Onset of effect of systemic therapy to enhance bone density (eg, bisphosphonates) is not immediate and may not adequately protect subjects with decreased bone density from fracture.Bisphosphonate therapy will typically require 2 to 3 years of active…
ID
Source
Brief title
Condition
- Bone, calcium, magnesium and phosphorus metabolism disorders
- Fractures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Demonstrate increased BMD of the proximal femur (total hip BMD) after injection
of rhBMP-2/CPM (either 1.0 mg/mL or 2.0 mg/mL) as an adjunct to systemic
osteoporosis therapy. Endpoint: BMD measured by dual-energy x-ray
absorptiometry (DXA) every 3 months from 6 to 12 months.
Secondary outcome
• Assess acute (6 weeks) and long-term (up to 36 months) safety of
administering rhBMP-2/CPM in subjects with decreased BMD.
• Assess the feasibility of administering rhBMP-2/CPM as a minimally invasive
technique in an outpatient (ambulatory care) setting.
• Identify a clinically meaningful difference in BMD between rhBMP-2/CPM
treatment groups, allowing for a single dose (concentration) to be selected for
the phase 3 program.
• Identify number of nonresponders-treated subjects who, after up to 12 months
of follow-up, have changes in BMD from baseline that are less than or equal to
changes observed in the contralateral (untreated) hip and for which an
attributable cause cannot otherwise be identified.
• Assess changes in BMD relative to femoral neck morphometry, exploring the
relation between the femoral neck volume of individual study subjects or groups
of subjects, the volume of rhBMP-2/CPM administered, and the overall response
to treatment, measured by bone densitometry.
• Evaluate long-term (up to 36 months) changes in BMD after injection of
rhBMP-2/CPM.
• Evaluate bone quality with emphasis on cortical thickness and trabecular
volume in region(s) of interest (ROIs), utilizing quantitative computed
tomography (volumetric rendering of proximal femur; vQCT).
• Evaluate changes in biochemical markers of bone turnover to identify markers
that are predictive of changes in BMD from baseline.
o Markers of bone formation: bone-specific alkaline phosphatase (bone ALP),
N-terminal propeptide of type I collagen (PINP), osteocalcin (OC).
o Markers of bone resorption: C-terminal cross-linked telopeptide of type I
collagen (CTX-I) and tartrate-resistant acid phosphatase isoenzyme 5b
(TRAcP5b).
Background summary
• Incidence of hip fracture continues to rise worldwide, representing an area
of high medical need.
• Onset of effect of systemic therapy to enhance bone density (eg,
bisphosphonates) is not immediate and may not adequately protect subjects with
decreased bone density from fracture.
• Bisphosphonate therapy will typically require 2 to 3 years of active
treatment in order to achieve a 40% to 50% reduction in the first occurrence of
a hip fracture.
• Preclinical studies in non human primates have established efficacy of
recombinant human bone morphogenetic protein 2/calcium phosphate matrix
(rhBMP-2/CPM) in osteoporotic bone, demonstrating increased cortical and
trabecular bone volume and increased bone strength at the site of injection.
rhBMP- 2/CPM offers a locally administered, minimally invasive surgical
treatment for increasing bone mass at skeletal sites at risk for fracture; the
effect of rhBMP-2/CPM is not inhibited by concomitant administration of
bisphosphonate therapy, making the treatment compatible with the current
standard of care (SOC).
Study objective
Onset of effect of systemic therapy to enhance bone density (eg,
bisphosphonates) is not immediate and may not adequately protect subjects with
decreased bone density from fracture.
Bisphosphonate therapy will typically require 2 to 3 years of active treatment
in order to achieve a 40% to 50% reduction in the first occurrence of a hip
fracture.
Preclinical studies in non human primates have established efficacy of
recombinant human bone morphogenetic protein 2/calcium phosphate matrix
(rhBMP-2/CPM) in osteoporotic bone, demonstrating increased cortical and
trabecular bone volume and increased bone strength at the site of injection.
rhBMP- 2/CPM offers a locally administered, minimally invasive surgical
treatment for increasing bone mass at skeletal sites at risk for fracture; the
effect of rhBMP-2/CPM is not inhibited by concomitant administration of
bisphosphonate therapy, making the treatment compatible with the current
standard of care (SOC).
Study design
Multicenter, randomized (by hip), active-controlled, stratified (by prior
osteoporosis therapy), parallel group study of 2 concentrations of rhBMP-2/CPM
as an adjunct to systemic osteoporosis (bisphosphonate) therapy, the active
comparator.
Intervention
Single percutaneous intraosseous injection of rhBMP-2/CPM (either 1.0 mg/mL or
2.0 mg/mL delivered in a volume of 6 mL), administered unilaterally through a
lateral approach under local anesthesia and conscious sedation and fluoroscopic
control to the femoral neck and intertrochanteric region. Treatment with rhBMP
2/CPM is administered as an adjunct to systemic osteoporosis therapy.
Study burden and risks
Possible risks of rhBMP-2 (The most frequently reported side effects of rhBMP-2
are):
• Headache
• Increased amounts of amylase (an enzyme used in digestion) in the blood (high
blood amylase) without obvious signs of inflammation of the pancreas
• Tachycardia (fast heart beat)
• Low magnesium in the blood
Other reported side effects are:
• Local swelling near the area of injection
• Fluid collection in some patients undergoing spine surgery with rhBMP-2/ACS,
at times resulting in nerve compression and pain.
• Loss of bone (leading to bone weakness)
• Excess bone growth (too much bone growth) or abnormal bone growth in the
surrounding tissues that could put pressure on nearby nerves or tendons.
• Antibodies to BMP-2 have been observed. Antibodies are substances in our
bodies that recognize foreign agents (e.g., germs) and help fight infection.
The long-term effects of antibodies to BMP-2 are unknown. Side effects
suggesting an allergy or immune effects (inability to fight infections) have
not been reported but cannot be excluded.
• Patients who take NSAID medications (certain pain killers) while being
treated with rhBMP-2 may have wound healing problems, such as persistent wound
drainage
• A 2mg/mL dose was tested in subjects with closed tibia fractures (broken
shinbones). It was found that this dose slowed down healing of these closed
broken bones. Therefore, this dose is no longer being tested for closed broken
shinbones.
Potential risks that may occur with any injection:
• Contamination at the site of injection
• Unintentional (accidental) nerve damage
• Unintentional (accidental) damage to ligaments and/or tendons (for fractures
occurring close to a joint)
• Unintentional (accidental) injection in a vein or artery (blood vessel)
leading to breathing and/or blood circulation complications
rhBMP-2 has not been studied in the following patients therefore the safety is
unknown:
• Patients with suppressed immune systems or autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus (lupus)
• Patients with kidney or liver problems
• Pediatric patients (children less than 18 years of age)
• Patients who have received this product previously
• Patients with diseases of the skeleton
Limited safety information is available for:
Elderly patients (>65 years of age)
Malignancy
Neither human nor animal studies have shown conclusively that rhBMP-2 can
change normal cells into cancers cells in the body. There have been reports
from laboratory experiments of existing cancer cells increasing in number when
they have been exposed to rhBMP-2; however, other laboratory studies have shown
that rhBMP-2 decreased the number of existing cancer cells. Because the risk
of stimulating existing cancer growth is still unknown, subjects who have a
previous history of cancer will not be included in studies (except for subjects
who have had a history only of certain types of skin cancer).
Risks of Blood Collection
The risks involved in taking blood include pain, swelling, bruising, or
infection around the vein where your blood is collected. You may feel dizzy or
you may faint. The total amount of blood that will be collected for the study
is 196 milliliters for the first group of patients that are enrolled in the
study and 179 milliliters for the rest of the patients. In comparison, about
500 milliliters/16 ounces is collected at one time for a typical blood donation.
Risks of Radiation
You will be exposed to radiation as a result of participating in the study. The
radiation comes from 4 different sources: X-rays, fluoroscopy, DXA and CT
scans. X-rays are used to look at the inside parts of your body, like your
bones or your lungs, to make sure nothing is wrong. Fluoroscopy is a special
X-ray machine that the doctor uses in the surgery room to see where the
injection should be put in your hip. DXA is the name of the bone density test
which tells how strong your bones are. CT scans give a better picture of the
bones than X-rays do and they can also be used to measure the size (thickness,
density) of bones. For the CT scan, you will be lying on your back and a
partly-open tunnel-shaped machine. You must not move, but relax and breathe
normally. Some patients have felt claustrophobic during this test.
The total amount of radiation that you will be exposed to by participating in
this study is approximately equal to 6.2 years of natural background radiation
that you would normally receive from the sun or the soil in everyday life. We
cannot guarantee that this amount of radiation exposure is not without risk.
Risks of Anesthesia
If you are chosen to receive an injection of rhBMP-2/CPM, you will be given a
light medication (anesthesia) to numb the area around your hip and to make you
feel more relaxed. The medication used for giving the injection may or may not
make you feel
sleepy. You should not feel any pain when the injection is given.
Spicalaan 31
2132JG Hoofddorp
Nederland
Spicalaan 31
2132JG Hoofddorp
Nederland
Listed location countries
Age
Inclusion criteria
1. postmenopausal woman, age >=65 years.
2. BMD T-score (total hip or femoral neck) of -2.5 or less in at least 1 hip. Subjects with BMD T-scores of -2.0 or less may be enrolled if at least 1 of the following risk factors is also present.
a. Age >=75 years
b. Family (maternal) history of fragility fracture
c. Previous fragility fracture (self) after 45 years
3. Bilaterally intact proximal femora, without evidence of acute fracture, surgical hardware, or prosthetic implant.
4. Subjects may either be treatment naive or on a previously established regimen (>=1 year, but <5 years duration) of bisphosphonate therapy.
5. Subjects must be willing to comply with 1 of the 3 protocol-designated oral bisphosphonates (risedronate, alendronate, or ibandronate sodium) with risedronate considered as first-line therapy.
Exclusion criteria
1. Metabolic bone disorder or disease affecting bone and mineral metabolism (eg, Pagets disease, vitamin D deficiency [<20 ng/mL], hyperparathyroidism, renal osteodystrophy, osteomalacia, hypocalcemia, hypercalcemia).
2. Previous use of agents that can be considered bone anabolic (eg, parathyroid hormone (PTH), growth hormone, anabolic steroids, or sodium fluoride at bone therapeutic doses).
3. Previous use of SERMs, HRT, or calcitonin within the past 12 months.
4. Previous use of strontium ranelate.
5. Continuous or intermittent disease that requires systemic glucocorticosteroid treatment within the past 6 months (eg, chronic obstructive pulmonary disease, asthma).
6. Active infection at any anatomical site.
7. History of severe pulmonary or respiratory disorder, such as acute respiratory distress syndrome (ARDS), pulmonary stenosis, or right-to-left venoarterial shunt.
8. Evidence of unstable clinically relevant disease (eg, cardiovascular, hepatic, renal, or thyroid disease).
9. Coagulopathy and/or history of venous thromboembolic events (deep vein thrombosis, pulmonary embolus, retinal vein thrombosis) within the past 12 months.
10. Body mass index (BMI) >35 kg/m2.
11. Documented history of malignancy, except basal or squamous cell carcinoma that has been treated and fully resolved.
12. Inflammatory arthritis including rheumatoid, psoriatic, or crystal-induced (gouty) arthritis, or those associated with systemic lupus erythematosus (SLE), spondyloarthropathy, Reiters syndrome, or Crohns disease.
13. Any condition requiring anticonvulsant therapy.
14. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin >=1.5 times the upper limit of normal (ULN) at screening.
15. ALP or serum creatinine >=2 times the (ULN) at screening.
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 | EUCTR2007-007456-34-NL |
| ClinicalTrials.gov | NCT00752557 |
| CCMO | NL28128.068.09 |