The primary objective in the glucocorticoid-continuing subpopulation of men and women treated with chronic glucocorticoid therapy (>= 7.5 mg daily prednisone or its equivalent for >= 3 months and are planning to continue treatment for a total…
ID
Source
Brief title
Condition
- Bone disorders (excl congenital and fractures)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective in the glucocorticoid-continuing subpopulation of men and
women treated with chronic glucocorticoid therapy (>= 7.5 mg daily prednisone or
its equivalent for >= 3 months and are planning to continue treatment for a
total of at least 6 months) is to demonstrate that treatment with denosumab 60
mg subcutaneously (SC) every 6 months (Q6M) is not inferior to treatment with
oral risedronate 5 mg every day (QD) with respect to the percent change from
baseline in lumbar spine bone mineral density (BMD) by dual X-ray
absorptiometry (DXA) at 12 months
The primary objective in the glucocorticoid-initiating subpopulation of men and
women treated with glucocorticoid therapy (>= 7.5 mg daily prednisone or its
equivalent for < 3 months and are planning to continue treatment for a total of
at least 6 months) is to demonstrate that treatment with denosumab 60 mg SC Q6M
is not inferior to treatment with oral risedronate 5 mg QD with respect to the
percent change from baseline in lumbar spine BMD by DXA at 12 months
Secondary outcome
Secondary objective
To compare the effects of denosumab with that of risedronate separately in the
glucocorticoid-continuing and glucocorticoid-initiating subpopulations on:
• Percent change from baseline in BMD by DXA at lumbar spine at 12 months
• Percent change from baseline in BMD by DXA at total hip at 12 months
• Percent change from baseline in BMD by DXA at lumbar spine at 24 months
• Percent change from baseline in BMD by DXA at total hip at 24 months
Background summary
Glucocorticoid therapy commonly used to treat a variety of chronic inflammatory
conditions such as rheumatoid arthritis (RA), asthma, chronic obstructive
pulmonary disease (COPD) and dermatologic conditions. Decreased bone formation
due to osteoblast inhibition and, especially early on, increased
osteoclast-mediated bone resorption both contribute to the development of
glucocorticoid induced osteoporosis (GIOP). Patients with GIOP have a higher
incidence of fracture, and fracture occurs at a higher bone density than in the
general population.
Denosumab may be effective in mitigating bone loss in subjects receiving
glucocorticoid therapy. In addition, denosumab could fulfill an unmet medical
need regarding compliance.
Study objective
The primary objective in the glucocorticoid-continuing subpopulation of men and
women treated with chronic glucocorticoid therapy (>= 7.5 mg daily prednisone or
its equivalent for >= 3 months and are planning to continue treatment for a
total of at least 6 months) is to demonstrate that treatment with denosumab 60
mg subcutaneously (SC) every 6 months (Q6M) is not inferior to treatment with
oral risedronate 5 mg every day (QD) with respect to the percent change from
baseline in lumbar spine bone mineral density (BMD) by dual X-ray
absorptiometry (DXA) at 12 months
The primary objective in the glucocorticoid-initiating subpopulation of men and
women treated with glucocorticoid therapy (>= 7.5 mg daily prednisone or its
equivalent for < 3 months and are planning to continue treatment for a total of
at least 6 months) is to demonstrate that treatment with denosumab 60 mg SC Q6M
is not inferior to treatment with oral risedronate 5 mg QD with respect to the
percent change from baseline in lumbar spine BMD by DXA at 12 months
Study design
The study consists of two parts. The first part will be carried out to define
if the patient is eligible for the study (screening). The second part is the
research/study phase whcih will take about 24 months. The complete study will
take 25 months (screening is 1 month, study pahse is 24 months). After a
positive screening outcome, patients will be assigned to one of the two study
arms (1:1 ratio):
1. Denosumab, subcutane injection, 60mg, every 6 months + Placebo for oral
Risedronate, daily
2. Risedronate, oral, 5mg, daily + Placebo for Denosumab, subcutane injection,
every 6 months
during the study phase, patients receive daily calcium- and vitamin D
supplements
In total, 776 patients will be randomized in 49 hospitals: 280 patients in the
glucocorticoid (GC) - initiating subpopulation and 496 patients in the
glucocorticoid (GC) - continuing subpopulation. Patients who have initiated
administration with prednisone >= 7.5 mg daily or its equivalent within 3 months
prior to screening will be assigned to the glucocorticoid (GC) - initiating
subpopulation and patients who are administering prednisone >= 7.5 mg daily or
its equivalent for >= 3 months preceding screening will be assigned to the
glucocorticoid (GC) - continuing subpopulation
Three substudies have been set-up:
1. HR pQCT (XtremeCT®)
During this substudy additional CT scans will be perfomred on day 1, months 12
and 24. About 100 patients in selected hospitals will be asked to take part in
this substudy. None of the Dutch sites will participate in this substudy.
2. Bot Biopt
During this substudy a bone biopsy will be taken month 12. About 30 patients in
selected hospitals will be asked to take part in this substudy. Only the VUmC
will participate in this substudy.
3. PK/BTM
During this substudy additional blood (about 70 ml) will be drawn for
pharmcokinetic analysis (PK) and bone turnover markers (BTM) on days 1 and 10,
months 3, 4, 5, 12 and 24. About 160 patients (80 from the glucocorticoid (GC)
- initiating subpopulation and 80 from the glucocorticoid (GC) - continuing
subpopulation) in selected hospitals will be asked to take part in this
substudy. Only the VUmC will participate in this substudy
Intervention
Patients will receive denosumab, subcutane injection, 60mg, every 6 months +
placebo for oral risedronate, daily or risedronate, oral, 5mg, daily + placebo
for denosumab, subcutane injection, every 6 months.
Study burden and risks
The following procedures will be performed according to appendix A (schedule of
assessments) of the protocol:
physical examination, vital signs, blood sampling, pregnancy test (serum test
and urine dipstick). DXA scans (hip, radius and spine) will be performed at 3
(hip, radius) or 5 (spine) of the 7 visits and at 3 of the 7 visits, an X-ray
of the spine will be done. A questionnaire will be completed at 2 of the 7
visits. When the patient takes part in the PK/BTM substudy, 3 extra visits will
be scheduled in which blood will be drawn. If the patient takes part in the
Extreme CT or Bone biopsy substudy, an extra CT scan of the radius and tibia
will be performed during 3 of the 7 visits or during one of the 7 visits a bone
biopsy will be taken.
Patients (including patients who take part in the Extreme CT and/or bone biopsy
substudies) need to come to the hospital for 7 times in total during a period
of 2 years. Patients who take part in the PK/BTM substudy have 3 extra visits
on top of that: in total 10 visits during a 2 year period.
For adverse event of denosumab and risedronate, please see question E9.
Minervum 7061
Breda 4800DH
NL
Minervum 7061
Breda 4800DH
NL
Listed location countries
Age
Inclusion criteria
4.1.1
- Glucocorticoid-initiating subpopulation: Men and women >= 18 years of age who have initiated Prednisone >= 7.5 mg daily or its equivalent within 3 months prior to screening and are expected to be treated with oral glucocorticoids for a total of at least 6 months, OR;
* Glucocorticoid-continuing subpopulation: Men and women >= 18 years of age who are taking Prednisone >= 7.5 mg daily or its equivalent for >= 3 months preceding screening and are expected to be treated with oral glucocorticoids for a total of at least 6 months.
4.1.2 Glucocorticoid-continuing subjects who are >= 50 years of age will be required to have a BMD value equivalent to a T-score <= -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD value equivalent to a T-score <= -1.0 at the lumbar spine, total hip, or femoral neck and with a history of osteoporotic fracture.
4.1.3 Men and women < 50 years old at the time of screening in both glucocorticoid-continuing and glucocorticoid-initiating subpopulations, will be required to have a history of osteoporotic fracture.
4.1.4 Ambulatory;
4.1.5 At least two lumbar vertebrae from L1 through L4 and one hip must be evaluable by DXA (duplicate scans required);
4.1.6 Subject or subject*s legally acceptable representative has provided informed consent prior to any study specific procedures.
Exclusion criteria
4.2.1 Received other OP treatment or bone active treatment with the following guidelines: a) Oral bisphosphonate use 1) > 3 months cumulatively in the past 2 years OR 2) > 1 month in the past year OR 3) Any use during the 3-month period prior to screening b) Administration of intravenous bisphosphonate, fluoride or strontium for OP within the last 5 years c) Parathyroid hormone (PTH) or PTH derivatives within the last year d) Denosumab for OP at any time in the past
4.2.2 Administration of any of the following treatment within 3 months of screening: Any selective estrogen receptor modulator (SERM) (estrogen agonist/ antagonist), Tibolone, Anabolic steroids or testosterone, Systemic hormone replacement therapy, Calcitonin, Other bone active drugs including anti-convulsants (except benzodiazepines) and heparin, Chronic systemic ketoconazole, androgens, adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors, gonadotropin-releasing hormone agonists
4.2.3 Administration of any of the following biologic agents within 4 weeks prior to screening: Anti alpha 4 integrin antibody (eg, natalizumab), Anti CD4/CD8 T-cells (eg, alefacept), Anti IL-12/IL-23 (eg, ustekinumab), CTLA4 inhibitor (eg, abatacept), IL1 receptor antagonist (eg, anakinra), IL6 inhibitor (eg, tocilizumab), Monoclonal antibody to CD20 (eg, rituximab), TNF antagonist (eg, adalimumab, certolizumab, golimumab, etanercept, infliximab)
4.2.4 Administering >1 biologic agent for the treatment of underlying inflammatory disease
4.2.5 Subject has an active infection or history of infections as follows: any active infection for which systemic anti-infectives were used within 4 weeks prior to screening, a serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to screening, recurrent or chronic infections or other active infection
4.2.6 Evidence of any of the following: History of hyperthyroidism (stable on antithyroid therapy is allowed), History of hypothyroidism (stable on thyroid replacement therapy is allowed), History of hypo- or hyperparathyroidism, History of Addison disease, History of osteomalacia, History of osteonecrosis of the jaw, History of recent tooth extraction or other dental surgery within the prior 6 months, Invasive dental work planned in the next 2 years, History of Paget*s disease of bone, Other bone diseases which affect bone metabolism
4.2.7 Abnormalities of the following per central laboratory reference ranges: Vitamin D deficiency, Hypercalcemia, Elevated transaminases, Elevated total bilirubin (TBL) as described in the protocol amendment 2 on page 30.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024393-19-NL |
| ClinicalTrials.gov | NCT01575873 |
| CCMO | NL39265.029.12 |