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

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ClinicalTrials.gov Identifier: NCT03027557
Recruitment Status : Active, not recruiting
First Posted : January 23, 2017
Last Update Posted : July 4, 2019
Sponsor:
Collaborator:
Aalborg University
Information provided by (Responsible Party):
Peter Vestergaard, Aalborg University Hospital

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.


Condition or disease Intervention/treatment Phase
Primary Hyperparathyroidism Parathyroid Adenoma Parathyroid Hyperplasia Drug: Cinacalcet 30 mg Tablet Drug: Denosumab Inj 60 mg/ml Other: Placebo tablets Other: Saline Injection (Placebo) Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.
Actual Study Start Date : March 1, 2017
Actual Primary Completion Date : April 1, 2019
Estimated Study Completion Date : September 30, 2019


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 Name: NaCl Fresenius "Kabi"




Primary Outcome Measures :
  1. Bone Mineral Density [ Time Frame: Baseline,one year ]
    Change of Bone Mineral Density in percentage after one year of treatment, for the subgroups as a whole from baseline, and in comparison between subgroups treated with the investigated medicinal products (IMP) vs placebo. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.


Secondary Outcome Measures :
  1. Volumetric BMD. [ Time Frame: Baseline, one year ]
    Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii by Q-CT.

  2. Changes in s-calcium and s-intact parathyroid hormone. [ Time Frame: Monthly up to one year. ]
    Blood samples will be acquired once every 4 weeks for safety-purposes. Data on treatment effect on s-calcium and PTH will be evaluated after termination of the project.

  3. Changes in markers of bone turnover in blood and urine [ Time Frame: Every twelve weeks up to 48 weeks. ]
    Bone turnover markers (p-CTX, P1NP(TP1NP), p-Trap5b, p-FGF-23, p-osteocalcin, p-sclerostin and alkaline phosphatase) are planned measured at baseline and throughout the project.

  4. The prevalence of, and changes over time of coronary calcification by agatston-score. [ Time Frame: Baseline, one year ]
    Simultaneously with Q-CT measurements coronary calcification will be measured.

  5. Development and prevalence of nephrolithiasis/nephrocalcinosis. [ Time Frame: Baseline, one year ]
    Size and number of renal stones and nephrocalcinosis will be evaluated by computed tomography.

  6. Development and prevalence of pancreatic calcifications by computed tomography. [ Time Frame: Baseline, one year. ]
    By CT.

  7. Reset of the Calcium sensing receptor? [ Time Frame: 2 weeks after termination of medication. ]
    Measured from effect on s-calcium and PTH weeks after termination of IMP

  8. Prevalence and development of osteoporotic fractures. [ Time Frame: Baseline, one year. ]
    By Vertebral Fracture Assessment (VFA) development and prevalence of osteoporotic fractures of the column is assessed.

  9. Changes in mood. [ Time Frame: Baseline, 6 mths, one year. ]
    Major Depression Inventory (MDI)-scoring at these points of time.

  10. Adverse reactions. [ Time Frame: Monthly up to one year. ]
    All participants will fill in questionnaires regarding symptoms related to the treatment.

  11. Bone Mineral Content [ Time Frame: Baseline, one year ]
    Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.

  12. Cortical and trabecular width and ratio between these. [ Time Frame: Baseline, one year. ]
    Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.


Other Outcome Measures:
  1. Safety measures [ Time Frame: Monthly up to one year. ]
    Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women of 18 years of age or older.
  • T-score by 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 QTc-interval.Risk factors of prolonged QTc-interval.
  • 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 IMP's.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03027557


Locations
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Denmark
Aalborg University Hospital
Aalborg, Denmark, 9000
Sponsors and Collaborators
Peter Vestergaard
Aalborg University
Investigators
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Principal Investigator: Julius Simoni Leere, MD Aalborg University and Aalborg University Hospital
Study Director: Peter Vestergaard, DMSc Aalborg University and Aalborg University Hospital

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Responsible Party: Peter Vestergaard, Professor, DMSc, Consultant, Aalborg University Hospital
ClinicalTrials.gov Identifier: NCT03027557     History of Changes
Other Study ID Numbers: 180987
2016-001510-20 ( EudraCT Number )
First Posted: January 23, 2017    Key Record Dates
Last Update Posted: July 4, 2019
Last Verified: July 2019

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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
Keywords provided by Peter Vestergaard, Aalborg University Hospital:
Primary Hyperparathyroidism
Parathyroid Adenoma
Parathyroid Hyperplasia
Cinacalcet
Denosumab
Drug Therapy
Bone Mineral Density
Calcium
Additional relevant MeSH terms:
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Adenoma
Parathyroid Neoplasms
Hyperparathyroidism
Hyperparathyroidism, Primary
Hyperplasia
Pathologic Processes
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Parathyroid Diseases
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Denosumab
Cinacalcet
Bone Density Conservation Agents
Physiological Effects of Drugs
Calcium-Regulating Hormones and Agents
Calcimimetic Agents
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists