Setrusumab vs Bisphosphonates for Osteogenesis Imperfecta

(Cosmic Trial)

Recruiting at 24 trial locations

Overseen By HCPs Contact: Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must be taking: IV bisphosphonates

Must not be taking: Growth hormone, Denosumab

Disqualifiers: Skeletal malignancies, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

69 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but it does require that you have not used certain bone-impacting medications other than bisphosphonates before. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Setrusumab vs Bisphosphonates for Osteogenesis Imperfecta?

Research shows that bisphosphonates, like alendronate and zoledronic acid, can increase bone mineral density and reduce fractures in patients with osteogenesis imperfecta, suggesting their effectiveness in managing this condition. ^{1 2 3 4 5}

What is the safety profile of bisphosphonates in humans?

Bisphosphonates are generally safe and well-tolerated, but they can cause side effects like stomach discomfort and flu-like symptoms. Rarely, they may lead to serious issues like jaw bone problems or unusual fractures. The risk of these serious side effects is low compared to the benefits, especially when used correctly. ^{6 7 8 9 10}

How does the drug Setrusumab differ from bisphosphonates in treating osteogenesis imperfecta?

Setrusumab is a newer treatment option for osteogenesis imperfecta that may offer a different mechanism of action compared to traditional bisphosphonates, which are known to increase bone mineral density. While bisphosphonates like alendronate and zoledronic acid have been extensively studied and used to strengthen bones in OI patients, Setrusumab represents a novel approach that could potentially provide additional benefits. ^{1 2 3 4 11}

What is the purpose of this trial?

This trial compares setrusumab, a new bone-strengthening drug, with standard treatments in children. It aims to see if setrusumab can better prevent bone fractures. Both treatments work by making bones stronger. Standard treatments have been used for a long time to increase bone mineral density and improve bone resistance, leading to a decrease in fracture rate.

Research Team

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Eligibility Criteria

This trial is for children with Osteogenesis Imperfecta (OI) types I, III, or IV who have had fractures in the past year and are currently on or have had bisphosphonate therapy. They must not have severe kidney issues, untreated hypocalcemia, a history of certain bone diseases other than OI, cardiovascular disease without clearance, or recent use of certain bone-impacting drugs.

Inclusion Criteria

My Osteogenesis Imperfecta (Types I, III, IV) is confirmed by a genetic test.

My vitamin D level is at least 20 ng/mL, or I've taken supplements to reach this.

I have had one or more bone fractures in the last 2 years.

Exclusion Criteria

I have a history of spinal nerve passage narrowing not caused by scoliosis.

I cannot use IV bisphosphonates as decided by my doctor.

I do not have severe kidney disease or disorders affecting my bones.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Active-controlled Period

Participants are randomized to receive either setrusumab or IV-BP for up to 24 months

24 months

Extension Period

All participants receive setrusumab for a minimum of 12 months or until it becomes commercially available

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Bisphosphonate
• Setrusumab

Trial Overview The study compares setrusumab to intravenous bisphosphonates in reducing fracture rates in pediatric patients with OI. It aims to see if setrusumab is more effective at preventing new fractures including specific spinal ones.

Participant Groups

Group I: Setrusumab Experimental Treatment 1 Intervention

Participants will receive Setrusumab during the active-controlled and extension period

Group II: Intravenous Bisphosphonates (IV-BP) -> Setrusumab Active Control 2 Interventions

Participants on IV-BP will continue their existing dose/regimen per investigator discretion; for participants not on IV-BP, the dose/regimen will be determined by the investigator. After the active-controlled period, participants will receive Setrusumab during the extension period

Bisphosphonate is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in United States as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• Glucocorticoid-induced osteoporosis
• High calcium levels in cancer patients
• Bone metastases

Approved in Canada as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Japan as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in China as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Switzerland as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Who Is Running the Clinical Trial?

Ultragenyx Pharmaceutical Inc

Lead Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Findings from Research

Alendronate treatment over 2 years significantly improved bone mineral density in children with osteogenesis imperfecta (OI), with increases of 47.8% to 106.6% in the lumbar spine and 24% to 51.4% in forearm bones.

The treatment was found to be safe and well-tolerated, with no significant side effects reported, suggesting that alendronate could be a promising oral alternative to pamidronate for increasing bone density in OI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alendronate treatment in osteogenesis imperfecta. Madenci, E., Yilmaz, K., Yilmaz, M., et al.[2013]

In a study of 161 children and adolescents with osteogenesis imperfecta, both intravenous zoledronic acid (ZOL) and oral alendronate (ALN) were effective in increasing bone mineral density (BMD), with ZOL showing a slightly higher increase in Z-scores.

ZOL was significantly more effective than ALN in reducing the clinical fracture rate, indicating it may provide better long-term safety and efficacy for patients with osteogenesis imperfecta.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZOLEDRONIC ACID VERSUS ALENDRONATE IN THE TREATMENT OF CHILDREN WITH OSTEOGENESIS IMPERFECTA: A 2-YEAR CLINICAL STUDY. Lv, F., Liu, Y., Xu, X., et al.[2021]

Intravenous zoledronic acid has been shown to be an effective treatment for children with mild osteogenesis imperfecta (OI), leading to an increase in bone mineral density (BMD) z-scores over 2 years of treatment.

The treatment was associated with some side effects, including transient decreases in serum calcium and phosphate levels, and two cases of symptomatic hypocalcemia, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid treatment in children with osteogenesis imperfecta. Vuorimies, I., Toiviainen-Salo, S., Hero, M., et al.[2022]

In a study of 90 adults with osteogenesis imperfecta (OI), bisphosphonate treatment, particularly intravenous pamidronate, significantly increased bone mineral density (BMD) in type I and type III/IV patients over an average treatment duration of 52 months.

While bisphosphonates improved BMD, they did not reduce fracture rates in type I OI patients, and only pamidronate treatment led to a decrease in fracture rates for type III/IV patients, suggesting that bisphosphonate therapy may not be suitable for all OI adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. Shapiro, JR., Thompson, CB., Wu, Y., et al.[2018]

Oral bisphosphonates, commonly used for osteoporosis, can cause various adverse events including gastrointestinal issues, musculoskeletal pain, and osteonecrosis of the jaw, while intravenous bisphosphonates are linked to similar issues but with added risks of renal toxicity.

The severity and frequency of adverse events from bisphosphonates are often related to the dosage and potency of the medication, highlighting the need for careful management in their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated adverse events. Papapetrou, PD.[2022]

Bisphosphonates are generally safe and well-tolerated for treating osteoporosis, with the most common side effects being gastrointestinal discomfort and flu-like symptoms, while serious adverse events are rare.

Skeletal complications like osteonecrosis of the jaw and atypical fragility fractures are infrequent compared to the risk of osteoporotic fractures, suggesting that the benefits of bisphosphonates often outweigh these risks, especially in patients with a similar fracture risk as those in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects of bisphosphonates. Abrahamsen, B.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Alendronate treatment in osteogenesis imperfecta. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

ZOLEDRONIC ACID VERSUS ALENDRONATE IN THE TREATMENT OF CHILDREN WITH OSTEOGENESIS IMPERFECTA: A 2-YEAR CLINICAL STUDY. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Zoledronic acid treatment in children with osteogenesis imperfecta. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Pamidronate treatment of children with moderate-to-severe osteogenesis imperfecta: a note of caution. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Risk of upper gastrointestinal tract events in risedronate users switched to alendronate. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Safety of bisphosphonates. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated adverse events. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Adverse effects of bisphosphonates. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Reshaping of vertebrae during treatment with neridronate or pamidronate in children with osteogenesis imperfecta. [2019]