Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

NCT ID: NCT03064074

Last Updated: 2024-12-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-15
• Study Completion Date: 2022-07-04

Brief Summary

Osteogenesis Imperfecta (OI) is a rare disorder that causes bones to break easily. People with OI may have broken bones with little or no trauma, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. OI can range from very severe to very mild. The current standard-of-care for severe types of OI involves the use of IV medications (bisphosphonates) and surgery to put rods in bones to strengthen them. These therapies, although often life-saving, are new and very little is known about their long-term effects on bone and other body systems.

Transforming growth factor beta (TGF-β) is a protein important in bone formation. Fresolimumab is an antibody that can silence TGF-β . In studies with mice with OI, it has been shown that silencing TGF-β can lead to higher bone mass, quality and strength. The purpose of this study is to determine if fresolimumab is safe in the treatment of OI.

Detailed Description

Osteogenesis Imperfecta (OI) is a rare disorder that causes bones to break easily. People with OI may have broken bones with little or no trauma, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. It is seen in both genders and all races. OI can range from very severe to very mild. Individuals with the most severe type of OI may die at birth. People with severe OI who survive may have bowed arms and legs, very short stature and be unable to walk. People with the mildest form of OI may only break bones occasionally and have normal height and lifespan. Breaks can occur in any bone, but are most common in the arms and legs. The current standard-of-care for severe types of OI involves the use of IV medications (bisphosphonates) and surgery to put rods in bones to strengthen them. These therapies, although often life-saving, are new and very little is known about their long-term effects on bone and other body systems.

TGF-β is a protein important in bone formation. Studies have shown that increased TGF-β activity leads to lower bone mass and strength and increased fractures. Fresolimumab is an antibody that can silence TGF-β . In studies with mice with OI, it has been shown that silencing TGF-β can lead to higher bone mass, quality and strength.

Conditions

Osteogenesis Imperfecta

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Stage 1 Low dose

There are a total of 6 study visits within approximately a 6 month timespan. Investigators will evaluate the safety of a single administration of fresolimumab in adult patients with OI. Subjects will receive a single-dose of 1 mg/kg of fresolimumab (n=4).

At each study visit, the participant may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If the participant is female, she will have a pregnancy test
• EKG
• DXA
• Infusion of the study drug

Group Type: EXPERIMENTAL

Fresolimumab

Intervention Type: DRUG

The purpose of this study is to determine if fresolimumab is safe as a treatment for OI. We will evaluate the safety of a single dose of fresolimumab in the 1st stage of the study. We will evaluate the safety of multiple doses of fresolimumab in the 2nd stage of the study. The Investigators will evaluate the effect of the two doses of fresolimumab in Stage 1 on markers of bone turnover and determine the dose that shows the greatest reduction in bone turnover markers compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no significant changes between the bone turnover markers with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

Stage 2 High dose

There are a total of 6 study visits within approximately a 6 month timespan. Investigators will evaluate the safety of a single administration of fresolimumab in adult patients with OI. Subjects will receive a single-dose of 4 mg/kg of fresolimumab (n=4).

At each study visit, the participant may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If the participant is female, she will have a pregnancy test
• EKG
• DXA
• Infusion of the study drug

Group Type: EXPERIMENTAL

Fresolimumab

Intervention Type: DRUG

The purpose of this study is to determine if fresolimumab is safe as a treatment for OI. We will evaluate the safety of a single dose of fresolimumab in the 1st stage of the study. We will evaluate the safety of multiple doses of fresolimumab in the 2nd stage of the study. The Investigators will evaluate the effect of the two doses of fresolimumab in Stage 1 on markers of bone turnover and determine the dose that shows the greatest reduction in bone turnover markers compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no significant changes between the bone turnover markers with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

Stage 2 Repeat dose every 6 months

Fresolimumab will be administered every six months for a total treatment period of 12 months (Total Anticipated n=4). The dose to be administered (1 or 4 mg/kg) will be chosen after completion of Stage 1. The primary Stage 2 endpoint will be safety measures assessed over 12 months. The secondary endpoints will be changes in markers of bone remodeling, bone mineral density, estimated strength.

At each study visit, participants may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If the participant is female, she will have a pregnancy test
• EKG
• DXA
• Infusion of the study drug
• Skeletal survey
• Peripheral quantitative CT (pQCT) of the forearm
• Quality of Life Surveys
• Pulmonary function test
• Walk test

Group Type: EXPERIMENTAL

Fresolimumab

Intervention Type: DRUG

The purpose of this study is to determine if fresolimumab is safe as a treatment for OI. We will evaluate the safety of a single dose of fresolimumab in the 1st stage of the study. We will evaluate the safety of multiple doses of fresolimumab in the 2nd stage of the study. The Investigators will evaluate the effect of the two doses of fresolimumab in Stage 1 on markers of bone turnover and determine the dose that shows the greatest reduction in bone turnover markers compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no significant changes between the bone turnover markers with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

Stage 2 Repeat doses every 3 months

Fresolimumab will be administered every three months for a total treatment period of 12 months (Total anticipated n=4). The dose to be administered (1 or 4 mg/kg) will be chosen after completion of Stage 1. The primary Stage 2 endpoint will be safety measures assessed over 12 months. The secondary endpoints will be changes in markers of bone remodeling, bone mineral density, estimated strength.

At each study visit, participants may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If the participant is female, she will have a pregnancy test
• EKG
• DXA
• Infusion of the study drug
• Skeletal survey
• Peripheral quantitative CT (pQCT) of the forearm
• Quality of Life Surveys
• Pulmonary function test
• Walk test

Group Type: EXPERIMENTAL

Fresolimumab

Intervention Type: DRUG

The purpose of this study is to determine if fresolimumab is safe as a treatment for OI. We will evaluate the safety of a single dose of fresolimumab in the 1st stage of the study. We will evaluate the safety of multiple doses of fresolimumab in the 2nd stage of the study. The Investigators will evaluate the effect of the two doses of fresolimumab in Stage 1 on markers of bone turnover and determine the dose that shows the greatest reduction in bone turnover markers compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no significant changes between the bone turnover markers with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

Interventions

Fresolimumab

The purpose of this study is to determine if fresolimumab is safe as a treatment for OI. We will evaluate the safety of a single dose of fresolimumab in the 1st stage of the study. We will evaluate the safety of multiple doses of fresolimumab in the 2nd stage of the study. The Investigators will evaluate the effect of the two doses of fresolimumab in Stage 1 on markers of bone turnover and determine the dose that shows the greatest reduction in bone turnover markers compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no significant changes between the bone turnover markers with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Willing and able to provide signed informed consent.

2. Are 18 years or older

3. Have a diagnosis of moderate-to-severe OI based on various clinical features

4. Have genetic mutations that include glycine substitution in COL1A1 or COL1A2, or pathogenic variants in CRTAP, PPIB, or LEPRE1 (if genetic information is unavailable at screening, this may be assessed at screening visit on a clinical or research basis).

5. Females of child-bearing potential must have a negative urine pregnancy test, agree to and have the ability to use acceptable birth control method for entire duration of the study.

6. For Males enrolled in the study, partners must agree to use an acceptable form of birth control for the entire duration of the study.

Exclusion Criteria

1. Fracture less than 3 months prior to the screening visit.

2. Rodding or instruments that prevents reliable bone mineral density (BMD) assessment.

3. Have a known unhealed fracture involving a long bone.

4. Do not meet laboratory safety requirements such as: Vitamin D < 15 ng/dL Serum albumin-corrected calcium levels below 8 mg/dL, Hemoglobin < 10 g/dL, Platelet count < 75,000mm3;, Prothrombin time/(PT/INR) international normalized ratio > 1.5 times Upper Limit of Normal (ULN), Clinical or laboratory abnormality of Grade III or higher as assessed by CTCAE v4.0 which in the view of investigator would compromise safety.

5. Have an EKG with QTc of > 450 ms

6. Have a known allergy to fresolimumab.

7. Have current clinically significant infection.

8. Have a personal history of basal cell carcinoma, squamous cell carcinoma or keratoacanthomas, a personal history of cancer, recent or remote.

9. Have evidence of untreated cavities or planned invasive dental work during the study period.

10. Have had organ transplantation.

11. Have known or suspected valvular heart disease.

12. Plan to have skeletal surgery in the study period.

13. Have had osteotomy 5 months prior to the screening visit.

14. Being treated with zoledronic acid or pamidronate less than 12 months of screening OR oral bisphosphonates less than 6 months of screening OR teriparatide less than one year of screening.

15. Being treated with systemic glucocorticoids

16. Have autoimmune diseases being treated with glucocorticoids or other biologic agents.

17. Enrolled in another clinical trial and receiving treatment with another investigational agent

18. Pregnant or planning to get pregnant during the study period.

19. Nursing mothers.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: collaborator

Oregon Health and Science University

OTHER

Sponsor Role: collaborator

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Brendan Lee

Chairman/Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sandesh Nagamani, M.D.

Role: STUDY_CHAIR

Baylor College of Medicine

VReid Sutton, M.D.

Role: STUDY_CHAIR

Baylor College of Medicine

Brendan Lee, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Locations

Oregon Health Science University

Portland, Oregon, United States

Baylor College of Medicine

Houston, Texas, United States

Countries

United States

References

Song IW, Nagamani SC, Nguyen D, Grafe I, Sutton VR, Gannon FH, Munivez E, Jiang MM, Tran A, Wallace M, Esposito P, Musaad S, Strudthoff E, McGuire S, Thornton M, Shenava V, Rosenfeld S, Huang S, Shypailo R, Orwoll E, Lee B. Targeting TGF-beta for treatment of osteogenesis imperfecta. J Clin Invest. 2022 Apr 1;132(7):e152571. doi: 10.1172/JCI152571.

Reference Type: DERIVED

PMID: 35113812 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

H37912

Identifier Type: -

Identifier Source: org_study_id