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Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

Primary Purpose

Osteogenesis Imperfecta

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Fresolimumab

About this trial

This is an interventional treatment trial for Osteogenesis Imperfecta

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Oregon Health Science University
Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Stage 1 Low dose

Stage 2 High dose

Stage 2 Repeat dose every 6 months

Stage 2 Repeat doses every 3 months

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

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

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

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.

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

Full Information

NCT ID

NCT03064074

First Posted

October 13, 2016

Last Updated

July 5, 2022

Sponsor

Baylor College of Medicine

Collaborators

Genzyme, a Sanofi Company, Oregon Health and Science University

1. Study Identification

Unique Protocol Identification Number

NCT03064074

Brief Title

Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

November 15, 2017 (Actual)

Primary Completion Date

July 4, 2022 (Actual)

Study Completion Date

July 4, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Baylor College of Medicine

Collaborators

Genzyme, a Sanofi Company, Oregon Health and Science University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteogenesis Imperfecta

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Stage 1 Low dose

Arm Type

Experimental

Arm Description

Arm Title

Stage 2 High dose

Arm Type

Experimental

Arm Description

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

Arm Title

Stage 2 Repeat dose every 6 months

Arm Type

Experimental

Arm Description

Arm Title

Stage 2 Repeat doses every 3 months

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fresolimumab

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Description

Safety of single and repeat doses of fresolimumab will be assessed in adult patients with moderate to severe osteogenesis imperfecta

Time Frame

6 months for single dose study and 12 months for repeat dose study

Secondary Outcome Measure Information:

Title

Percentage change in type 1 procollagen, N-terminal or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or CTX

Description

Markers of bone turnover in blood will be assessed

Time Frame

6 months in single dose study and 12 months in repeat dose study

Title

Percent change in the areal BMD at the lumbar spine and hip

Description

Areal bone mineral density (aBMD) at the hip or the lumbar spine as measured by DXA Scan

Time Frame

6 months in single dose study and 12 months in repeat dose study

Title

Difference in score of numeric rating scale for pain

Description

The difference between baseline values and at month 12 will be assessed in the repeat dose study only

Time Frame

12 months

Title

Change in ml in FEV1

Description

The change in absolute volumes of FEV1 will be assessed between baseline and 12 months in the repeat dose study only

Time Frame

12 months

Title

Change in ml in FVC

Description

The change in absolute volumes of FVC will be assessed between baseline and 12 months in the repeat dose study only

Time Frame

12 months

Title

Percent change in volumetric bone mineral density at the radius

Description

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.

Time Frame

12 months

Title

Number of meters walked in 6 minutes

Description

Standard 6 minute walk test will be performed to assess the difference between baseline and 12 months in the repeat dose study only

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sandesh Nagamani, M.D.

Organizational Affiliation

Baylor College of Medicine

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

VReid Sutton, M.D.

Organizational Affiliation

Baylor College of Medicine

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

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

Organizational Affiliation

Baylor College of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oregon Health Science University

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Facility Name

Baylor College of Medicine

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

35113812

Citation

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.

Results Reference

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Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

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