Clinical trial NCT03027557: Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.
Official title: Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Primary Hyperparathyroidism
Parathyroid Adenoma
Parathyroid Hyperplasia
Keywords: Primary Hyperparathyroidism
Parathyroid Adenoma
Parathyroid Hyperplasia
Cinacalcet
Denosumab
Drug Therapy
Bone Mineral Density
Calcium
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Aalborg University
First posted: 2017-01-23
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The only known cure for primary hyperparathyroidism is surgical removal of one or more parathyroid glands. Some patients however, do not fulfill criteria for surgery or do not want to undergo a procedure due to fear of the associated risks. Therefore a medical alternative is warranted.

This study aims to evaluate the effects of Denosumab alone, and in combination with Cinacalcet, as a medical treatment for patients suffering from primary hyperparathyroidism, with mild osteoporosis. To the best of our knowledge no previously reported randomized controlled trial has investigated the use of denosumab in primary hyperparathyroidism.

60 patients will be enrolled in three different treatment-groups: 20 receiving both Denosumab and Cinacalcet, 20 Denosumab and placebo and 20 placebo and placebo. Patients included do not meet the criteria for, or have no wish for a surgical procedure.

By combining the two drugs, this study could possibly contribute to the discovery of a realistic medical alternative to surgery. It is expected that the therapy will be able to both control s-calcium and s-intact parathyroid hormone (iPTH), and simultaneously enhance bone-structure. The therapy thus has the potential of preventing fractures and possibly other long-term effects of primary hyperparathyroidism such as formation of kidney stones, and coronary calcification. Another objective of this project is to investigate whether the combined therapy can facilitate an actual reset of the Calcium-sensing receptor, and thereby de facto cure the disease.

Detailed description: Background/Context:

This project deals with medical treatment of primary hyperparathyroidism. The only cure currently available is surgical removal of one or more parathyroid glands, but this option is neither feasible, nor desirable in all patients with the diagnosis.

Today a major group of patients are being diagnosed by coincidence with biochemical blood-screening, and are therefore in an asymptomatic state of the disease at the time of diagnosis. Long term studies show that these patients over time often have progression in their disease, and develop complications such as osteoporosis. Thus a medical alternative is warranted.

Previous studies have investigated the effects of well known antiresorptive drugs such as bisphosphonates, as well as estrogen-related compounds. These drugs have had effects on particularly bone mineral density (BMD) and biochemical bone-turnover markers, but have been able only transiently to lower blood-calcium levels. Combined with too many unwanted side-effects and a high prevalence of contraindications for a large proportion of the patients needing treatment, these drugs have not provided a realistic alternative to surgery.

Treatment today generally follows the international consensus for treatment of asymptomatic patients with primary hyperparathyroidism. Briefly this includes watchful waiting with biannual control-sessions for indication of surgery, screening for kidney stones/nephrolithiasis, osteoporosis and s-calcium - and s-iPTH levels.

This randomized controlled trial involves the drugs Cinacalcet og Denosumab. Denosumab has previously been shown to greatly improve BMD, lower s-calcium, lower the rate of bone-turnover and prevent osteoporotic fractures in several populations with different diseases, but has never been tested in a published randomized controlled trial in patients with primary hyperparathyroidism.

Cinacalcet has been proved able to lower s-iPTH, lower s-Calcium and thereby relieve symptoms of hypercalcaemia caused by primary hyperparathyroidism. It does not however, lower the rate of bone turnover, and it has not been show to improve BMD.

By combining the two drugs, this study could possibly contribute to the discovery of a realistic medical alternative to surgery. It is expected that the therapy will be able to both control s-calcium and s-iPTH, and simultaneously enhance bone-structure. The therapy thus has the potential of preventing fractures and possibly other long-term effects of primary hyperparathyroidism such as formation of kidney stones, and coronary calcification. Another objective of this project is to investigate whether the combined therapy can facilitate an actual reset of the Calcium-sensing receptor, and thereby de facto cure the disease.

Eligibility criteria: Inclusion Criteria:

* Men and women of 18 years of age or older.
* T-score by Dual X-ray Absorptiometry (DXA) between -1,0 og -3,5
* Patients from The North Jutland Region diagnosed with primary hyperparathyroidism at the Department of Endocrinology, Aalborg University Hospital. (Hypercalcaemia measured at two different time-points and simultaneous elevated/inappropriately high PTH, and exclusion of differential diagnosis.)

Exclusion Criteria:

* Medical history of diseases leading to hypercalcaemia other than Primary Hyperparathyroidism.
* Patients being treated with Denosumab or Cinacalcet prior to inclusion or previously treated with Denosumab or Cinacalcet.
* Moderately - Severely decreased liver function (alanine aminotransferase \>250u/l, gamma-glutamyl transferase\>150u/l, Bilirubin \>30)
* Acute myocardial infarction or apoplexia in the 3 months before inclusion.
* Medical record of heart failure
* Risk factors of prolonged corrected QT interval (QTc).
* Open lesions from oral surgery.
* Primary diseases of the bone other than osteoporosis.
* Patients suffering from kidney disease or renal failure.
* Patients under treatment with thiazide or lithium.
* Medical record of generalized seizures or epilepsy.
* Active malignant disease.
* Known allergies towards the specified medicinal products (IMPs).
* Pregnancy or breastfeeding.
* Fertile women who do not agree to the usage of effective contraception.
* Other circumstances, evaluated by the responsible investigator, making the subject unsuitable for participation.

Primary outcomes:
measure: Change in Lumbar Spine Bone Mineral Density
timeFrame: Baseline,one year
measure: Change in Total Hip Bone Mineral Density
timeFrame: Baseline,one year
measure: Change in Femoral Neck Bone Mineral Density
timeFrame: Baseline,one year
measure: Change in 1/3 Forearm Bone Mineral Density
timeFrame: Baseline,one year
measure: Percentage Change in Lumbar Spine Bone Mineral Density
timeFrame: Baseline,one year
measure: Percentage Change in Total Hip Bone Mineral Density
timeFrame: Baseline,one year
measure: Percentage Change in Femoral Neck Bone Mineral Density
timeFrame: Baseline,one year
measure: Percentage Change in 1/3 Forearm Bone Mineral Density
timeFrame: Baseline,one year
Secondary outcomes:
measure: Change in Volumetric BMD for the Lumbar Spine.
timeFrame: Baseline, one year
measure: Mean P-calcium During Treatment.
timeFrame: Monthly up to one year.
measure: Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)
timeFrame: Change from baseline at 48 weeks reported.
measure: Median Agatstons Score Final
timeFrame: Baseline, one year
measure: Patients With Nephrolithiasis Final Scan.
timeFrame: Patients with nephrolithiasis at one year reported.
measure: Patients With Pancreas-calcifications Final Scan.
timeFrame: Patients with pancreas-calcifications at one year reported.
measure: Reset of the Calcium Sensing Receptor?
timeFrame: 2 weeks after termination of medication.
measure: Vertebral Fracture Assessment - Final Scan
timeFrame: Patients with vertebral fractures at one year reported.
measure: Change MDI-score
timeFrame: Baseline, 6 mths, one year.
measure: Adverse Reactions.
timeFrame: Monthly up to one year.
measure: Bone Mineral Content
timeFrame: Baseline, one year
measure: Change in Cortical Width.
timeFrame: Baseline, one year.
measure: Change in Volumetric BMD for the Distal Forearm.
timeFrame: Baseline, one year
measure: Percentage Change in Volumetric BMD for the Lumbar Spine.
timeFrame: Baseline, one year
measure: Percentage Change in Volumetric BMD for the Distal Forearm.
timeFrame: Baseline, one year
measure: Mean p-PTH During Treatment.
timeFrame: Monthly up to one year.
measure: Mean p-Phosphate During Treatment.
timeFrame: Monthly up to one year.
measure: Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP).
timeFrame: Change from baseline at 48 weeks reported.
measure: Percent Change From Baseline in P-osteocalcin.
timeFrame: Change from baseline at 48 weeks reported.
measure: Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP).
timeFrame: Change from baseline at 48 weeks reported.
measure: Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b).
timeFrame: Change from baseline at 48 weeks reported.
measure: Percent Change From Baseline in p-Sclerostin.
timeFrame: Change from baseline at 48 weeks reported.
measure: Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23).
timeFrame: Change from baseline at 48 weeks reported.
measure: Changes in p-25-vitamin D
timeFrame: Change from baseline at 48 weeks reported.
measure: Changes in s-1,25-vitamin D
timeFrame: Change from baseline at 48 weeks reported.
measure: Patients With Nephrocalcinosis, Final Scan.
timeFrame: Baseline, one year
Other outcomes:
measure: Safety Measures
timeFrame: Monthly up to one year.
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
Study officials:
affiliation: Aalborg University and Aalborg University Hospital
name: Julius Simoni Leere, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aalborg University and Aalborg University Hospital
name: Peter Vestergaard, DMSc
role: STUDY_DIRECTOR
References:
citation: Leere JS, Karmisholt J, Robaczyk M, Lykkeboe S, Handberg A, Steinkohl E, Brondum Frokjaer J, Vestergaard P. Denosumab and cinacalcet for primary hyperparathyroidism (DENOCINA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2020 May;8(5):407-417. doi: 10.1016/S2213-8587(20)30063-2.