Effectiviteit en veiligheid van behandeling met cinacalcet bij patiënten met primaire hyperparathyreoïdie door een MEN-I mutatie.|
|- candidate number||8474|
|- NTR Number||NTR2525|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||21-sep-2010|
|- Secondary IDs||P10-038 / NL30971.058.10 ; METC LUMC / CCMO|
|- Public Title||Effectiviteit en veiligheid van behandeling met cinacalcet bij patiënten met primaire hyperparathyreoïdie door een MEN-I mutatie.|
|- Scientific Title||Efficacy and safety of the calcimimetic Cinacalcet in the management of patients with Primary Hyperparathyroidism due to a MEN-1 mutation.|
|- hypothesis||Patients with MEN-1 have a high risk of developing primary hyperparathyroidism (PHPT). Surgical removal of all pathological parathyroid glands is the only approach that provides definitive cure, however, the recurrence rate in patients with a MEN-1 mutation is reported to be 50% 8-12 years after subtotal parathyroidectomy. Revision neck explorations are technically more challenging than initial surgery and associated with an up to a 3-fold increase in morbidity. The potential of non-invasive approaches such as the use of calcimimetics has been explored in patients with PHPT who cannot or will not have surgery and was found to be promising. The use of these agents would be particularly beneficial in patients with MEN-1 where recurrence and persistence of hyperparathyroidism is common after initial parathyroidectomy. |
In addition to the parathyroid glands, the CaSR has also been identified in cells of the kidneys, bone, colon, thyroid, brain, pancreas and gastrinoma cells of the stomach. Stimulation of the CaSR by cinacalcet has been reported to increase urine calcium excretion and increase bone turnover, without having a significant effect on the bone mineral density. In contrast to patients with sporadic PHPT, patients with PHPT due to a MEN-1 mutation have a 33-50% chance of developing pituitary tumors, insulinomas, gastrinomas and other pancreatic tumors. The effect of cinacalcet on these associated endocrine pathologies has not been previously studied.
|- Healt Condition(s) or Problem(s) studied||MEN-1, Primary Hyperparathyroidism, Cinacalcet, CaSR|
|- Inclusion criteria||A diagnosis of primary hyperparathyroidism due to a genetically confirmed germline mutation in the MEN-1 gene.|
|- Exclusion criteria||1. Sporadic primary hyperparathyroidism;|
2. Autonomous hyperparathyroidism due to chronic renal failure or vitamin D deficiency;
3. Absence of genetic confirmation of a mutation in the MEN-1 gene;
4. Contraindications for MRI scanning, such as metallic fragments, pacemakers and defibrillators, nerve stimulators, intracranial clips, cochlear implants. ferromagnetic implants or claustrophobia;
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||Single arm|
|- planned startdate ||26-aug-2010|
|- planned closingdate||26-aug-2012|
|- Target number of participants||30|
|- Interventions||Treatment with Cinacalcet (Primpara ®). Patients will be treated with cinacalcet for 1 year at a starting dose of 30 mg once daily and a maximum dose of 30 mg twice daily.|
|- Primary outcome||Effects of cinacalcet on clinical and biochemical parameters, including bone turnover markers.|
|- Secondary outcome||1. Effect of cinacalcet on bone mineral density, nephrocalcinosis and nephrolithiasis;|
2. Effect of cinacalcet on the development and/or growth of pituitary adenomas, insulinomas, gastrinomas and/or other pancreatic tumors;
3. Is there a loss or decrease of the CaR expression in pathological specimens obtained at surgery in patients with primary hyperparathyroidism due to a MEN-I mutation? And does this influence the response to treatment with cinacalcet?
|- Timepoints||Primary Endpoints:|
1. Specific and non-specific symptoms will be assessed using the validated Pasieka’s “Parathyroid Assessment of Symptoms Score (PAS)” before and 1, 2, 3, 6 and 12 months after start of cinacalcet;
2. Global cognitive function will be assessed using a battery of neuropsychological tests before and 1, 2, 3, 6 and 12 months after start of cinacalcet;
3. Quality of life will be assessed using the SF-36 questionnaire before and 12 months after the start of cinacalcet;
4. Blood will be collected to measure for serum calcium, PTH, phosphate, creatinine, albumin, 25OH vitamin D, alkaline phosphatase, B-crosslaps, P1NP, TSH, FT4, gastrin, insulin, prolactin, testosterone, FSH and LH before and 1, 2, 3, 6 and 12 months after the start of cinacalcet;
5. Two times 24-hrs urine will be collected to measure for calcium, phosphate and creatinine (TMP/GFR) before and 1, 2, 3, 6 and 12 months after the start of cinacalcet.
1. BMD will be measured using dual energy X-ray absorptiometry (DXA, Hologic QDR 4500; Waltham, MA, USA) before and 12 months after the start of cinacalcet;
2. Lateral X-rays of spine will be performed before and 12 months after the start of cinacalcet;
3. An ultrasound of the kidneys will be performed before and 12 months after the start of cinacalcet;
4. An MRI of the abdomen and the brain will be performed before and 12 months after the start of cinacalcet;
5. CaR and VDR expression on pathological parathyroid samples will be determined and DNA analysis for somatic and germline mutations of the following genes will be performed; PTH, MEN-1, HRPT2, CaSR including newly identified gene targets.
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Drs. J.E. Witteveen|
|- CONTACT for SCIENTIFIC QUERIES||Dr. N.A.T. Hamdy|
|- Sponsor/Initiator ||Leiden University Medical Center (LUMC)|
(Source(s) of Monetary or Material Support)
|Leiden University Medical Center (LUMC)|
|- Brief summary||This study will look at the efficacy and safety of cinacalcet in patients with PHPT due to a MEN-1 mutation.|
Efficacy will be evaluated on the basis of clinical and biochemical data.
Safety will be evaluated on the basis of neurocognitive function tests, biochemical data and radiological data.
Patients will be treated with cinacalcet for 1 year at a starting dose of 30 mg once daily and a maximum dose of 30 mg twice daily.
Patients will be recruited from medical centers in the Netherlands.
|- Main changes (audit trail)|
|- RECORD||21-sep-2010 - 3-okt-2010|
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