Octreotide, 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…
ID
Bron
Aandoening
Cushing's disease
Ziekte van Cushing
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
Urinary free cortisol excretion.
Achtergrond van het onderzoek
N/A
Doel van het onderzoek
Octreotide, 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.
Onderzoeksopzet
Baseline, followed by monthly evaluation untill the end of the study period (ie 9 months).
Onderzoeksproduct en/of interventie
The 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.
Publiek
Department of Internal Medicine
Endocrine Section
R.A. Feelders
's Gravendijkwal 230
Rotterdam 3015 EC
The Netherlands
+31 (0)10 7040704
r.feelders@erasmusmc.nl
Wetenschappelijk
Department of Internal Medicine
Endocrine Section
R.A. Feelders
's Gravendijkwal 230
Rotterdam 3015 EC
The Netherlands
+31 (0)10 7040704
r.feelders@erasmusmc.nl
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
Both 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.
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
1. 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.
Opzet
Deelname
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Geen registraties gevonden.
In overige registers
Register | ID |
---|---|
NTR-new | NL3038 |
NTR-old | NTR3186 |
CCMO | NL37105.078.11 |
ISRCTN | ISRCTN wordt niet meer aangevraagd. |
OMON | NL-OMON36055 |