Phenoxybenzamine Versus Doxazosin in PCC Patients (PRESCRIPT)

This study is currently recruiting participants.
Verified January 2012 by University Medical Centre Groningen
Sponsor:
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 Klinieken
Information provided by (Responsible Party):
Michiel N. Kerstens, University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT01379898
First received: May 19, 2011
Last updated: January 25, 2012
Last verified: January 2012
  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 frequency of intraoperative blood pressure episodes 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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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 University Medical Centre Groningen:

Primary Outcome Measures:
  • The number of patients demonstrating more than three intraoperative episodes of 5 minutes with blood pressure outside the predefined target range after pretreatment with either phenoxybenzamine or doxazosin. [ Time Frame: Duration of surgery, i.e. on average 3 hours ] [ Designated as safety issue: No ]
    Blood pressure and heart rate will be monitored at 5 minute intervals 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    • 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. ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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 2014
Estimated Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Phenoxybezamine Drug: Phenoxybenzamine

Titration protocol of phenoxybenzamine:

  • starting dose 20 mg q.d. (=10 mg b.i.d.)
  • 4 incremental dosage steps:

    • 40 mg q.d. (=20 mg b.i.d.)
    • 60 mg q.d. (=30 mg b.i.d.)
    • 80 mg q.d. (=40 mg b.i.d.)
    • 100 mg q.d. (=50 mg b.i.d.)
Other Name: Dibenzyran
Active Comparator: Doxazosin Drug: Doxazosin

Titration protocol of doxazosin:

  • starting dose 8 mg q.d. (=4 mg b.i.d.)
  • 4 incremental dosage steps:

    • 12 mg q.d. (=8 mg in the morning and 4 mg in the evening)
    • 16 mg q.d. (=8 mg b.i.d.)
    • 24 mg q.d.(=16 mg in the morning and 8 mg in the evening)
    • 32 mg q.d. (=16 mg b.i.d.)
Other Name: Cardura

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: 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 Centre 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 Klinieken
Investigators
Study Director: Michiel N. Kerstens, MD PhD University Medical Centre Groningen
Principal Investigator: Thera P. Links, MD PhD University Medical Centre Groningen
Principal Investigator: Gütz J. Wietasch, MD PhD University Medical Centre 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:

Responsible Party: Michiel N. Kerstens, MD, PhD, University Medical Centre Groningen
ClinicalTrials.gov Identifier: NCT01379898     History of Changes
Other Study ID Numbers: PRESCRIPT2010.369, 2010:022417-25
Study First Received: May 19, 2011
Last Updated: January 25, 2012
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Centre 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
Phenoxybenzamine
Doxazosin
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Vasodilator Agents
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic alpha-1 Receptor Antagonists

ClinicalTrials.gov processed this record on April 14, 2014