Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta

NCT03064074 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: H37912
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

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.

Conditions

Osteogenesis Imperfecta

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Percentage Change in Bone Turnover Markers or P1NP, Osteocalcin or Ocn, and C-terminal Telopeptide or CTX

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

Study Arms (4)

Stage 1 Low dose

EXPERIMENTAL

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

Stage 2 High dose

EXPERIMENTAL

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

Stage 2 Repeat dose every 6 months

EXPERIMENTAL

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

Drug: Fresolimumab

Stage 2 Repeat doses every 3 months

EXPERIMENTAL

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

Drug: Fresolimumab

Interventions

Fresolimumab 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 1 Low dose; Stage 2 High dose; Stage 2 Repeat dose every 6 months; Stage 2 Repeat doses every 3 months

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Baylor College of Medicine: lead
• Genzyme, a Sanofi Company: collaborator
• Oregon Health and Science University: collaborator

Study Sites (2)

Oregon Health Science University

Portland, Oregon, 97239, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 35113812 DERIVED

MeSH Terms

Conditions

Osteogenesis Imperfecta

Interventions

fresolimumab

Condition Hierarchy (Ancestors)

Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: dianne Nguyen
• Organization: Baylor

diannen@bcm.edu

7137986694

Study Officials

• Sandesh Nagamani, M.D.

  Baylor College of Medicine

  STUDY CHAIR

• VReid Sutton, M.D.

  Baylor College of Medicine

  STUDY CHAIR

• Brendan Lee, M.D., Ph.D.

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chairman/Professor

Study Record Dates

• First Submitted: October 13, 2016
• First Posted: February 24, 2017
• Study Start: November 15, 2017
• Primary Completion: July 4, 2022
• Study Completion: July 4, 2022
• Last Updated: December 4, 2024
• Results First Posted: October 8, 2024

Record last verified: 2024-12

Locations

US (2)