Denosumab in Children With Osteogenesis Imperfecta
Research type
Research Study
Full title
Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta
IRAS ID
160002
Contact name
Nicholas Bishop
Contact email
Sponsor organisation
Amgen Ltd
Eudract number
2014-000184-40
Duration of Study in the UK
5 years, 5 months, 30 days
Research summary
Research Summary
The study is to evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by DXA scan in children 2 to 17 years of age with osteogenesis imperfecta (Brittle Bone Disease). Safety, efficacy and pharmacokinetics will be evaluated in the study. 150 subjects will receive denosumab 1 mg/kg (up to a maximum of 60 mg) given subcutaneously every 6 months for 36 months with appropriate calcium and vitamin D supplementation. Enrolment into the study will be gated by age starting with patient’s age 11-17, then age 7-10 and finally for subjects aged 2-6 years. At least 30 subjects age 2-6 will be enrolled. Subjects will be enrolled from approximately 40 centres across North America, Europe and Australia over approximately 3 years.
Subjects will undergo: DXA assessment of lumbar spine and proximal femur; x-ray radiographic assessment of the spine (thoracic and lumbar) and knees (in those with open growth plates); dental x-ray. Blood samples will be taken to measure chemistry and haematology as well as blood levels of denosumab. Patient reported outcomes will be gathered by both subject and parent completed questionnaires. The first 5 subjects in the study (all age 11-17) and the first 5 subjects who have increased bone turnover (criteria apply; any age) will be monitored more frequently for mineral homeostasis with additional visits in the 14 days following enrolment.Summary of Results
1.Study Name Title of the Study:
Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta Brief Title:
Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta Protocol Number:
20130173
EU Trial Number:
2014-000184-40
Other Identifiers:
NCT02352753
Date of This Summary:
08 September 2022
What does this summary cover?
This summary shows the main results from one clinical study. The results are only for this study. Other studies may find different results. Researchers and health authorities look at the results of many studies to decide which medicines work best and are safest for patients.
Amgen has committed to make research results available to the public. This summary has been provided as part of that commitment and should not be used for any other purpose. It should not be considered to make a claim for any product or to guide treatment decisions.
Some information in this summary may be different from the approved labelling for denosumab. Your healthcare professional should refer to the full prescribing information for proper use of denosumab.2. Who Sponsored This Study?
Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Phone (United Kingdom): +44 1223 436441 Amgen Inc. is the sponsor of the study who made denosumab, the medicine tested in the study. Amgen would like to thank everyone who participated in this study and feels it is important to share the results of this study.
3. General Information About the Clinical Study Where and when was the study done?
• This study took place in Australia, Belgium, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, and United States.
• The study began in June 2015 and ended in March 2022.
• The study was stopped earlier than planned due to safety concerns about high levels of calcium in the blood of the participants.
Why was the study done?
Osteogenesis imperfecta (OI) is an inherited disorder that affects the development of bones. People with OI may have bones that break very easily. OI is also known as “brittle bone disease”.
Denosumab is a medicine that was being studied as a possible treatment for OI. Denosumab is approved for use in adults with a different bone disease, but it has not been approved for use in children or for the treatment of OI.
This was a phase 3 study, the late stage of the development process of medicines for humans. The main purpose of this study was to find out more about the use of denosumab in children and young adults with OI.4. Who Was Included in This Study?
This study included 153 participants. 73 participants (48%) were girls/young women and 80 participants (52%) were boys/young men. They ranged in age from 2 to 18 years at the beginning of the study.
This study took place at 32 study centers. The numbers of participants in each country are listed below.
• Australia: 2 participants
• Belgium: 7 participants
• Bulgaria: 2 participants
• Canada: 15 participants
• Czech Republic: 5 participants
• France: 3 participants
• Germany: 40 participants
• Hungary: 13 participants
• Italy: 13 participants
• Poland: 6 participants
• Spain: 6 participants
• United Kingdom: 11 participants
• United States: 30 participants
Participants were examined by a study doctor and chosen to be in the study if they were 2 to 17 years old and had been diagnosed with OI.5. Which Medicines Were Studied?
A total of 153 children joined this study. All children initially received denosumab every 6 months. The dose was 1 milligram per kilogram of body weight (mg/kg), up to a maximum dose of 60 mg, given as an injection under the skin. Children also received daily calcium and vitamin D supplements. Children were assigned to 3 groups based on age: 11 to 17 years, 7 to 10 years, and 2 to 6 years. This was an open-label study, which means that the researchers, study doctors, children, and their parents/guardians knew which treatments the children received during the study.
Children in the 11 to 17 years group joined the study first. The first 5 children from this group were monitored closely for changes in bone minerals, for 14 days. The rest of the children from this group could then begin denosumab treatment. After the first 5 children had completed 12 months of denosumab treatment, children from the 7 to 10 years group could join the study.
The first 5 children of any age with increased bone turnover were also monitored closely for changes in bone minerals, for 14 days.
After the first 5 children of the 7 to 10 years group had completed 6 months of denosumab treatment, children from the 2 to 6 years group could join the study.
The researchers had originally planned to give the children denosumab every 6 months for 3 years. However, early results from the study suggested that denosumab dosing should be changed from every 6 months to every 3 months. So, the children were switched to a schedule of denosumab every 3 months for up to 18 months. If their parent/guardian did not want their child to switch to the new dosing schedule, they were given the option to stop this study and join a long-term follow-up study.
This study was stopped earlier than planned due to safety concerns about high levels of calcium in the children’s blood. All children immediately stopped receiving denosumab. The researchers monitored the children for any medical problems or other safety concerns for 6 months after their last dose of denosumab.6. What Were the Side Effects?
What is a side effect?
All medicines can cause side effects, or unwanted medical problems that may happen when you take a medicine. In this study, doctors reported all the medical problems participants had. Doctors believed some of the problems could have been caused by the study medicine(s). These possible side effects are listed below.What side effects were seen?
The table below shows how many participants had side effects. Side Effects During the Study Denosumab 1 mg/kg every 6 months (153 participants) Denosumab 1 mg/kg every 3 months (60 participants) How many participants had serious side effects?
6 participants (4%)
6 participants (10%) How many participants had non-serious side effects? 99 participants (65%) 24 participants (40%) How many participants died from side effects?
0 participants (0%)
0 participants (0%) How many participants stopped taking the study medicine because of side effects? 4 participants (3%) 1 participant (2%) If a participant had to stay in the hospital or died because of a side effect, the doctor reported that the side effect was serious. No participant died due to a side effect.
The tables below show the serious side effects. Serious Side Effects During the Study: Every 6 Months Serious side effect Denosumab 1 mg/kg every 6 months (153 participants) Thigh bone fracture
3 participants (2%) Arm bone fracture 1 participant (1%) Joint dislocated
1 participant (1%) Spine fracture 1 participant (1%) Pain
1 participant (1%)Serious Side Effects During the Study: Every 3 Months Serious side effect Denosumab 1 mg/kg every 3 months (60 participants) High level of calcium in blood
6 participants (10%)
The tables below show the non-serious side effects that occurred in at least 10% of participants (or about 10 out of 100). Non-serious Side Effects During the Study: Every 6 Months Non-serious side effect Denosumab 1 mg/kg every 6 months (153 participants) High level of calcium in urine
47 participants (31%) Joint pain 36 participants (24%) High level of calcium in blood
24 participants (16%) Pain in arm or leg 22 participants (14%) Non-serious Side Effects During the Study: Every 3 Months Non-serious side effect Denosumab 1 mg/kg every 3 months (60 participants) High level of calcium in blood
11 participants (18%) Low level of calcium in blood 6 participants (10%) This section only shows the most often reported side effects considered by the study doctor as related to study medicine. No single clinical study can give a complete picture of the benefits and risks of a medicine. Information about other side effects may be available at the websites listed at the end of this summary.7. What Were the Overall Results of the Study?
Did participants who received denosumab every 3 months for 1 year have an increase in the amount of minerals in their bones?
• To answer this question, the researchers used a type of X-ray to measure the amount of minerals, such as calcium, in the participants’ bones. Researchers measured the amount of minerals in the bones before participants started taking denosumab, and after 12 months of treatment.
• They found that, after 12 months of treatment, participants had an increase in the amount of minerals in their bones.
• The study was stopped earlier than planned due to safety concerns about high levels of calcium in the blood of the participants.
• The researchers considered the potential risks and benefits, and concluded that using denosumab to treat OI in children is not recommended.
More results may be available at the websites listed at the end of this summary.8. How Has This Study Helped Participants and Researchers?
What else is important to know about these results?
These results are only for this clinical study, which looked at a sample of 153 children and young adults with OI. Not all participants in the study had the same results. The results for any single participant could have been better or worse than the results for their group. Other studies may find different results. These results do not explain how a study medicine may work in a single person. Many studies are needed to show the benefits and risks of a medicine that is still being tested. This research may help future participants and families by helping doctors understand more about the study medicine being studied.9. Are There Plans for Further Studies?
If more clinical studies are done, they may be listed on public websites, such as those below. Search for study medicine name denosumab on the websites below.
10. Where Can I Find More Information About This Study?
To find out more about this study, check these websites: • EU Clinical Trials Information System https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7Cbfbbee2a2fed45f7169b08daf88d64fa%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638095583408084367%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=BEgj4i7ktgh05equ2vIQzwELvqNf9ULjaX%2BfpJSVBL8%3D&reserved=0. Use the study identifier 2014-000184-40• https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7Cbfbbee2a2fed45f7169b08daf88d64fa%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638095583408084367%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=jy8JOhuteJFO8mr%2Fzr4bU8OInYR9rqwoCfGmGhyYkr0%3D&reserved=0. Use the study identifier NCT02352753
If you or your child participated in the study and have questions about the study results, the doctor or staff at your study center may be able to answer them.
REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
15/NW/0009
Date of REC Opinion
30 Jan 2015
REC opinion
Further Information Favourable Opinion