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van CCT (UK)

van CCT (UK)

Ketoconazole and octreotide as medical treatment for Cushing's disease.

- candidate number10653
- NTR NumberNTR3186
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR8-dec-2011
- Secondary IDsNL37105.078.11 CCMO
- Public TitleKetoconazole and octreotide as medical treatment for Cushing's disease.
- Scientific TitleA prospective trial with ketoconazole and octreotide combination therapy for treatment of Cushing’s disease.
- hypothesisOctreotide, a somatostatin analog that preferentially binds with sst2, is frequently used in the treatment of somatotropic pituitary adenomas and neuroendocrine tumors. The glucocorticoid-mediated sst2 downregulation in corticotroph adenoma cells explains why octreotide is hardly effective with respect to inhibition of ACTH production in patients with Cushing’s disease. In contrast, octreotide does inhibit ACTH production in Nelson’s syndrome, a condition in which patients with Cushing’s disease have undergone bilateral adrenalectomy and hence, the corticotroph adenoma cells are not exposed to high levels of cortisol (9). From this, it can be hypothesized that cortisol-lowering therapy with adrenal blocking agents like ketoconazole may induce upregulation of sst2 in corticotroph adenomas of patients with Cushing’s disease. Indeed, preliminary data show that corticotroph adenomas from patients with normalized preoperative UFC excretion (after medical pre-treatment) have significantly higher sst2 mRNA expression levels compared to adenomas from patients with elevated preoperative UFC concentrations. This could potentially have consequences for the efficacy of octreotide in lowering ACTH production by corticotroph tumor cells.
- Healt Condition(s) or Problem(s) studiedCushing's disease
- Inclusion criteriaBoth naïve patients with Cushing’s disease and patients with residual hypercortisolism after recent transsphenoidal adenomectomy are eligible for enrolment. Finally, patients with recurrent Cushing’s disease can also be included.
- Exclusion criteria1. Patients with a disturbed liver function indicated by serum bilirubin, ALAT, ASAT or alkaline phosphatase levels > 2.5 x ULN;
2. Patients with renal insufficiency indicated by serum creatinine levels > 2.0 x ULN;
3. Patients who are already treated with cortisol lowering therapy can only be included after a wash-out period of 4 weeks followed by re-assessment for hypercortisolism;
4. Patients with symptomatic cholelithiasis;
5. Patients with a history of pituitary irradiation;
6. Pregnant patients or patients who desire to become pregnant during the study period.
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupFactorial
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 13-dec-2011
- planned closingdate13-dec-2012
- Target number of participants10
- InterventionsThe total study period is estimated at 9 months. Treatment starts with administration of ketoconazole 200 mg four times daily. Urinary free cortisol (UFC) excretion will be measured after 1, 2 and 3 months. As soon as UFC excretion has normalized, octreotide treatment will be initialized at a dose of 20 mg every 4 weeks. Before start of octreotide treatment, an octreotide test will be performed with serial measurement of ACTH concentrations. If UFC has not normalized after 2 months of ketoconazole monotherapy, the ketoconazole dosage will be increased to 3 times 400 mg daily. If after two months of ketoconazole-octreotide combination therapy UFC levels are still normal, ketoconazole will be stopped. Patients are then treated with octreotide monotherapy until the end of the study period. If UFC excretion (mean of 2 collections) increases again (>125% the upper limit of normal (ULN)) under octreotide/ketoconazole combination therapy or octreotide monotherapy, the octreotide dosage will be increased to 30 mg every 4 weeks. If UFC excretion does not normalize under ketoconazole monotherapy, combination therapy with cabergoline (0.5 mg every other day (qod), which is gradually increased to 1 to 2 mg qod in 15 days) will be started. After 15 days, the ketoconazole dosage will then be decreased from 1200 mg daily to 800, 600 and 400 mg daily, respectively, in 4 weeks. These patients will not be treated with octreotide.
- Primary outcomeUrinary free cortisol excretion.
- Secondary outcome1. Parameters of coagulation and fibrinolysis;
2. Parameters of bone turnover;
3. Quality of life.
- TimepointsBaseline, followed by monthly evaluation untill the end of the study period (ie 9 months).
- Trial web siteN/A
- statusopen: patient inclusion
- Sponsor/Initiator Erasmus Medical Center, Rotterdam
- Funding
(Source(s) of Monetary or Material Support)
Erasmus Medical Center
- PublicationsN/A
- Brief summaryN/A
- Main changes (audit trail)
- RECORD8-dec-2011 - 17-dec-2011

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