Clinical Trial: Phenoxybenzamine Versus Doxazosin in PCC Patients

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment

Brief 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. 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 p

Detailed Summary:

  1. 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).

    Blood pressure and heart rate will be monitored continuesly during surgery.



Original Primary Outcome: 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 ]

Blood pressure and heart rate will be monitored at 5 minute intervals during surgery.


Current Secondary Outcome:

  • 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.


Original Secondary Outcome: Same as current

Information By: University Medical Center Groningen

Dates:
Date Received: May 19, 2011
Date Started: December 2011
Date Completion: December 2017
Last Updated: May 9, 2017
Last Verified: May 2017