PheochromocytomaPhase 4PRESCRIPTNCT01379898
Phenoxybenzamine Versus Doxazosin in PCC Patients
A Phase 4 study testing Phenoxybenzamine and Doxazosin in people with Pheochromocytoma, run by University Medical Center Groningen at 1 site in Netherlands.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pheochromocytoma
- What is being tested?
- Phenoxybenzamine and Doxazosin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 134 participants
- Where
- 1 siteNetherlands
- Study dates
- Dec 2011to Jan 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Department of Endocrinology, University Medical Center Groningen
Groningen, 9700 RB
About this study
Official title: Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment
- 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.
Read the detailed description
- INTRODUCTION AND RATIONALE Pheochromocytoma (PCC) is a rare but clinically important catecholamine secreting neuro-endocrine tumour that typically arises from the adrenal gland. In addition, this neuro-endocrine tumour can also originate from chromaffin cells in sympathetic ganglia(1)(2). In this protocol, PCC refers to both adrenal and extra-adrenal chromaffin tumours with hypersecretion of catecholamines (i.e. norepinephrine and/or epinephrine). The annual incidence rate in the US population has been estimated to be 1-2 cases per 100,000 adult individuals (3). Data on the incidence and prevalence of PCC in the Netherlands have not been published. Based on the Dutch registry of pathology diagnoses (PALGA), we found an incidence of 117 cases of PCC in the year 2007 (unpublished observation). PCCs may occur as part of an autosomal dominant inherited tumor syndrome, caused by germline mutations in the RET proto-oncogene (Multiple Endocrine Neoplasia type 2 syndrome), VHL gene (von Hippel-Lindau disease), NF1 gene (Neurofibromatosis type 1), or in one of the genes encoding the subunits of mitochondrial complex II, also called succinate dehydrogenase (SDHB, SDHC, SDHD)(4). PCCs are termed 'sporadic' when the family history for PCC is negative. Overall, about 25% of all PCC patients harbour a germline mutation. Notably, germline mutations in one of the PCC susceptibility genes may also be present in a significant number of patients with a sporadic PCC, with mutation rates varying between 7.5 - 14.6% in the populations studied(5-7). Therefore, genetic testing is recommended in all patients with PCC(7). Very recently, a new PCC susceptibility gene has been described, and it seems likely that future research will result in the discovery of other genetic mutations associated with PCC(8). PCC constitutes a surgically curable cause of hypertension. Hypertension in patients with PCC can be either persistent or paroxysmal, but is absent in a minority of patients. It is a potentially life-threatening disease with a high risk for cardiovascular complications such as myocardial infarction, arrhythmias, cardiomyopathy, stroke and pulmonary edema(1). The clinical picture results from release of catecholamines by the tumour. This release can be evoked by stimuli that would normally not pose a hazard, such as surgery or general anaesthesia. Thus, preoperative treatment with alpha-adrenoceptor antagonists is usually recommended for prevention of these serious and potentially fatal complications(9). In one of the largest surgical series reported so far, perioperative mortality and morbidity were 2.4% and 23.6%, respectively(10). According to the literature, about 10% of the patients with PCC are normotensive(1). A normal blood pressure at diagnosis is relatively frequent among carriers of one the aforementioned germline mutations, as these individuals are subjected to periodic biochemical screening for the presence of PCC. It has been demonstrated that intraoperative hemodynamic instability during adrenalectomy for PCC occurred to the same extent in MEN2a patients (most of whom were normotensive) as in patients without MEN2a (most of whom were hypertensive)(11). Thus, preoperative treatment with alpha -adrenoceptor antagonists is also recommended for normotensive patients with PCC (9,11), Historically, the noncompetitive and nonselective alpha -adrenoceptor antagonist phenoxybenzamine has been the drug of choice(12). Alternatively, doxazosin - a competitive and selective alpha 1-adrenoceptor antagonist - might be at least as effective asphenoxybenzamine with fewer side effects. Notably, it has been suggested that doxazosin results in a significant and clinically relevant reduction of postoperative hypotension(13). Severe postoperative hypotension necessitates admission to the intensive care unit (ICU), where volume resuscitation and norepinephrine are administered under strict monitoring of hemodynamics. Data on the optimal preoperative pharmacological management of patients with PCC are conflicting. For example, a recent study reported comparable effects of phenoxybenzamine and doxazosin on intraoperative hemodynamic control(14).This study, however, was retrospective in design and therefore affected by several confounding factors such as lack of randomisation, non-standardised intraoperative care, and use of historical controls. Until now, prospective randomised controlled trials comparing phenoxybenzamine and doxazosin have not been conducted. Thus, the preoperative drug therapy of choice remains an unresolved issue, and at a recent international PCC symposium it was concluded that no specific recommendations can be made on this subject(9). We performed a survey among all university medical centers in the Netherlands, showing that almost half of the centers prescribed phenoxybenzamine, whereas the other centers used doxazosine as the preoperative drug of choice for patients with PCC(15). Usually, these drugs are administered during 2-3 weeks before surgery. This preoperative medical preparation takes place either in the outpatient or inpatient clinic, depending on patient-related factors (e.g. disease severity, geographical considerations) and local experience. Preoperative volume expansion is recommended in all patients with PCC(9). The rationale behind this recommendation is based on the notion that PCC is associated with a decreased intravascular volume, which is restored under influence of treatment with alpha -adrenoceptor antagonists. Without administration of volume expansion severe hypotension might ensue. Therefore, it is common practice to advise a liberal salt intake during alpha -adrenoceptor antagonist therapy and to administer a saline infusion (e.g. 2L NaCL 0.9% in 24 hours) shortly before surgery(9,15). Several drugs, including certain anaesthetics, may evoke an uncontrolled catecholamine release with resulting severe hemodynamic instability(16). Patients are advised to carry a document enlisting all medications which are contra-indicated in case of a PCC. There is no consensus on the optimal anaesthetic management during resection of a PCC, as randomised controlled trials on this subject are not available(16,17). In a survey on the anaesthetic management of PCC in the Netherlands, we found as many different protocols as the number of hospitals (=10) which had responded (including all university medical centers; unpublished observation). PRESCRIPT represents the first randomised controlled trial comparing the effects of pretreatment with either phenoxybenzamine or doxazosin on the intraoperative hemodynamic control in patients with PCC. The relevance of conducting a trial as described in this study protocol was recently expressed again by experts in the field of PCC research(18). In addition, PRESCRIPT provides a unique opportunity to prospectively collect data containing detailed information on items such as presenting symptoms and signs, perioperative outcome and results of biochemical, imaging and genetic studies in patients with PCC. Of interest, results of this study are expected to have a direct impact on national and international guidelines regarding the perioperative care of patients with PCC.
- OBJECTIVES Primary Objective: The primary objective is to determine which of two commonly used drugs for preoperative management provides the best intraoperative hemodynamic control in patients undergoing resection of a PCC. Secondary Objective(s):
- to identify other determinants of intraoperative hemodynamic control. Potential determinants are: gender or age of the patient, clinical setting for preoperative management (i.e. outpatient or inpatient clinic), preoperative levels, of catecholamines or N-terminal pro-brain-type natriuretic peptide (NT-proBNP) PCC size, sporadic or hereditary PCC,
- to describe prospectively symptoms and signs of PCC in a large cohort of patients. Note: until now, data on symptoms and signs have been described retrospectively
- to describe prospectively the results of several diagnostic techniques
- to assess prospectively the distribution of sporadic and hereditary PCC in a large cohort of Dutch patients
- to build a biobank with blood and tissue samples for future studies on PCC
- STUDY DESIGN Randomised open-label controlled trial.
- Conditions
- Pheochromocytoma
- Being tested
- Phenoxybenzamine, Doxazosin
- Keywords
- Pheochromocytoma, Doxazosin, Phenoxybenzamine
- Medical subject headings
- Pheochromocytoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhenoxybenzamineDrug
Also called Dibenzyran
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.)
DoxazosinDrug
Also called Cardura
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.)
| Study group | Role | What they receive |
|---|---|---|
| Phenoxybezamine | Active comparator | Phenoxybenzamine (capsules 10 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC. Receives: Drug: Phenoxybenzamine |
| Doxazosin | Active comparator | Phenoxybenzamine (slow release tablets 4 or 8 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC. Receives: Drug: Doxazosin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Blood pressure and heart rate will be monitored continuesly during surgery.
Measured: Duration of surgery, i.e. on average 3 hours
Secondary outcomes (12)
To attain preoperative blood pressure target values without co-medication
success rate of doxazosin and phenoxybenzamine to attain preoperative blood pressure target values without co-medication
Measured: an expected average of 2 to 6 weeks before surgery
Resolution of (paroxysmal) symptoms and signs of pheochromocytoma.
Resulution of headache, palpitations, sweeting, paleness, nausea, flushes, fatigue and anxiety.
Measured: an expected average of 2-6 weeks before surgery
Need for additional antihypertensive agents
Assessment of the number of patients who need additional antihypertensive drugs on top of the study drugs
Measured: an expected average of 2-6 weeks before surgery
Adverse effects of study medication
Adverse effects of doxazosin or phenoxybenzamine
Measured: an expected average of 2-6 weeks before surgery
Length of preoperative treatment in either outpatient or inpatient clinic.
Comparing duration of preoperative treatment in either outpatient or inpatient clinic
Measured: an expected average of 2-6 weeks before surgery
Control of blood pressure and heart rate.
- 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
Measured: Duration of surgery, i.e. on average 3 hours
Length of hospital stay.
Number of days the patient is staying in the hospital before and after surgery
Measured: Participants will be followed for the duration of hospital stay an expected average of 2-5 weeks.
Composite semi-quantitative score of intra- and postoperative hemodynamic control.
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
Measured: During surgery and the first 24 hours after surgery at the intensive/ medium care unit
Postoperative hypoglycaemia
Frequency and severity (in mmol/L)of hypoglycaemia during first 24 hours after surgery.
Measured: First 24 hours postoperative
Perioperative mortality.
Death from any cause occurring during period from first administration of study medication until 30 days after surgery.
Measured: From first administration of study medication until 30 days after surgery.
Perioperative cardiovascular morbidity.
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.
Measured: From first administation of study medicaion until 30 days after surgery.
Composite endpoint of perioperative mortality and perioperative cardiovascular morbidity.
Death from any cause occurring or cardiovascular events occurring during period from first administration of study medication until 30 days after surgery.
Measured: From first administration of study medication until 30 days after surgery.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2011 (estimated)
- Study startDec 2011
- Primary completionJan 2018
- Study completionJan 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for PheochromocytomaStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 134 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Radboud University Medical Center, 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
- Responsible party
- Sponsor
- Investigators
- Michiel N. Kerstens, MD PhD, Study director, University Medical Center GroningenThera P. Links, MD PhD, Principal investigator, University Medical Center GroningenGütz J. Wietasch, MD PhD, Principal investigator, University Medical Center GroningenJaques W. Lenders, MD PhD, Principal investigator, UMC St Radboud NijmegenG D. Valk, MD PhD, Principal investigator, UMC UtrechtE M. Eekhoff, MD PhD, Principal investigator, Free University UMC AmsterdamP H. Bisschop, MD PhD, Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)R A Feelders, MD PhD, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01379898
- Sponsor's protocol ID
- PRESCRIPT2010.369
- Other IDs
- 2010:022417-25
- Acronym
- PRESCRIPT
- Status last verified
- Sep 2024
- First submitted
- 19 May 2011
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
Publications
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-75. doi: 10.1016/S0140-6736(05)67139-5.
PubMed 16112304Lenders 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.
PubMed 8419068Beard 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.
PubMed 6645626Neumann 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. doi: 10.2302/kjm.54.15.
PubMed 15832076Amar 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. doi: 10.1200/JCO.2005.03.1484.
PubMed 16314641Korpershoek 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. doi: 10.1196/annals.1353.014.
PubMed 17102080Gimenez-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. doi: 10.1111/j.1365-2265.2006.02714.x.
PubMed 17121518Qin 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.
PubMed 20154675Pacak 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. doi: 10.1038/ncpendmet0396.
PubMed 17237836Plouin 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. doi: 10.1210/jcem.86.4.7392.
PubMed 11297571Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007 Nov;92(11):4069-79. doi: 10.1210/jc.2007-1720.
PubMed 17989126Prys-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. doi: 10.1007/s00268-002-6667-z. Epub 2002 Jun 19.
PubMed 12192533Bruynzeel 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.
PubMed 19965926van der Horst-Schrivers AN, Kerstens MN, Wolffenbuttel BH. Preoperative pharmacological management of phaeochromocytoma. Neth J Med. 2006 Sep;64(8):290-5.
PubMed 16990692Eisenhofer 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. doi: 10.2165/00002018-200730110-00004.
PubMed 17973541
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment
- ClinicalTrials.gov ID
- NCT01379898
- Acronym / sponsor ID
- PRESCRIPT / PRESCRIPT2010.369
- Conditions
- Pheochromocytoma
- Keywords
- Pheochromocytoma, Doxazosin, Phenoxybenzamine
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 134 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Radboud University Medical Center, 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
- Study start
- Dec 2011
- Primary completion
- Jan 2018 (actual)
- Study completion
- Jan 2018 (actual)
- First posted
- 23 Jun 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
- 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.
Detailed description
- INTRODUCTION AND RATIONALE Pheochromocytoma (PCC) is a rare but clinically important catecholamine secreting neuro-endocrine tumour that typically arises from the adrenal gland. In addition, this neuro-endocrine tumour can also originate from chromaffin cells in sympathetic ganglia(1)(2). In this protocol, PCC refers to both adrenal and extra-adrenal chromaffin tumours with hypersecretion of catecholamines (i.e. norepinephrine and/or epinephrine). The annual incidence rate in the US population has been estimated to be 1-2 cases per 100,000 adult individuals (3). Data on the incidence and prevalence of PCC in the Netherlands have not been published. Based on the Dutch registry of pathology diagnoses (PALGA), we found an incidence of 117 cases of PCC in the year 2007 (unpublished observation). PCCs may occur as part of an autosomal dominant inherited tumor syndrome, caused by germline mutations in the RET proto-oncogene (Multiple Endocrine Neoplasia type 2 syndrome), VHL gene (von Hippel-Lindau disease), NF1 gene (Neurofibromatosis type 1), or in one of the genes encoding the subunits of mitochondrial complex II, also called succinate dehydrogenase (SDHB, SDHC, SDHD)(4). PCCs are termed 'sporadic' when the family history for PCC is negative. Overall, about 25% of all PCC patients harbour a germline mutation. Notably, germline mutations in one of the PCC susceptibility genes may also be present in a significant number of patients with a sporadic PCC, with mutation rates varying between 7.5 - 14.6% in the populations studied(5-7). Therefore, genetic testing is recommended in all patients with PCC(7). Very recently, a new PCC susceptibility gene has been described, and it seems likely that future research will result in the discovery of other genetic mutations associated with PCC(8). PCC constitutes a surgically curable cause of hypertension. Hypertension in patients with PCC can be either persistent or paroxysmal, but is absent in a minority of patients. It is a potentially life-threatening disease with a high risk for cardiovascular complications such as myocardial infarction, arrhythmias, cardiomyopathy, stroke and pulmonary edema(1). The clinical picture results from release of catecholamines by the tumour. This release can be evoked by stimuli that would normally not pose a hazard, such as surgery or general anaesthesia. Thus, preoperative treatment with alpha-adrenoceptor antagonists is usually recommended for prevention of these serious and potentially fatal complications(9). In one of the largest surgical series reported so far, perioperative mortality and morbidity were 2.4% and 23.6%, respectively(10). According to the literature, about 10% of the patients with PCC are normotensive(1). A normal blood pressure at diagnosis is relatively frequent among carriers of one the aforementioned germline mutations, as these individuals are subjected to periodic biochemical screening for the presence of PCC. It has been demonstrated that intraoperative hemodynamic instability during adrenalectomy for PCC occurred to the same extent in MEN2a patients (most of whom were normotensive) as in patients without MEN2a (most of whom were hypertensive)(11). Thus, preoperative treatment with alpha -adrenoceptor antagonists is also recommended for normotensive patients with PCC (9,11), Historically, the noncompetitive and nonselective alpha -adrenoceptor antagonist phenoxybenzamine has been the drug of choice(12). Alternatively, doxazosin - a competitive and selective alpha 1-adrenoceptor antagonist - might be at least as effective asphenoxybenzamine with fewer side effects. Notably, it has been suggested that doxazosin results in a significant and clinically relevant reduction of postoperative hypotension(13). Severe postoperative hypotension necessitates admission to the intensive care unit (ICU), where volume resuscitation and norepinephrine are administered under strict monitoring of hemodynamics. Data on the optimal preoperative pharmacological management of patients with PCC are conflicting. For example, a recent study reported comparable effects of phenoxybenzamine and doxazosin on intraoperative hemodynamic control(14).This study, however, was retrospective in design and therefore affected by several confounding factors such as lack of randomisation, non-standardised intraoperative care, and use of historical controls. Until now, prospective randomised controlled trials comparing phenoxybenzamine and doxazosin have not been conducted. Thus, the preoperative drug therapy of choice remains an unresolved issue, and at a recent international PCC symposium it was concluded that no specific recommendations can be made on this subject(9). We performed a survey among all university medical centers in the Netherlands, showing that almost half of the centers prescribed phenoxybenzamine, whereas the other centers used doxazosine as the preoperative drug of choice for patients with PCC(15). Usually, these drugs are administered during 2-3 weeks before surgery. This preoperative medical preparation takes place either in the outpatient or inpatient clinic, depending on patient-related factors (e.g. disease severity, geographical considerations) and local experience. Preoperative volume expansion is recommended in all patients with PCC(9). The rationale behind this recommendation is based on the notion that PCC is associated with a decreased intravascular volume, which is restored under influence of treatment with alpha -adrenoceptor antagonists. Without administration of volume expansion severe hypotension might ensue. Therefore, it is common practice to advise a liberal salt intake during alpha -adrenoceptor antagonist therapy and to administer a saline infusion (e.g. 2L NaCL 0.9% in 24 hours) shortly before surgery(9,15). Several drugs, including certain anaesthetics, may evoke an uncontrolled catecholamine release with resulting severe hemodynamic instability(16). Patients are advised to carry a document enlisting all medications which are contra-indicated in case of a PCC. There is no consensus on the optimal anaesthetic management during resection of a PCC, as randomised controlled trials on this subject are not available(16,17). In a survey on the anaesthetic management of PCC in the Netherlands, we found as many different protocols as the number of hospitals (=10) which had responded (including all university medical centers; unpublished observation). PRESCRIPT represents the first randomised controlled trial comparing the effects of pretreatment with either phenoxybenzamine or doxazosin on the intraoperative hemodynamic control in patients with PCC. The relevance of conducting a trial as described in this study protocol was recently expressed again by experts in the field of PCC research(18). In addition, PRESCRIPT provides a unique opportunity to prospectively collect data containing detailed information on items such as presenting symptoms and signs, perioperative outcome and results of biochemical, imaging and genetic studies in patients with PCC. Of interest, results of this study are expected to have a direct impact on national and international guidelines regarding the perioperative care of patients with PCC.
- OBJECTIVES Primary Objective: The primary objective is to determine which of two commonly used drugs for preoperative management provides the best intraoperative hemodynamic control in patients undergoing resection of a PCC. Secondary Objective(s):
- to identify other determinants of intraoperative hemodynamic control. Potential determinants are: gender or age of the patient, clinical setting for preoperative management (i.e. outpatient or inpatient clinic), preoperative levels, of catecholamines or N-terminal pro-brain-type natriuretic peptide (NT-proBNP) PCC size, sporadic or hereditary PCC,
- to describe prospectively symptoms and signs of PCC in a large cohort of patients. Note: until now, data on symptoms and signs have been described retrospectively
- to describe prospectively the results of several diagnostic techniques
- to assess prospectively the distribution of sporadic and hereditary PCC in a large cohort of Dutch patients
- to build a biobank with blood and tissue samples for future studies on PCC
- STUDY DESIGN Randomised open-label controlled trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phenoxybezamine | Active comparator | Drug: PhenoxybenzaminePhenoxybenzamine (capsules 10 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC. |
| Doxazosin | Active comparator | Drug: DoxazosinPhenoxybenzamine (slow release tablets 4 or 8 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- age > 18 years
- diagnosis of benign Pheochromocytoma (adrenal or extra-adrenal, sporadic or hereditary:
- planned for surgical removal of the PCC
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PhenoxybenzamineAlso: DibenzyranStarting 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.) | Drug | Phenoxybezamine |
| DoxazosinAlso: CarduraStarting 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.) | Drug | Doxazosin |
Primary outcome
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.
12 secondary outcomes
To attain preoperative blood pressure target values without co-medication
Time frame: an expected average of 2 to 6 weeks before surgery
Resolution of (paroxysmal) symptoms and signs of pheochromocytoma.
Time frame: an expected average of 2-6 weeks before surgery
Need for additional antihypertensive agents
Time frame: an expected average of 2-6 weeks before surgery
Adverse effects of study medication
Time frame: an expected average of 2-6 weeks before surgery
Length of preoperative treatment in either outpatient or inpatient clinic.
Time frame: an expected average of 2-6 weeks before surgery
Control of blood pressure and heart rate.
Time frame: Duration of surgery, i.e. on average 3 hours
Length of hospital stay.
Time frame: Participants will be followed for the duration of hospital stay an expected average of 2-5 weeks.
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
Postoperative hypoglycaemia
Time frame: First 24 hours postoperative
Perioperative mortality.
Time frame: 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.
Composite endpoint of perioperative mortality and perioperative cardiovascular morbidity.
Time frame: From first administration of study medication until 30 days after surgery.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Background: PubMed 16112304Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-75. doi: 10.1016/S0140-6736(05)67139-5.
- Background: PubMed 8419068Lenders 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.
- Background: PubMed 6645626Beard 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.
- Background: PubMed 15832076Neumann 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. doi: 10.2302/kjm.54.15.
- Background: PubMed 16314641Amar 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. doi: 10.1200/JCO.2005.03.1484.
- Background: PubMed 17102080Korpershoek 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. doi: 10.1196/annals.1353.014.
- Background: PubMed 17121518Gimenez-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. doi: 10.1111/j.1365-2265.2006.02714.x.
- Background: PubMed 20154675Qin 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.
- Background: PubMed 17237836Pacak 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. doi: 10.1038/ncpendmet0396.
- Background: PubMed 11297571Plouin 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. doi: 10.1210/jcem.86.4.7392.
- Background: PubMed 17989126Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007 Nov;92(11):4069-79. doi: 10.1210/jc.2007-1720.
- Background: PubMed 12192533Prys-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. doi: 10.1007/s00268-002-6667-z. Epub 2002 Jun 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michiel N. Kerstens, MD PhD study director
University Medical Center Groningen
Thera P. Links, MD PhD principal investigator
University Medical Center Groningen
Gütz J. Wietasch, MD PhD principal investigator
University Medical Center Groningen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Phenoxybenzamine and Doxazosin in people with Pheochromocytoma, run by University Medical Center Groningen at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01379898, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.