Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

Study Overview
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Brief Summary
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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
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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.

Official Title
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Multicenter Study to Evaluate Safety of Fresolimumab in Adults With Moderate-to-severe Osteogenesis Imperfecta

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Drug: Fresolimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide signed informed consent. Are 18 years or older Have a diagnosis of moderate-to-severe OI based on various clinical features 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). 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. 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: Fracture less than 3 months prior to the screening visit. Rodding or instruments that prevents reliable bone mineral density (BMD) assessment. Have a known unhealed fracture involving a long bone. 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. Have an EKG with QTc of > 450 ms Have a known allergy to fresolimumab. Have current clinically significant infection. Have a personal history of basal cell carcinoma, squamous cell carcinoma or keratoacanthomas, a personal history of cancer, recent or remote. Have evidence of untreated cavities or planned invasive dental work during the study period. Have had organ transplantation. Have known or suspected valvular heart disease. Plan to have skeletal surgery in the study period. Have had osteotomy 5 months prior to the screening visit. 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. Being treated with systemic glucocorticoids Have autoimmune diseases being treated with glucocorticoids or other biologic agents. Enrolled in another clinical trial and receiving treatment with another investigational agent Pregnant or planning to get pregnant during the study period. Nursing mothers.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 Low dose<br>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 | Drug: Fresolimumab<br>* 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.<br>|
| Experimental: Stage 2 High dose<br>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 | Drug: Fresolimumab<br>* 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.<br>|
| Experimental: Stage 2 Repeat dose every 6 months<br>Fresolimumab will be administered every six months for a total treatment period of 12 months (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 | Drug: Fresolimumab<br>* 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.<br>|
| Experimental: Stage 2 Repeat doses every 3 months<br>Fresolimumab will be administered every three months for a total treatment period of 12 months (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 | Drug: Fresolimumab<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Safety of single and repeat doses of fresolimumab will be assessed in adult patients with moderate to severe osteogenesis imperfecta | 6 months for single dose study and 12 months for repeat dose study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in type 1 procollagen, N-terminal or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or CTX | Markers of bone turnover in blood will be assessed | 6 months in single dose study and 12 months in repeat dose study | 
| Percent change in the areal BMD at the lumbar spine and hip | Areal bone mineral density (aBMD) at the hip or the lumbar spine as measured by DXA Scan | 6 months in single dose study and 12 months in repeat dose study | 
| Difference in score of numeric rating scale for pain | The difference between baseline values and at month 12 will be assessed in the repeat dose study only | 12 months | 
| Change in ml in FEV1 | The change in absolute volumes of FEV1 will be assessed between baseline and 12 months in the repeat dose study only | 12 months | 
| Change in ml in FVC | The change in absolute volumes of FVC will be assessed between baseline and 12 months in the repeat dose study only | 12 months | 
| Percent change in volumetric bone mineral density at the radius | pQCT of forearm will be performed to assess the change in volumetric bone mineral density between baseline and 12 months in the repeat dose study only. | 12 months | 
| Number of meters walked in 6 minutes | Standard 6 minute walk test will be performed to assess the difference between baseline and 12 months in the repeat dose study only | 12 months |