Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis (DenosuMast)

September 26, 2022 updated by: Assistance Publique - Hôpitaux de Paris

The study is looking at the efficacy of subcutaneously administrated denosumab 60 mg every 6 months versus placebo after 3 years, by analyze of lumbar spine bone mineral density (BMD) in systemic mastocytosis.

Investigators hypothesize that use of denosumab subcutaneously in patients with osteoporosis related to systemic mastocytosis is effective and safe to improve bone mineral density and prevent new bone events, based on targeted specific RANKL secretion by mast cells and short half-life of denosumab.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Systemic mastocytosis (SM) represents a heterogenous group of disease characterized by abnormal proliferation of mast cells caused by activating mutations in c-Kit receptor; a tyrosine kinase family receptor present in mast cell that control cell proliferation. Prevalence of SM is estimated to 1/20 000 person. According to the World Health Organization (WHO) criteria (Johnson et al, 2009), SM can be separated into two different groups : indolent SM and aggressive SM.

Aggressive SM are defined by a poor prognostic disease either because of an important mast cell tumor mass as sarcoma mastocytosis or mast cell leukemia, or due to an association with an other myeloid hemopathy as myelodysplasic/myeloproliferative syndrome.

Indolent SM are the most common cases with a very good prognostic similar to general population. Symptoms related to mast cell proliferation in indolent SM are very various (Theoharides et al., 2015) and could be divided into 2 entities : those related to mast cell proliferation in tissue as the urticaria pigmentosa and those related to the mast cell degranulation.

There are many clinical relevant mediators released by mast cells after activation that could have putative effects on different systems as cardiovascular, cutaneous, neurologic, digestive, systemic, respiratory and musculoskeletal (Frenzel et al., 2013). Tryptase, histamine, prostaglandin, interleukine-6 and Tumor Necrosis Factor (TNF)-α are the most common and ubiquitous mediators released by mast cells but there are also some specific mediator targeting an organ as RANKL ; expression of RANKL by mast cells directly control regulation of osteoclast activity and is involved in osteoporosis associated to SM (Rabenhorst et al., 2013).

In systemic mastocytoses, bone lesions are found in about half of patients. A third have osteoporosis defined as a lumbar spine or hip bone T score of -2,5 Standard Deviation (SD) or less. In most cases, osteoporosis was complicated at least by one vertebral fracture with pain and functional disorders (Barete et al, 2010). The median time to fragility fracture after mastocytoses diagnosis is up to 5 years, even in very young population usually considering as low risk of fracture in non mastocytoses associated osteoporosis (Van de Veer et al., 2014)

By default, these patients are generally treated with bisphosphonate per os or intravenously with some efficiency on bone mineral density gain and bone turnover marker decrease (Rossini et al, 2014). However, no study with bisphosphonate in SM has showed durable prevention of new bone events and there are no randomized studies that proved their efficacy in systemic mastocytosis. Moreover, these drugs are not well tolerated in SM wether per os due to worsening of digestive symptoms by mast cells activation, or intravenously with an important number of acute phase characterized by some systemic symptoms as fever ; really experiences with intravenous biphosphonate but very increased in SM. Additional, the use of a bisphosphonate ask the question of the residual long-term effect of this drug that may be several years or even decades with a significant risk of atypical fracture secondary to a adynamic bone remodeling (Edwards et al. , 2013) and the long-term presence of crystals of bisphosphonate in the skeleton, particularly worrying in women of childbearing age. In postmenopausal osteoporosis, importance of residual long-term effect is weighted with advanced median age of patient. The fact that mostly patients with a systemic mastocytosis are young people led to restrict the use of bisphosphonate due to those effects.

Among different treatment available in post menopausal osteoporosis, the use of an anti-RANKL antibody, denosumab, in SM associated osteoporosis could be interesting. First, denosumab has already shown significant efficacy in the treatment of postmenopausal osteoporosis in women (Cummings et al , 2009). Second, this treatment is proposed every 6 months by a subcutaneous injection with very few side effects and half-life drug is shorter than biphosphonate with probably low residual long-time effect. Third, as mast cells expressed mainly RANKL with a direct role on bone turnover in SM. The use of a specific drug seems to be obvious and attractive.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Besançon, France, 25030
        • Jean Minjoz Hospital, Dermatology department
      • Caen, France, 14033
        • Caen Hospital, Clinical haematology department
      • Clermont-Ferrand, France, 63100
        • Estaing Hospital, Cellular therapy and clinical haematology department
      • Lille, France, 59037
        • Lille CHRU Hospital, Internal medicine and clinical immunology department
      • Marseille, France, 13385
        • La Timone Hospital, Dermatology and cutaneous oncology department
      • Montpellier, France, 34295
        • Lapeyronie Hospital, Rheumatology and Immunology department
      • Paris, France, 75013
        • La Pitié-Salpêtrière Hospital, Internal medicine and clinical immunology department
      • Paris, France, 75014
        • Cochin Hospital, Rheumatology Department
      • Paris, France, 75015
        • Necker Hospital, Adult haematology department
      • Strasbourg, France, 67098
        • Strasbourg Hospital, Rheumatology department
      • Toulouse, France, 31060
        • Toulouse Hospital, Dermatology department

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male or female >/= 18 years of age at time of informed consent
  • Willingness and ability to sign informed consent, comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
  • Patient with Indolent systemic or cutaneous mastocytosis according to WHO criteria (Appendix 4) with any specific treatment including corticosteroid, chemotherapy and immunomodulating drugs.

  • Patient with:

    • osteoporosis defined as bone mineral density T score ≤ -2.5 at the lumbar spine, OR
    • osteopenia defined as BMD T-score >-2,5 and ≤ -1 at the lumbar spine and low energy fracture (defined as fractures that are associated with decreased bone mineral density. Are excluded fractures of skull, face, mandible, metacarpals, fingers, or toes, pathologic fracture, and fracture that are associated with severe trauma).

(in case of osteoarthritis at the lumbar spine, the T score at left femoral neck or total left hip can be used to define osteoporosis or osteopenia)

Exclusion Criteria:

  • Patient with aggressive mastocytosis or/and Associated Hematologic Non-Mastocytosis Disease (AHNMD)
  • Patient with conditions that influence bone metabolism (primitive hyperparathyroidism, hyperaldosteronism, hypercorticism, etc …)
  • Patient treated with intravenous bisphosphonate within 1 year prior to enrolment or with any other antiosteoporotic treatment within 3 months before enrolment. (per os bisphosphonate, strontium ranelate) Calcium and vitamin supplementation will be accepted
  • Patient previously treated with denosumab
  • Patient with hypocalcemia and/or hypo25-hydroxyvitamin D level non substituted prior enrolment
  • Woman without contraceptive treatment if of childbearing age.
  • Pregnant or breastfeeding woman
  • Patient with contraindication to denosumab
  • Patient with medical, psychiatric or other conditions that may interfere with patient safety
  • Patient with dental problem that need any dental surgery within 6 months after enrolment.
  • Patient with clearance of creatinine less than 30 mL/min/1,73m2 (MDRD) or patient receiving dialysis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental medication 1
Denosumab 60 mg subcutaneously injection with prefilled syringe
Drug: Denosumab
Each subcutaneous injection will occur every 6 months during 3 years for a total of 7 injections
Other Names:
  • XGeva®
Placebo Comparator: Experimental medication 2
NaCl 0.9%, 20ml phial, solution for injection
Drug: Placebo
Each subcutaneous injection will occur every 6 months during 3 years for a total of 7 injections

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Analysis of the lumbar spine bone mineral density (BMD)
Time Frame: 3 years
Dual energy x-ray absorptiometry at lumbar spine (L2-L4)
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of a low energy vertebral fracture and non vertebral fracture
Time Frame: Baseline, 1 year, 2 years and 3 years
Lateral and front lumbar x-ray
Baseline, 1 year, 2 years and 3 years
BMD at the total left hip
Time Frame: Baseline, 3 years
Dual energy x-ray absorptiometry at lumbar spine (L2-L4)
Baseline, 3 years
BMD at lumbar spine and the total left hip
Time Frame: Baseline, 1 year, 2 years
Dual energy x-ray absorptiometry at left femoral neck and total left hip
Baseline, 1 year, 2 years
Biological assays with bone turnover marker of resorption and tryptase levels to assess mastocytosis activity
Time Frame: Baseline, then every 6 months in 3 years
Withdrawal of 45 ml of blood
Baseline, then every 6 months in 3 years
Number of serious adverse events to evaluate drug tolerance
Time Frame: Every 6 months in 3 years
  • Biological assessment: complete blood count, creatinemia, electrolytes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, c-reactive protein (CRP), phosphocalcic analyses with calcemia, phosphoremia, parathormone, vitamin D (25-OH-D), β-Human Chorionic Gonadotropin (HCG) (if needed)
  • Clinical assessment: blood pressure, pulse, weight, height, PS, temperature
Every 6 months in 3 years
Number of non-serious adverse events to evaluate drug tolerance
Time Frame: Every 6 months in 3 years
  • Biological assessment: complete blood count, creatinemia, electrolytes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, c-reactive protein (CRP), phosphocalcic analyses with calcemia, phosphoremia, parathormone, vitamin D (25-OH-D), β-Human Chorionic Gonadotropin (HCG) (if needed)
  • Clinical assessment: blood pressure, pulse, weight, height, PS, temperature
Every 6 months in 3 years
Annual variation of BMD in placebo group and number of low energy fracture compared to historical postmenopausal data
Time Frame: Baseline, 1 year, 2 years, 3 years
Dual energy x-ray absorptiometry at lumbar spine (L2-L4), left femoral neck and total left hip
Baseline, 1 year, 2 years, 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

CEREMAST

Investigators

  • Study Director: Olivier Hermine, MD, Assistance Publique - Hôpitaux de Paris
  • Principal Investigator: Laurent FRENZEL, MD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 5, 2018

Primary Completion (Anticipated)

November 1, 2023

Study Completion (Anticipated)

November 1, 2023

Study Registration Dates

First Submitted

January 4, 2018

First Submitted That Met QC Criteria

January 15, 2018

First Posted (Actual)

January 17, 2018

Study Record Updates

Last Update Posted (Actual)

September 27, 2022

Last Update Submitted That Met QC Criteria

September 26, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P150918J
  • 2016-000596-25 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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