Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 11
- 主要终点
- Analysis of the lumbar spine bone mineral density (BMD)
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Experimental medication 1
Denosumab 60 mg subcutaneously injection with prefilled syringe
干预措施: Denosumab (Drug)
Experimental medication 2
NaCl 0.9%, 20ml phial, solution for injection
干预措施: Placebo (Drug)
结局指标
主要结局
Analysis of the lumbar spine bone mineral density (BMD)
时间窗: 3 years
Dual energy x-ray absorptiometry at lumbar spine (L2-L4)
次要结局
- Number of non-serious adverse events to evaluate drug tolerance(Every 6 months in 3 years)
- Annual variation of BMD in placebo group and number of low energy fracture compared to historical postmenopausal data(Baseline, 1 year, 2 years, 3 years)
- Occurrence of a low energy vertebral fracture and non vertebral fracture(Baseline, 1 year, 2 years and 3 years)
- BMD at the total left hip(Baseline, 3 years)
- BMD at lumbar spine and the total left hip(Baseline, 1 year, 2 years)
- Number of serious adverse events to evaluate drug tolerance(Every 6 months in 3 years)
- Biological assays with bone turnover marker of resorption and tryptase levels to assess mastocytosis activity(Baseline, then every 6 months in 3 years)