmherzige Brüder

Regensburg, Germany

Location

Treant Zorggroep

Emmen, Drenthe, 7824AA, Netherlands

Location

Gelre Ziekenhuizen

Apeldoorn, Gelderland, 7334DZ, Netherlands

Location

Rijnstate

Arnhem, Gelderland, 6815 AD, Netherlands

Location

Slingeland Ziekenhuis

Doetinchem, Gelderland, 7009BL, Netherlands

Location

Elisabeth TweeSteden Ziekenhuis

Tilburg, Noord-Braband, 5022 GC, Netherlands

Location

Amphia

Breda, North Brabant, 4818 CK, Netherlands

Location

Catharina Ziekenhuis

Eindhoven, North Brabant, 5623 EJ, Netherlands

Location

AUMC Location VUmc

Amsterdam, North Holland, 1081 HV, Netherlands

Location

AUMC Location AMC

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Dijklander Ziekenhuis

Hoorn, North Holland, 1624NP, Netherlands

Location

Medisch Spectrum Twente

Enschede, Overijssel, 7512 KZ, Netherlands

Location

Isala

Zwolle, Overijssel, 8025 AB, Netherlands

Location

Groene Hart

Gouda, South Holland, 2803 HH, Netherlands

Location

Leiden Universitair Medisch Centrum

Leiden, South Holland, 2333 ZA, Netherlands

Location

Alrijne

Leiderdorp, South Holland, 2353 GA, Netherlands

Location

Maasstad Ziekenhuis

Rotterdam, South Holland, 3079 DZ, Netherlands

Location

Haaglanden Medisch Centrum

The Hague, South Holland, 2597AX, Netherlands

Location

Ziekenhuisgroep Twente

Almelo, Netherlands

Location

Universitair Medisch Centrum Groningen

Groningen, Netherlands

Location

St. Antonius ziekenhuis

Nieuwegein, 3435 CM, Netherlands

Location

Related Publications (33)

• Burgers LT, Vahl AC, Severens JL, Wiersema AM, Cuypers PW, Verhagen HJ, Redekop WK. Cost-effectiveness of Elective Endovascular Aneurysm Repair Versus Open Surgical Repair of Abdominal Aortic Aneurysms. Eur J Vasc Endovasc Surg. 2016 Jul;52(1):29-40. doi: 10.1016/j.ejvs.2016.03.001. Epub 2016 Apr 23.

  PMID: 27118618 BACKGROUND

• Behrendt CA, Sedrakyan A, Riess HC, Heidemann F, Kolbel T, Petersen J, Debus ES. Short-term and long-term results of endovascular and open repair of abdominal aortic aneurysms in Germany. J Vasc Surg. 2017 Dec;66(6):1704-1711.e3. doi: 10.1016/j.jvs.2017.04.040. Epub 2017 Aug 7.

  PMID: 28780975 BACKGROUND

• Behrendt CA, Riess HC, Schwaneberg T, Larena-Avellaneda A, Kolbel T, Tsilimparis N, Spanos K, Debus ES, Sedrakyan A. Incidence, Predictors, and Outcomes of Colonic Ischaemia in Abdominal Aortic Aneurysm Repair. Eur J Vasc Endovasc Surg. 2018 Oct;56(4):507-513. doi: 10.1016/j.ejvs.2018.06.010. Epub 2018 Jul 20.

  PMID: 30037737 BACKGROUND

• Deery SE, O'Donnell TFX, Bodewes TCF, Dalebout BA, Pothof AB, Shean KE, Darling JD, Schermerhorn ML. Early reintervention after open and endovascular abdominal aortic aneurysm repair is associated with high mortality. J Vasc Surg. 2018 Feb;67(2):433-440.e1. doi: 10.1016/j.jvs.2017.06.104. Epub 2017 Sep 21.

  PMID: 28943011 BACKGROUND

• Trenner M, Haller B, Storck M, Reutersberg B, Kallmayer MA, Eckstein HH. Trends in Patient Safety of Intact Abdominal Aortic Aneurysm Repair: German Registry Data on 36,594 Procedures. Eur J Vasc Endovasc Surg. 2017 May;53(5):641-647. doi: 10.1016/j.ejvs.2016.12.024. Epub 2017 Jan 19.

  PMID: 28110907 BACKGROUND

• Hynes CF, Endicott KM, Iranmanesh S, Amdur RL, Macsata R. Reoperation rates after open and endovascular abdominal aortic aneurysm repairs. J Vasc Surg. 2017 May;65(5):1323-1328. doi: 10.1016/j.jvs.2016.09.053. Epub 2017 Jan 7.

  PMID: 28073669 BACKGROUND

• Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R, Buskens E, Grobbee DE, Blankensteijn JD; Dutch Randomized Endovascular Aneurysm Management (DREAM)Trial Group. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med. 2004 Oct 14;351(16):1607-18. doi: 10.1056/NEJMoa042002.

  PMID: 15483279 BACKGROUND

• Lo RC, Bensley RP, Hamdan AD, Wyers M, Adams JE, Schermerhorn ML; Vascular Study Group of New England. Gender differences in abdominal aortic aneurysm presentation, repair, and mortality in the Vascular Study Group of New England. J Vasc Surg. 2013 May;57(5):1261-8, 1268.e1-5. doi: 10.1016/j.jvs.2012.11.039. Epub 2013 Feb 4.

  PMID: 23384493 BACKGROUND

• Wiersema A, Bruijninckx C, Reijnen M, Vos J, Van Delden O, Vahl A, Zeebregts C, Moll F. Perioperative prophylactic antithrombotic strategies in vascular surgery: current practice in the Netherlands. J Cardiovasc Surg (Torino). 2015 Feb;56(1):119-25. Epub 2013 Jan 22.

  PMID: 23337406 BACKGROUND

• Wiersema AM, Jongkind V, Bruijninckx CM, Reijnen MM, Vos JA, van Delden OM, Zeebregts CJ, Moll FL; CAPPAStudy Group Consensus on Arterial PeriProcedural Anticoagulation. Prophylactic perioperative anti-thrombotics in open and endovascular abdominal aortic aneurysm (AAA) surgery: a systematic review. Eur J Vasc Endovasc Surg. 2012 Oct;44(4):359-67. doi: 10.1016/j.ejvs.2012.06.008. Epub 2012 Jul 24.

  PMID: 22831869 BACKGROUND

• Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):188S-203S. doi: 10.1378/chest.126.3_suppl.188S.

  PMID: 15383472 BACKGROUND

• Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013 Jun;116(6):1210-22. doi: 10.1213/ANE.0b013e31827e4e62. Epub 2013 Feb 13.

  PMID: 23408671 BACKGROUND

• Arsenault KA, Paikin JS, Hirsh J, Dale B, Whitlock RP, Teoh K, Young E, Ginsberg JS, Weitz JI, Eikelboom JW. Subtle differences in commercial heparins can have serious consequences for cardiopulmonary bypass patients: A randomized controlled trial. J Thorac Cardiovasc Surg. 2012 Oct;144(4):944-950.e3. doi: 10.1016/j.jtcvs.2012.05.065. Epub 2012 Jun 27.

  PMID: 22743176 BACKGROUND

• Nath FC, Muller DW, Rosenschein U, Ellis SG, Topol EJ. Heparin monitoring during coronary intervention: activated clotting time versus activated partial thromboplastin time. Can J Cardiol. 1993 Nov;9(9):797-801.

  PMID: 8281479 BACKGROUND

• Chew DP, Bhatt DL, Lincoff AM, Moliterno DJ, Brener SJ, Wolski KE, Topol EJ. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation. 2001 Feb 20;103(7):961-6. doi: 10.1161/01.cir.103.7.961.

  PMID: 11181470 BACKGROUND

• Kasapis C, Gurm HS, Chetcuti SJ, Munir K, Luciano A, Smith D, Aronow HD, Kassab EH, Knox MF, Moscucci M, Share D, Grossman PM. Defining the optimal degree of heparin anticoagulation for peripheral vascular interventions: insight from a large, regional, multicenter registry. Circ Cardiovasc Interv. 2010 Dec;3(6):593-601. doi: 10.1161/CIRCINTERVENTIONS.110.957381. Epub 2010 Nov 9.

  PMID: 21062999 BACKGROUND

• Veerhoek D, Groepenhoff F, van der Sluijs MGJM, de Wever JWB, Blankensteijn JD, Vonk ABA, Boer C, Vermeulen CFW. Individual Differences in Heparin Sensitivity and Their Effect on Heparin Anticoagulation During Arterial Vascular Surgery. Eur J Vasc Endovasc Surg. 2017 Oct;54(4):534-541. doi: 10.1016/j.ejvs.2017.07.006. Epub 2017 Aug 9.

  PMID: 28802634 BACKGROUND

• Coyne TJ, Wallace MC, Benedict C. Peri-operative anticoagulant effects of heparinization for carotid endarterectomy. Aust N Z J Surg. 1994 Oct;64(10):679-83. doi: 10.1111/j.1445-2197.1994.tb02056.x.

  PMID: 7945064 BACKGROUND

• Poisik A, Heyer EJ, Solomon RA, Quest DO, Adams DC, Baldasserini CM, McMahon DJ, Huang J, Kim LJ, Choudhri TF, Connolly ES. Safety and efficacy of fixed-dose heparin in carotid endarterectomy. Neurosurgery. 1999 Sep;45(3):434-41; discussion 441-2. doi: 10.1097/00006123-199909000-00003.

  PMID: 10493364 BACKGROUND

• de Sousa AA, Dellaretti MA, Faglioni W Jr, Carvalho GT. Monitoring of activated coagulation time in carotid endarterectomy. Surg Neurol. 2005;64 Suppl 1:S1:6-9. doi: 10.1016/j.surneu.2005.04.016.

  PMID: 15967231 BACKGROUND

• Saw J, Bajzer C, Casserly IP, Exaire E, Haery C, Sachar R, Lee D, Abou-Chebl A, Yadav JS. Evaluating the optimal activated clotting time during carotid artery stenting. Am J Cardiol. 2006 Jun 1;97(11):1657-60. doi: 10.1016/j.amjcard.2005.12.062. Epub 2006 Apr 19.

  PMID: 16728233 BACKGROUND

• Goldhammer JE, Zimmerman D. Pro: Activated Clotting Time Should Be Monitored During Heparinization For Vascular Surgery. J Cardiothorac Vasc Anesth. 2018 Jun;32(3):1494-1496. doi: 10.1053/j.jvca.2017.04.047. Epub 2017 Apr 26. No abstract available.

  PMID: 28943189 BACKGROUND

• Dieplinger B, Egger M, Luft C, Hinterreiter F, Pernerstorfer T, Haltmayer M, Mueller T. Comparison between activated clotting time and anti-activated factor X activity for the monitoring of unfractionated heparin therapy in patients with aortic aneurysm undergoing an endovascular procedure. J Vasc Surg. 2018 Aug;68(2):400-407. doi: 10.1016/j.jvs.2017.11.079. Epub 2018 Mar 20.

  PMID: 29571622 BACKGROUND

• Lee JM, Park EY, Kim KM, Won JC, Jung TK, Lee SK. Comparison of activated clotting times measured using the Hemochron Jr. Signature and Medtronic ACT Plus during cardiopulmonary bypass with acute normovolemic haemodilution. J Int Med Res. 2018 Feb;46(2):873-882. doi: 10.1177/0300060517731952. Epub 2017 Oct 4.

  PMID: 28974132 BACKGROUND

• Chia S, Van Cott EM, Raffel OC, Jang IK. Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation. Thromb Haemost. 2009 Mar;101(3):535-40.

  PMID: 19277416 BACKGROUND

• Biancari F, Ruggieri VG, Perrotti A, Svenarud P, Dalen M, Onorati F, Faggian G, Santarpino G, Maselli D, Dominici C, Nardella S, Musumeci F, Gherli R, Mariscalco G, Masala N, Rubino AS, Mignosa C, De Feo M, Della Corte A, Bancone C, Chocron S, Gatti G, Gherli T, Kinnunen EM, Juvonen T. European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG registry): Study Protocol for a Prospective Clinical Registry and Proposal of Classification of Postoperative Complications. J Cardiothorac Surg. 2015 Jun 30;10:90. doi: 10.1186/s13019-015-0292-z.

  PMID: 26123033 BACKGROUND

• Brascia D, Reichart D, Onorati F, Perrotti A, Ruggieri VG, Bounader K, Verhoye JP, Santarpino G, Fischlein T, Maselli D, Dominici C, Mariscalco G, Gherli R, Rubino AS, De Feo M, Bancone C, Gatti G, Santini F, Dalen M, Saccocci M, Faggian G, Tauriainen T, Kinnunen EM, Nicolini F, Gherli T, Rosato S, Biancari F. Validation of Bleeding Classifications in Coronary Artery Bypass Grafting. Am J Cardiol. 2017 Mar 1;119(5):727-733. doi: 10.1016/j.amjcard.2016.11.027. Epub 2016 Dec 3.

  PMID: 28024656 BACKGROUND

• Mazzalai F, Piatto G, Toniato A, Lorenzetti R, Baracchini C, Ballotta E. Using protamine can significantly reduce the incidence of bleeding complications after carotid endarterectomy without increasing the risk of ischemic cerebral events. World J Surg. 2014 May;38(5):1227-32. doi: 10.1007/s00268-013-2347-4.

  PMID: 24276985 BACKGROUND

• Yamamoto S, Sakakura K, Taniguchi Y, Yamamoto K, Wada H, Momomura SI, Fujita H. Safety of Reversing Anticoagulation by Protamine Following Elective Transfemoral Percutaneous Coronary Intervention in the Drug-Eluting Stent Era. Int Heart J. 2018 May 30;59(3):482-488. doi: 10.1536/ihj.17-352. Epub 2018 May 9.

  PMID: 29743410 BACKGROUND

• Wanhainen A, Verzini F, Van Herzeele I, Allaire E, Bown M, Cohnert T, Dick F, van Herwaarden J, Karkos C, Koelemay M, Kolbel T, Loftus I, Mani K, Melissano G, Powell J, Szeberin Z, Esvs Guidelines Committee, de Borst GJ, Chakfe N, Debus S, Hinchliffe R, Kakkos S, Koncar I, Kolh P, Lindholt JS, de Vega M, Vermassen F, Document Reviewers, Bjorck M, Cheng S, Dalman R, Davidovic L, Donas K, Earnshaw J, Eckstein HH, Golledge J, Haulon S, Mastracci T, Naylor R, Ricco JB, Verhagen H. Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms. Eur J Vasc Endovasc Surg. 2019 Jan;57(1):8-93. doi: 10.1016/j.ejvs.2018.09.020. Epub 2018 Dec 5. No abstract available.

  PMID: 30528142 BACKGROUND

• Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug;8(4):R204-12. doi: 10.1186/cc2872. Epub 2004 May 24.

  PMID: 15312219 BACKGROUND

• M Versteegh M, M Vermeulen K, M A A Evers S, de Wit GA, Prenger R, A Stolk E. Dutch Tariff for the Five-Level Version of EQ-5D. Value Health. 2016 Jun;19(4):343-52. doi: 10.1016/j.jval.2016.01.003. Epub 2016 Mar 30.

  PMID: 27325326 BACKGROUND

• Wiersema AM, Roosendaal LC, Koelemaij MJW, Tijssen JGP, van Dieren S, Blankensteijn JD, Debus ES, Middeldorp S, Heyligers JMM, Fokma YS, Reijnen MMPJ, Jongkind V. ACTION-1: study protocol for a randomised controlled trial on ACT-guided heparinization during open abdominal aortic aneurysm repair. Trials. 2021 Sep 19;22(1):639. doi: 10.1186/s13063-021-05552-7.

  PMID: 34538275 DERIVED

MeSH Terms

Conditions

Aortic Aneurysm, Abdominal

Condition Hierarchy (Ancestors)

Aortic Aneurysm; Aneurysm; Vascular Diseases; Cardiovascular Diseases; Aortic Diseases

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Patients will be randomized using a computerized program (CASTOR EDC) with a random block size of a maximum of 8. The randomization will be stratified by participating centre. The participant is blinded to the allocated treatment. Separate evaluation of results and if complications can be labelled as TEC, will be performed by an Independent Central Adjudication Committee. The 3 members of this Committee will be blinded to the allocated treatment. Since the care provider and investigator have to do the ACT measuring, it is impossible to blind them to the allocated treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Vascular Surgeon

Model Details: Intervention group: Heparin is given to reach an ACT of 200-220 seconds. At the start of the procedure, before any heparin is given, a baseline ACT measurement is performed. 3-5 minutes before clamping of the aorta 100 IU/kg bodyweight of heparin is administrated intravenously. 5 minutes after administration of heparin, ACT measurement is performed. Comparative group: A single dose of 5 000 IU of heparin is given 3-5 minutes before clamping of the aorta. No ACT measurements are performed, except for one ACT measurement after re-establishing blood flow and removing all clamps.

Study Record Dates

• First Submitted: August 18, 2019
• First Posted: August 20, 2019
• Study Start: March 2, 2020
• Primary Completion: April 13, 2024
• Study Completion: April 29, 2024
• Last Updated: February 6, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: after data lock, 07-2024
• Access Criteria: contract with pre-defined criteria according to government regulation concerning science research

Locations

NL (20); DE (2)