Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.

Primary Hyperparathyroidism Clinical Trial

— DENOCINA  

Official title:

Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03027557
• Other study ID #: 180987
• Secondary ID: 2016-001510-20
• Status: Completed
• Phase: Phase 3
• Start date: March 1, 2017
• Est. completion date: September 12, 2019

Study information

• Verified date: May 2021
• Source: Aalborg University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 12, 2019
• Est. primary completion date: April 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenoma
• Hyperparathyroidism
• Hyperparathyroidism, Primary
• Hyperplasia
• Parathyroid Adenoma
• Parathyroid Hyperplasia
• Parathyroid Neoplasms
• Primary Hyperparathyroidism

Intervention

Drug:
• Cinacalcet 30 mg Tablet
Participants in one arm will receive 30 mg cinacalcet each day.
• Denosumab Inj 60 mg/ml
Participants in two arms will receive 60 mg Denosumab biannually.

Other:
• Placebo tablets
Participants in two arms will receive one placebo-tablet each day.
• Saline Injection (Placebo)
Participants in one arm will receive saline injections as placebo for denosumab.

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg

Sponsors (2)

Lead Sponsor	Collaborator
Peter Vestergaard	Aalborg University

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety Measures	Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.	Monthly up to one year.
Primary	Change in Lumbar Spine Bone Mineral Density	Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Change in Total Hip Bone Mineral Density	Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Change in Femoral Neck Bone Mineral Density	Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Change in 1/3 Forearm Bone Mineral Density	Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Percentage Change in Lumbar Spine Bone Mineral Density	Percentage change of Bone Mineral Density after one year of treatment from baseline.; Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Percentage Change in Total Hip Bone Mineral Density	Percentage change of Bone Mineral Density after one year of treatment from baseline.; Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Percentage Change in Femoral Neck Bone Mineral Density	Percentage change of Bone Mineral Density after one year of treatment from baseline.; Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Primary	Percentage Change in 1/3 Forearm Bone Mineral Density	Percentage change of Bone Mineral Density after one year of treatment from baseline.; Measured with Dual-energy X-ray absorptiometry (DXA)-scan.	Baseline,one year
Secondary	Change in Volumetric BMD for the Lumbar Spine.	Measured at baseline and after one year by QCT.	Baseline, one year
Secondary	Mean P-calcium During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
Secondary	Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)	p-CTX, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Median Agatstons Score Final	Simultaneously with QCT-measurements coronary calcification was be assessed. Agatston score is a score based on the extent of coronary artery calcification calculated on the amount of plaque observed in a CT scan. A score of zero indicates absence of coronary calcium, 1-10: minimal calcification, 11-100 mild calcification, 101-400 moderate calcification, >400 severe calcification.; Thus the score increases with increasing level of calcification in the coronary vessels.	Baseline, one year
Secondary	Patients With Nephrolithiasis Final Scan.	Number of subjects w. renal stones at final scan.	Patients with nephrolithiasis at one year reported.
Secondary	Patients With Pancreas-calcifications Final Scan.	By QCT.	Patients with pancreas-calcifications at one year reported.
Secondary	Reset of the Calcium Sensing Receptor?	Measured from effect on s-calcium and PTH weeks after termination of IMP	2 weeks after termination of medication.
Secondary	Vertebral Fracture Assessment - Final Scan	Number of participants with vertebral fractures as assessed by VFA at final scan.	Patients with vertebral fractures at one year reported.
Secondary	Change MDI-score	Major Depression Inventory (MDI)-score, Baseline, 6 months, one year (week 52)., change between baseline and 1 year reported.; The Major Depression Inventory (MDI) is a mood questionnaire developed by the World Health Organization. To calculate the total score, a sum of ten individual items (each with an individual score between 0-5, with 0 indicating absence of a symptom and 5 indicating constant presence of a given symptom) is used. A higher score signifies deeper depression with 50 being the maximum score.	Baseline, 6 mths, one year.
Secondary	Adverse Reactions.	All participants filled in questionnaires regarding symptoms related to the treatment.; Results are reported in the Adverse Events section.	Monthly up to one year.
Secondary	Bone Mineral Content	Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.	Baseline, one year
Secondary	Change in Cortical Width.	Measured at baseline and after one year at the distal non-dominant antebrachii.	Baseline, one year.
Secondary	Change in Volumetric BMD for the Distal Forearm.	Measured at baseline and after one year by QCT.	Baseline, one year
Secondary	Percentage Change in Volumetric BMD for the Lumbar Spine.	Measured at baseline and after one year by QCT.	Baseline, one year
Secondary	Percentage Change in Volumetric BMD for the Distal Forearm.	Measured at baseline and after one year by QCT.	Baseline, one year
Secondary	Mean p-PTH During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
Secondary	Mean p-Phosphate During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
Secondary	Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP).	p-P1NP, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Percent Change From Baseline in P-osteocalcin.	p-osteocalcin, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP).	S-Bone specific alkaline phosphatase, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b).	P-Trap5b, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Percent Change From Baseline in p-Sclerostin.	P-Sclerostin, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23).	P-FGF23 , change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Changes in p-25-vitamin D	P-25-vitD , change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Changes in s-1,25-vitamin D	S-1,25-vitD, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Secondary	Patients With Nephrocalcinosis, Final Scan.	Number of subjects w. renal calcifications at final scan.	Baseline, one year