Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet. (DENOCINA)

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.

Study Overview

• Status: Completed
• Conditions: Primary Hyperparathyroidism; Parathyroid Adenoma; Parathyroid Hyperplasia
• Intervention / Treatment: Drug: Cinacalcet 30 mg Tablet; Drug: Denosumab Inj 60 mg/ml; Other: Placebo tablets; Other: Saline Injection (Placebo)

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combined treatment.; 20 subjects will be treated with combined 60mg denosumab bi-annually , 30 mg cinacalcet daily and 50 micrograms vitamin-D daily.	Drug: Cinacalcet 30 mg Tablet; Participants in one arm will receive 30 mg cinacalcet each day.; Other Names: Mimpara; Sensipar; Drug: Denosumab Inj 60 mg/ml; Participants in two arms will receive 60 mg Denosumab biannually.; Other Names: Prolia; Xgeva
Active Comparator: Monotherapy; 20 subjects will receive 60mg denosumab bi-annually, placebo and 50 micrograms vitamin-D daily.	Drug: Denosumab Inj 60 mg/ml; Participants in two arms will receive 60 mg Denosumab biannually.; Other Names: Prolia; Xgeva; Other: Placebo tablets; Participants in two arms will receive one placebo-tablet each day.
Placebo Comparator: Placebo; 20 subjects will receive a saline injection bi-annually (blinded), placebo-tablets and 50 micrograms vitamin-D daily.	Other: Placebo tablets; Participants in two arms will receive one placebo-tablet each day.; Other: Saline Injection (Placebo); Participants in one arm will receive saline injections as placebo for denosumab.; Other Names: Sodium Chloride (NaCl) Fresenius "Kabi"

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Volumetric BMD for the Lumbar Spine.	Measured at baseline and after one year by QCT.	Baseline, one year
Mean P-calcium During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
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.
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
Patients With Nephrolithiasis Final Scan.	Number of subjects w. renal stones at final scan.	Patients with nephrolithiasis at one year reported.
Patients With Pancreas-calcifications Final Scan.	By QCT.	Patients with pancreas-calcifications at one year reported.
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.
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.
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.
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.
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
Change in Cortical Width.	Measured at baseline and after one year at the distal non-dominant antebrachii.	Baseline, one year.
Change in Volumetric BMD for the Distal Forearm.	Measured at baseline and after one year by QCT.	Baseline, one year
Percentage Change in Volumetric BMD for the Lumbar Spine.	Measured at baseline and after one year by QCT.	Baseline, one year
Percentage Change in Volumetric BMD for the Distal Forearm.	Measured at baseline and after one year by QCT.	Baseline, one year
Mean p-PTH During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
Mean p-Phosphate During Treatment.	Blood samples were acquired once every 4 weeks for safety-purposes.	Monthly up to one year.
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.
Percent Change From Baseline in P-osteocalcin.	p-osteocalcin, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
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.
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.
Percent Change From Baseline in p-Sclerostin.	P-Sclerostin, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
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.
Changes in p-25-vitamin D	P-25-vitD , change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Changes in s-1,25-vitamin D	S-1,25-vitD, change from baseline at 48 weeks.	Change from baseline at 48 weeks reported.
Patients With Nephrocalcinosis, Final Scan.	Number of subjects w. renal calcifications at final scan.	Baseline, one year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Measures	Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.	Monthly up to one year.

Collaborators and Investigators

• Sponsor: Peter Vestergaard
• Collaborators: Aalborg University
• Investigators: Principal Investigator: Julius Simoni Leere, MD, Aalborg University and Aalborg University Hospital; Study Director: Peter Vestergaard, DMSc, Aalborg University and Aalborg University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): September 12, 2019

Study Registration Dates

• First Submitted: January 16, 2017
• First Submitted That Met QC Criteria: January 20, 2017
• First Posted (Estimate): January 23, 2017

Study Record Updates

• Last Update Posted (Actual): May 25, 2021
• Last Update Submitted That Met QC Criteria: May 1, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Primary Hyperparathyroidism; Drug Therapy; Cinacalcet; Calcium; Denosumab; Bone Mineral Density; Parathyroid Adenoma; Parathyroid Hyperplasia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Parathyroid Diseases; Head and Neck Neoplasms; Hyperparathyroidism; Hyperparathyroidism, Primary; Adenoma; Hyperplasia; Parathyroid Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcimimetic Agents; Cinacalcet; Denosumab
• Other Study ID Numbers: 180987; 2016-001510-20 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes