Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.

NCT ID: NCT03027557

Last Updated: 2021-05-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-01
• Study Completion Date: 2019-09-12

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.

Conditions

Primary Hyperparathyroidism; Parathyroid Adenoma; Parathyroid Hyperplasia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Combined treatment.

20 subjects will be treated with combined 60mg denosumab bi-annually , 30 mg cinacalcet daily and 50 micrograms vitamin-D daily.

Group Type: EXPERIMENTAL

Cinacalcet 30 mg Tablet

Intervention Type: DRUG

Participants in one arm will receive 30 mg cinacalcet each day.

Denosumab Inj 60 mg/ml

Intervention Type: DRUG

Participants in two arms will receive 60 mg Denosumab biannually.

Monotherapy

20 subjects will receive 60mg denosumab bi-annually, placebo and 50 micrograms vitamin-D daily.

Group Type: ACTIVE_COMPARATOR

Denosumab Inj 60 mg/ml

Intervention Type: DRUG

Participants in two arms will receive 60 mg Denosumab biannually.

Placebo tablets

Intervention Type: OTHER

Participants in two arms will receive one placebo-tablet each day.

Placebo

20 subjects will receive a saline injection bi-annually (blinded), placebo-tablets and 50 micrograms vitamin-D daily.

Group Type: PLACEBO_COMPARATOR

Placebo tablets

Intervention Type: OTHER

Participants in two arms will receive one placebo-tablet each day.

Saline Injection (Placebo)

Intervention Type: OTHER

Participants in one arm will receive saline injections as placebo for denosumab.

Interventions

Cinacalcet 30 mg Tablet

Participants in one arm will receive 30 mg cinacalcet each day.

Intervention Type: DRUG

Denosumab Inj 60 mg/ml

Participants in two arms will receive 60 mg Denosumab biannually.

Intervention Type: DRUG

Placebo tablets

Participants in two arms will receive one placebo-tablet each day.

Intervention Type: OTHER

Saline Injection (Placebo)

Participants in one arm will receive saline injections as placebo for denosumab.

Intervention Type: OTHER

Other Intervention Names

Mimpara; Sensipar; Prolia; Xgeva; Sodium Chloride (NaCl) Fresenius "Kabi"

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aalborg University

OTHER

Sponsor Role: collaborator

Peter Vestergaard

OTHER

Sponsor Role: lead

Responsible Party

Peter Vestergaard

Professor, DMSc, Consultant

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Julius Simoni Leere, MD

Role: PRINCIPAL_INVESTIGATOR

Aalborg University and Aalborg University Hospital

Peter Vestergaard, DMSc

Role: STUDY_DIRECTOR

Aalborg University and Aalborg University Hospital

Locations

Aalborg University Hospital

Aalborg, , Denmark

Countries

Denmark

References

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.

Reference Type: DERIVED

PMID: 32333877 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2016-001510-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

180987

Identifier Type: -

Identifier Source: org_study_id