A Phase 4 interventional study of Phenoxybenzamine and Doxazosin in Pheochromocytoma, sponsored by University Medical Center Groningen. Completed at 1 site in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-09-19.
Sponsored by University Medical Center Groningen · Phase 4, Interventional, and Treatment
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.
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Based on the Dutch registry of pathology diagnoses (PALGA), we found an incidence of 117 cases of PCC in the year 2007 (unpublished observation).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):
151 studies on the registry are indexed under Pheochromocytoma; 56 are open to participants now.
This study's enrollment of 134 is above the median of 34 across 82 interventional studies indexed under Pheochromocytoma.
Browse Pheochromocytoma studies →University Medical Center Groningen is the lead sponsor of 625 studies on the registry; 174 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
diagnosis of benign Pheochromocytoma (adrenal or extra-adrenal, sporadic or hereditary:
Exclusion Criteria:
Phenoxybenzamine (capsules 10 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC.
Drug: Phenoxybenzamine
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 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.)
Also known as: Dibenzyran
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.)
Also known as: Cardura
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.
Time frame: Duration of surgery, i.e. on average 3 hours
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
Time frame: 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.
Time frame: 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
Time frame: an expected average of 2-6 weeks before surgery
Adverse effects of study medication
Adverse effects of doxazosin or phenoxybenzamine
Time frame: 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
Time frame: 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
Time frame: 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
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.
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
Time frame: 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.
Time frame: First 24 hours postoperative
Perioperative mortality.
Death from any cause occurring during period from first administration of study medication until 30 days after surgery.
Time frame: 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.
Time frame: 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.
Time frame: From first administration of study medication until 30 days after surgery.
This study is completed, as verified in Sep 2024. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drugs tested here: Phenoxybenzamine · Doxazosin
University Medical Center Groningen →