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NCT03027557 · REGISTRY CONDITION SEARCH

Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2021-05-25

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Change in Lumbar Spine Bone Mineral Density

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outcome · POSTED

Change in Total Hip Bone Mineral Density

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outcome · POSTED

Change in Femoral Neck Bone Mineral Density

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outcome · POSTED

Change in 1/3 Forearm Bone Mineral Density

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outcome · POSTED

Percentage Change in Lumbar Spine Bone Mineral Density

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outcome · POSTED

Percentage Change in Total Hip Bone Mineral Density

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outcome · POSTED

Percentage Change in Femoral Neck Bone Mineral Density

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outcome · POSTED

Percentage Change in 1/3 Forearm Bone Mineral Density

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outcome · POSTED

Change in Volumetric BMD for the Lumbar Spine.

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outcome · POSTED

Mean P-calcium During Treatment.

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outcome · POSTED

Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)

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outcome · POSTED

Median Agatstons Score Final

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outcome · POSTED

Patients With Nephrolithiasis Final Scan.

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outcome · POSTED

Patients With Pancreas-calcifications Final Scan.

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outcome · NOT POSTED

Reset of the Calcium Sensing Receptor?

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outcome · POSTED

Vertebral Fracture Assessment - Final Scan

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outcome · POSTED

Change MDI-score

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outcome · NOT POSTED

Adverse Reactions.

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outcome · POSTED

Bone Mineral Content

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outcome · POSTED

Change in Cortical Width.

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outcome · POSTED

Change in Volumetric BMD for the Distal Forearm.

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outcome · POSTED

Percentage Change in Volumetric BMD for the Lumbar Spine.

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outcome · POSTED

Percentage Change in Volumetric BMD for the Distal Forearm.

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outcome · POSTED

Mean p-PTH During Treatment.

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outcome · POSTED

Mean p-Phosphate During Treatment.

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outcome · POSTED

Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP).

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outcome · POSTED

Percent Change From Baseline in P-osteocalcin.

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outcome · POSTED

Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP).

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outcome · POSTED

Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b).

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outcome · POSTED

Percent Change From Baseline in p-Sclerostin.

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outcome · POSTED

Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23).

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outcome · POSTED

Changes in p-25-vitamin D

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outcome · POSTED

Changes in s-1,25-vitamin D

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outcome · POSTED

Patients With Nephrocalcinosis, Final Scan.

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outcome · NOT POSTED

Safety Measures

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    20 subjects will be treated with combined 60mg denosumab bi-annually , 30 mg cinacalcet daily and 50 micrograms vitamin-D daily.
    intervention Names
    1. Drug: Cinacalcet 30 mg Tablet
    2. Drug: Denosumab Inj 60 mg/ml
    label
    Combined treatment.
    type
    EXPERIMENTAL
  2. description
    20 subjects will receive 60mg denosumab bi-annually, placebo and 50 micrograms vitamin-D daily.
    intervention Names
    1. Drug: Denosumab Inj 60 mg/ml
    2. Other: Placebo tablets
    label
    Monotherapy
    type
    ACTIVE_COMPARATOR
  3. description
    20 subjects will receive a saline injection bi-annually (blinded), placebo-tablets and 50 micrograms vitamin-D daily.
    intervention Names
    1. Other: Placebo tablets
    2. Other: Saline Injection (Placebo)
    label
    Placebo
    type
    PLACEBO_COMPARATOR
interventions
  1. arm Group Labels
    1. Combined treatment.
    description
    Participants in one arm will receive 30 mg cinacalcet each day.
    name
    Cinacalcet 30 mg Tablet
    other Names
    1. Mimpara
    2. Sensipar
    type
    DRUG
  2. arm Group Labels
    1. Combined treatment.
    2. Monotherapy
    description
    Participants in two arms will receive 60 mg Denosumab biannually.
    name
    Denosumab Inj 60 mg/ml
    other Names
    1. Prolia
    2. Xgeva
    type
    DRUG
  3. arm Group Labels
    1. Monotherapy
    2. Placebo
    description
    Participants in two arms will receive one placebo-tablet each day.
    name
    Placebo tablets
    type
    OTHER
  4. arm Group Labels
    1. Placebo
    description
    Participants in one arm will receive saline injections as placebo for denosumab.
    name
    Saline Injection (Placebo)
    other Names
    1. Sodium Chloride (NaCl) Fresenius "Kabi"
    type
    OTHER
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
TRIPLE
who Masked
  1. PARTICIPANT
  2. CARE_PROVIDER
  3. INVESTIGATOR
primary Purpose
TREATMENT
Enrollment
count
46
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.
    measure
    Safety Measures
    time Frame
    Monthly up to one year.
primary Outcomes
  1. description
    Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Change in Lumbar Spine Bone Mineral Density
    time Frame
    Baseline,one year
  2. description
    Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Change in Total Hip Bone Mineral Density
    time Frame
    Baseline,one year
  3. description
    Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Change in Femoral Neck Bone Mineral Density
    time Frame
    Baseline,one year
  4. description
    Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Change in 1/3 Forearm Bone Mineral Density
    time Frame
    Baseline,one year
  5. description
    Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Percentage Change in Lumbar Spine Bone Mineral Density
    time Frame
    Baseline,one year
  6. description
    Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Percentage Change in Total Hip Bone Mineral Density
    time Frame
    Baseline,one year
  7. description
    Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Percentage Change in Femoral Neck Bone Mineral Density
    time Frame
    Baseline,one year
  8. description
    Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
    measure
    Percentage Change in 1/3 Forearm Bone Mineral Density
    time Frame
    Baseline,one year
secondary Outcomes
  1. description
    Measured at baseline and after one year by QCT.
    measure
    Change in Volumetric BMD for the Lumbar Spine.
    time Frame
    Baseline, one year
  2. description
    Blood samples were acquired once every 4 weeks for safety-purposes.
    measure
    Mean P-calcium During Treatment.
    time Frame
    Monthly up to one year.
  3. description
    p-CTX, change from baseline at 48 weeks.
    measure
    Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)
    time Frame
    Change from baseline at 48 weeks reported.
  4. description
    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.
    measure
    Median Agatstons Score Final
    time Frame
    Baseline, one year
  5. description
    Number of subjects w. renal stones at final scan.
    measure
    Patients With Nephrolithiasis Final Scan.
    time Frame
    Patients with nephrolithiasis at one year reported.
  6. description
    By QCT.
    measure
    Patients With Pancreas-calcifications Final Scan.
    time Frame
    Patients with pancreas-calcifications at one year reported.
  7. description
    Measured from effect on s-calcium and PTH weeks after termination of IMP
    measure
    Reset of the Calcium Sensing Receptor?
    time Frame
    2 weeks after termination of medication.
  8. description
    Number of participants with vertebral fractures as assessed by VFA at final scan.
    measure
    Vertebral Fracture Assessment - Final Scan
    time Frame
    Patients with vertebral fractures at one year reported.
  9. description
    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.
    measure
    Change MDI-score
    time Frame
    Baseline, 6 mths, one year.
  10. description
    All participants filled in questionnaires regarding symptoms related to the treatment. Results are reported in the Adverse Events section.
    measure
    Adverse Reactions.
    time Frame
    Monthly up to one year.
  11. description
    Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.
    measure
    Bone Mineral Content
    time Frame
    Baseline, one year
  12. description
    Measured at baseline and after one year at the distal non-dominant antebrachii.
    measure
    Change in Cortical Width.
    time Frame
    Baseline, one year.
Full study description
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.
Source references
references
  1. 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.
    pmid
    32333877
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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    Preserved source evidence · Not medical advice