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Phenoxybenzamine Versus Doxazosin in PCC Patients (PRESCRIPT)

This study is currently recruiting participants.
Verified May 2017 by Michiel N. Kerstens, University Medical Center Groningen
Sponsor:
ClinicalTrials.gov Identifier:
NCT01379898
First Posted: June 23, 2011
Last Update Posted: May 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Radboud University
UMC Utrecht
VU University of Amsterdam
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Leiden University Medical Center
Erasmus Medical Center
Maastricht University Medical Center
St. Antonius Hospital
Medisch Spectrum Twente
Maxima Medical Center
Canisius-Wilhelmina Hospital
Onze Lieve Vrouwe Gasthuis
Atrium Medical Center
Isala
Information provided by (Responsible Party):
Michiel N. Kerstens, University Medical Center Groningen
  Purpose
  • Rationale: The optimal preoperative medical management for patients with a pheochromocytoma is currently unknown. In particular, there is no agreement with respect to whether phenoxybenzamine or doxazosin is the optimal alfa-adrenoreceptor antagonist to be administered before surgical resection of a pheochromocytoma. We hypothesized that the competitive alfa1-antagonist doxazosin is superior to the non-competitive alfa1- and alfa2-antagonist phenoxybenzamine.
  • Objective: comparing effects of preoperative treatment with either phenoxybenzamine or doxazosin on intraoperative hemodynamic control in patients undergoing surgical resection of a pheochromocytoma.
  • Study design: Randomised controlled open-label trial.
  • Study population: 18 - 55 yr old. Adult patients with a recently diagnosed benign pheochromocytoma.
  • Intervention: Patients are randomised to receive oral treatment with either phenoxybenzamine or doxazosin preoperatively.
  • Main study parameters/endpoints: The main study parameter is defined as the percentage of intraoperative time that blood pressure is outside the predefined target range after pretreatment with either phenoxybenzamine or doxazosin.

In this multicenter trial, we compare the effects of two commonly used drugs in patients being medically prepared for resection of a benign pheochromocytoma. Participants are not subjected to an experimental treatment of any kind, as we merely aim to describe in detail the perioperative course in general and, in particular, the intraoperative hemodynamic control in patients treated preoperatively with either phenoxybenzamine or doxazosin. A routine diagnostic work-up for pheochromocytoma will be performed in all participants. One extra blood sample (volume: 48,5 mL) is drawn before start of the study medication, and participants need to record their symptoms in a diary. In addition, patients who are pretreated in the outpatient clinic monitor their blood pressure and pulse rate at home with an automated device. Treatment with an alfa-adrenoreceptor antagonist is initiated at least 2 - 3 weeks prior to surgery. Patients who are admitted to the hospital for pretreatment with an alfa-adrenoreceptor antagonist have their blood pressure and pulse rate measured by the nursing staff. The final site visit is planned at 30 days after surgery, in line with current practice.


Condition Intervention Phase
Pheochromocytoma Drug: Phenoxybenzamine Drug: Doxazosin Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment

Resource links provided by NLM:


Further study details as provided by Michiel N. Kerstens, University Medical Center Groningen:

Primary Outcome Measures:
  • The main study parameter is defined as the percentage of intraoperative time that blood pressure is outside the predefined target range after pretreatment with either phenoxybenzamine or doxazosin. [ Time Frame: Duration of surgery, i.e. on average 3 hours ]
    Blood pressure and heart rate will be monitored continuesly during surgery.


Secondary Outcome Measures:
  • To attain preoperative blood pressure target values without co-medication [ Time Frame: an expected average of 2 to 6 weeks before surgery ]
    success rate of doxazosin and phenoxybenzamine to attain preoperative blood pressure target values without co-medication

  • Resolution of (paroxysmal) symptoms and signs of pheochromocytoma. [ Time Frame: an expected average of 2-6 weeks before surgery ]
    Resulution of headache, palpitations, sweeting, paleness, nausea, flushes, fatigue and anxiety.

  • Need for additional antihypertensive agents [ Time Frame: an expected average of 2-6 weeks before surgery ]
    Assessment of the number of patients who need additional antihypertensive drugs on top of the study drugs

  • Adverse effects of study medication [ Time Frame: an expected average of 2-6 weeks before surgery ]
    Adverse effects of doxazosin or phenoxybenzamine

  • Length of preoperative treatment in either outpatient or inpatient clinic. [ Time Frame: an expected average of 2-6 weeks before surgery ]
    Comparing duration of preoperative treatment in either outpatient or inpatient clinic

  • Control of blood pressure and heart rate. [ Time Frame: Duration of surgery, i.e. on average 3 hours ]
    • number of episodes with systolic blood pressure (SBP) > 160 mmHg
    • number of episodes with mean arterial blood pressure (MAP) < 60 mmHg
    • duration (in minutes) of SBP > 160 mmHg
    • duration (in minutes) of MAP < 60 mmHg
    • number of episodes with heart rate > 100/min
    • duration (in minutes) of heart rate > 100/min
    • amount and type of vasoactive agents needed during surgery for adequate blood pressure control.
    • cumulative amount and type of intravenous fluids administered

  • Length of hospital stay. [ Time Frame: Participants will be followed for the duration of hospital stay an expected average of 2-5 weeks. ]
    Number of days the patient is staying in the hospital before and after surgery

  • Composite semi-quantitative score of intra- and postoperative hemodynamic control. [ Time Frame: During surgery and the first 24 hours after surgery at the intensive/ medium care unit ]

    Composite semi-quantitative score of intra- and postoperative hemodynamic control based on the following parameters:

    • blood pressure and heart rate outside target range
    • need for administration of vasoactive agents
    • need for administration of intravenous fluids

  • Postoperative hypoglycaemia [ Time Frame: First 24 hours postoperative ]
    Frequency and severity (in mmol/L)of hypoglycaemia during first 24 hours after surgery.

  • Perioperative mortality. [ Time Frame: From first administration of study medication until 30 days after surgery. ]
    Death from any cause occurring during period from first administration of study medication until 30 days after surgery.

  • Perioperative cardiovascular morbidity. [ Time Frame: From first administation of study medicaion until 30 days after surgery. ]
    Cardiovascular events occurring during period from first administration of study medication until 30 days after surgery. Cardiovascular events are: myocardial infarction, cardiac arrhythmia requiring medical intervention, heart failure, cerebrovascular ischemia, cerebrovascular haemorrhage.

  • Composite endpoint of perioperative mortality and perioperative cardiovascular morbidity. [ Time Frame: From first administration of study medication until 30 days after surgery. ]
    Death from any cause occurring or cardiovascular events occurring during period from first administration of study medication until 30 days after surgery.


Estimated Enrollment: 134
Study Start Date: December 2011
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Phenoxybezamine
Phenoxybenzamine (capsules 10 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC.
Drug: Phenoxybenzamine
Starting dosage of phenoxybenzamine in hypertensive subjects:20 mg q.d. (=10 mg b.i.d.) and in normotensive subjects 10 mg q.d. (in the evening). Dose escalation until blood pressure targets are reached, with a maximum dose of 140 mg q.d. (=70 mg b.i.d.)
Other Name: Dibenzyran
Active Comparator: Doxazosin
Phenoxybenzamine (slow release tablets 4 or 8 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC.
Drug: Doxazosin
Starting dosage of doxazosine in hypertensive subjects:8 mg q.d. (=4 mg b.i.d.)and in normotensive subjects starting dose 4 mg q.d. (in the evening). Dose escalation until blood pressure targets are reached, with a maximum dose of 48 mg q.d. .(=24 mg b.i.d.)
Other Name: Cardura

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age > 18 years
  • diagnosis of benign Pheochromocytoma (adrenal or extra-adrenal, sporadic or hereditary:

    • hypertension
    • elevated plasma and/or urinary (nor)metanephrines. From each patient, a blood sample is collected for measurement of plasma (nor)metanephrines with the reference laboratory assay (i.e. XLC-MS/MS) at the Department of Laboratory Medicine of the UMCG.
    • localisation of PCC by anatomical (MRI/CT) and functional imaging (I123-MIBG scintigraphy or 18F-DOPA PET)
  • planned for surgical removal of the PCC

Exclusion Criteria:

  • age < 18 years
  • malignant PCC, i.e. presence of lesions on imaging studies suggestive of distant metastases
  • severe hemodynamic instability before surgery necessitating admission to intensive care unit
  • pregnancy
  • incapability to adhere to the study protocol
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01379898


Contacts
Contact: Michiel N Kerstens, MD PhD 0031- 50-3613962 m.n.kerstens@int.umcg.nl

Locations
Netherlands
Department of Endocrinology, University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700 RB
Contact: Michiel N. Kerstens, MD PhD    0031-50-3613962    m.n.kerstens@int.umcg.nl   
Principal Investigator: Thera P. Links, MD PhD         
Principal Investigator: Gütz J. Wietasch, MD PhD         
Sponsors and Collaborators
University Medical Center Groningen
Radboud University
UMC Utrecht
VU University of Amsterdam
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Leiden University Medical Center
Erasmus Medical Center
Maastricht University Medical Center
St. Antonius Hospital
Medisch Spectrum Twente
Maxima Medical Center
Canisius-Wilhelmina Hospital
Onze Lieve Vrouwe Gasthuis
Atrium Medical Center
Isala
Investigators
Study Director: Michiel N. Kerstens, MD PhD University Medical Center Groningen
Principal Investigator: Thera P. Links, MD PhD University Medical Center Groningen
Principal Investigator: Gütz J. Wietasch, MD PhD University Medical Center Groningen
Principal Investigator: Jaques W. Lenders, MD PhD UMC St Radboud Nijmegen
Principal Investigator: G D. Valk, MD PhD UMC Utrecht
Principal Investigator: E M. Eekhoff, MD PhD Free University UMC Amsterdam
Principal Investigator: P H. Bisschop, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: R A Feelders, MD PhD Erasmus Medical Center, Rotterdam
Principal Investigator: Bas Havekes, MD PhD Maastricht University Medical Center
Principal Investigator: Peter Oomen, MD PhD Medical Center Leeuwarden
Principal Investigator: I Eland, MD PhD St. Antonius Ziekenhuis Nieuwegein
Principal Investigator: P H. Geelhoed- Duijvestijn, MD PhD Medical Center Haaglanden
Principal Investigator: P Groote Veldman, MD PhD Medisch Spectrum Twente
Principal Investigator: H R Haak, MD PhD Máxima Medisch Centrum
Principal Investigator: J R. Meinardi, MD PhD Canisius-Wilhelmina Hospital
Principal Investigator: C B. Brouwer, MD PhD Canisius-Wilhelmina Hospital
Principal Investigator: P L. van Battum, MD Atrium Medical Center
Principal Investigator: A A. Franken, MD PhD Isala Klinieken, Zwolle
  More Information

Publications:
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-75. Review.
Lenders JW, Eisenhofer G, Armando I, Keiser HR, Goldstein DS, Kopin IJ. Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. Clin Chem. 1993 Jan;39(1):97-103.
Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983 Dec;58(12):802-4.
Neumann HP, Cybulla M, Shibata H, Oya M, Naruse M, Higashihara E, Terachi T, Ling H, Takami H, Shuin T, Murai M. New genetic causes of pheochromocytoma: current concepts and the clinical relevance. Keio J Med. 2005 Mar;54(1):15-21. Review.
Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005 Dec 1;23(34):8812-8.
Korpershoek E, Van Nederveen FH, Dannenberg H, Petri BJ, Komminoth P, Perren A, Lenders JW, Verhofstad AA, De Herder WW, De Krijger RR, Dinjens WN. Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience. Ann N Y Acad Sci. 2006 Aug;1073:138-48.
Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher ER, Plouin PF; European Network for the Study of Adrenal Tumours (ENS@T) Pheochromocytoma Working Group. Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf). 2006 Dec;65(6):699-705.
Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010 Mar;42(3):229-33. doi: 10.1038/ng.533. Epub 2010 Feb 14.
Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS; International Symposium on Pheochromocytoma. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007 Feb;3(2):92-102.
Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab. 2001 Apr;86(4):1480-6.
Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007 Nov;92(11):4069-79. Review.
Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg. 2002 Aug;26(8):1037-42. Epub 2002 Jun 19.
Bruynzeel H, Feelders RA, Groenland TH, van den Meiracker AH, van Eijck CH, Lange JF, de Herder WW, Kazemier G. Risk Factors for Hemodynamic Instability during Surgery for Pheochromocytoma. J Clin Endocrinol Metab. 2010 Feb;95(2):678-85. doi: 10.1210/jc.2009-1051. Epub 2009 Dec 4.
van der Horst-Schrivers AN, Kerstens MN, Wolffenbuttel BH. Preoperative pharmacological management of phaeochromocytoma. Neth J Med. 2006 Sep;64(8):290-5. Review.
Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf. 2007;30(11):1031-62. Review.
Kinney MA, Warner ME, vanHeerden JA, Horlocker TT, Young WF Jr, Schroeder DR, Maxson PM, Warner MA. Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection. Anesth Analg. 2000 Nov;91(5):1118-23.
Eisenhofer G, Bornstein SR. Surgery: Risks of hemodynamic instability in pheochromocytoma. Nat Rev Endocrinol. 2010 Jun;6(6):301-2. doi: 10.1038/nrendo.2010.65.
Karthikeyan G, Moncur RA, Levine O, Heels-Ansdell D, Chan MT, Alonso-Coello P, Yusuf S, Sessler D, Villar JC, Berwanger O, McQueen M, Mathew A, Hill S, Gibson S, Berry C, Yeh HM, Devereaux PJ. Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies. J Am Coll Cardiol. 2009 Oct 20;54(17):1599-606. doi: 10.1016/j.jacc.2009.06.028. Review.
Kim AW, Quiros RM, Maxhimer JB, El-Ganzouri AR, Prinz RA. Outcome of laparoscopic adrenalectomy for pheochromocytomas vs aldosteronomas. Arch Surg. 2004 May;139(5):526-9; discussion 529-31.
Shen WT, Grogan R, Vriens M, Clark OH, Duh QY. One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. Arch Surg. 2010 Sep;145(9):893-7. doi: 10.1001/archsurg.2010.159.
Kocak S, Aydintug S, Canakci N. Alpha blockade in preoperative preparation of patients with pheochromocytomas. Int Surg. 2002 Jul-Sep;87(3):191-4.
Weingarten TN, Cata JP, O'Hara JF, Prybilla DJ, Pike TL, Thompson GB, Grant CS, Warner DO, Bravo E, Sprung J. Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma. Urology. 2010 Aug;76(2):508.e6-11. doi: 10.1016/j.urology.2010.03.032. Epub 2010 May 23.
Mueller T, Gegenhuber A, Dieplinger B, Poelz W, Haltmayer M. Capability of B-type natriuretic peptide (BNP) and amino-terminal proBNP as indicators of cardiac structural disease in asymptomatic patients with systemic arterial hypertension. Clin Chem. 2005 Dec;51(12):2245-51. Epub 2005 Oct 13.

Responsible Party: Michiel N. Kerstens, MD, PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT01379898     History of Changes
Other Study ID Numbers: PRESCRIPT2010.369
2010:022417-25 ( EudraCT Number )
First Submitted: May 19, 2011
First Posted: June 23, 2011
Last Update Posted: May 10, 2017
Last Verified: May 2017

Keywords provided by Michiel N. Kerstens, University Medical Center Groningen:
Pheochromocytoma
Doxazosin
Phenoxybenzamine

Additional relevant MeSH terms:
Pheochromocytoma
Paraganglioma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Doxazosin
Phenoxybenzamine
Antihypertensive Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Vasodilator Agents


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