Conditions: Osteogenesis Imperfecta
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

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.

Arms:
arm 1: 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 arm 2: 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 3: 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 arm 4: 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

Interventions: intervention 1: Fresolimumab
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
RDCRN Protocol 7706 
Fresolimumab 
Version Date: 22Mar2020 
 
 
 
 
Rare Diseases Clinical Research Network 
 
 
 
Multicenter study to evaluate safety of 
fresolimumab in adults with moderate-to-severe 
Osteogenesis Imperfecta 
 
 
 
 
 
 
 
 
Study Chairs: 
 
 
Brendan Lee, M.D. 
Baylor College of Medicine 
One Baylor Plaza MS 227, R814 
Houston, TX 77030 
blee@bcm.edu 
 
Sandesh Nagamani, M.D. 
Baylor College of Medicine 
One Baylor Plaza MS 227, R812 
Houston, TX 77030 
nagamani@bcm.edu  
 
V. Reid Sutton, M.D. 
Baylor College of Medicine 
One Baylor Plaza 
Houston, TX 77030 
vsutton@bcm.edu 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose. The procedures in this 
protocol are intended only for use by Consortium investigators in carefully 
controlled settings. The Chair of this study should be consulted before 
using or attempting any procedure in this protocol. 


2 
 
 
Participating Institutions 
 
Baylor College of Medicine 
Principal Investigator: Sandesh Nagamani, M.D. 
Address: 
1 Baylor Plaza BCM225 
Houston, TX 77030 
  Phone: 
832-822-4296 
       Fax: 
832-825-4294 
    Email: 
nagamani@bcm.edu 
Sub-Investigator: 
V. Reid Sutton, M.D. 
 
Oregon Health and Science University 
Principal Investigator: Eric Orwoll, M.D. 
Address: 
3181 SW Sam Jackson Park Road, CR113 
Portland, OR 97239 
Phone: 
503-494-0225 
Fax: 503-494-6595 
Email: orwoll@ohsu.edu 
 
Data Management and Coordinating Center (DMCC): 
Principal Investigator: RDCRN DMCC Principal Investigators 
Address: Cincinnati Children’s Medical Center (CCHMC)  
Division of Biostatistics and Epidemiology 
3333 Burnett Ave Cincinnati, OH 45229 
Phone:   
Fax:  
Email: 
Rd.dmcc@cchmc.org 
 
 
 


Protocol Version Date: 24Feb17 
3 
 
 
Table of Contents 
Participating Institutions ..................................................................................................... 2 
Table of Contents .............................................................................................................. 3 
1. Protocol Synopsis .......................................................................................................... 5 
1.1 Overview .................................................................................................................. 8 
2. Specific Aims (Hypothesis and Objectives) .................................................................... 9 
3. Background ................................................................................................................. 10 
4. Study Design and Methods .......................................................................................... 12 
4.1 Inclusion Criteria (Stage 1 and Stage 2) ................................................................ 13 
4.2 Exclusion criteria (Stage 1 and Stage 2) ................................................................ 13 
4.3 Rescreening .......................................................................................................... 15 
4.4 Recruitment of Participants .................................................................................... 15 
4.5 Retention Strategies .............................................................................................. 15 
4.6 Investigational Product(s) ...................................................................................... 16 
4.7 Single Dose Administration Study (Stage 1) .......................................................... 16 
4.8 Repeat Dose Administration study (Stage 2) ......................................................... 19 
4.9 Data Elements ....................................................................................................... 24 
4.10 Schedule of Events ............................................................................................ 26 
5. Data and Safety Monitoring Plan ................................................................................. 28 
5.1 Study Oversight ..................................................................................................... 28 
5.2 Adverse Event Definitions and Standards .............................................................. 28 
5.3 Expected/ Known Risks/ Discomforts/ Adverse Event Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events ................... 29 
5.4 Adverse Event Reporting Timeline ......................................................................... 31 
5.5 RDCRN Adverse Event Data Management System (AEMS) .................................. 32 
5.6 Unanticipated Problem Reporting .......................................................................... 32 
5.7 Study Discontinuation ............................................................................................ 33 
5.8 Subject Discontinuation .......................................................................................... 33 
5.9 Data Quality and Monitoring Measures .................................................................. 34 
5.10 Quality Control: Study Related Procedures .......................................................... 34 
6. Statistical Considerations ............................................................................................. 34 
7. Data Management ....................................................................................................... 34 
7.1 Registration ........................................................................................................... 35 
7.2 Data Entry .............................................................................................................. 35 


4 
 
 
7.3 Laboratory Data Flow ............................................................................................. 35 
7.4 Study Records Retention ....................................................................................... 35 
7.5 Protocol Deviations ................................................................................................ 36 
8. Human Subjects .......................................................................................................... 36 
8.1 GCP Statement ...................................................................................................... 36 
8.2 Benefits .................................................................................................................. 36 
8.3 Risks ...................................................................................................................... 37 
8.4 Written Informed Consent ...................................................................................... 37 
8.5 Process of Consent ................................................................................................ 38 
8.6 Certificate of Confidentiality .................................................................................... 38 
9. References .................................................................................................................. 39 
 


Protocol Version Date: 24Feb17 
5 
 
 
1. Protocol Synopsis 
Protocol Number: 
7706 
Protocol Title: 
Multicenter study to evaluate safety of fresolimumab in adults with 
moderate-to-severe osteogenesis imperfecta 
Study Chair: 
Brendan Lee, M.D.; Sandesh Nagamani, M.D.; V. Reid Sutton, M.D. 
Statistician: 
David Cuthbertson, MS 
Consortium: 
Brittle Bone Disorders 
Participating Sites: 
Baylor College of Medicine; Shriners Hospital for Children, Montreal; 
Kennedy Krieger Institute / Hugo W. Moser Research Institute; Hospital 
for Special Surgery; University of California Los Angeles; Oregon Health 
and Science University; University of Nebraska Medical Center 
Activation Date: 
TBD 
Sample Size: 
16 
Target Enrollment Period: 
August 2016-August 2019 
Study Design: 
Interventional 
Primary Study Objective: 
To evaluate the safety of single and repeat dose administrations of 
fresolimumab in adult patients with moderate-to-severe OI. 
Secondary Study 
Objective(s): 
To determine the effects of fresolimumab on bone remodeling, areal bone 
mineral density, pain scores, pulmonary function tests and quality of      
life for patients on fresolimumab therapy. 
Study Population and Main 
Eligibility/ Exclusion 
Criteria: 
Inclusion criteria (Stage 1 and Stage 2) 
1. Willing and able to provide signed informed consent. 
2. Age > 18 years 
3. Diagnosis of moderate-to-severe OI based on history of more than 
20 fractures in lifetime. 
4. 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. Negative urine pregnancy test and ability to use acceptable birth 
control method for entire duration of the study (if subject is of child- 
bearing potential) 
6. Males who enroll in the study (and their partners) should agree to 
use an acceptable form of birth control for the entire duration of the 
study 
Exclusion criteria (Stage 1 and Stage 2) 
1. Long bone fracture less than 3 months of screening. These patients 
can be rescreened after radiologically documented healing of 
fracture. If individual sustains fracture in the period after the 
screening visit but before the day 1 of the trial, rescreening will be 
allowed after 3 months from the date of the fracture  
2. Instrumentation in the lumbosacral (LS) and both hips that prevents 
reliable bone mineral density (BMD) assessment in at least one site 


6 
 
 
 
 
3. Known unhealed fracture involving a long bone (Nonunion or malunion 
of greater than 1 year duration will not be considered as unhealed 
fracture). 
4. Vitamin D < 15 ng/dL; rescreening for vitamin D levels will be allowed 
after supplementation 
5. Serum albumin-corrected calcium levels below 8 mg/dL. Rescreening 
will be allowed after calcium supplementation. 
6. Hemoglobin < 10 g/dL 
7. Platelet count < 75,000/mm3; rescreening will be allowed to confirm 
that this is not due to a technical error   
8. Prothrombin time/ (PT/INR) international normalized ratio  > 1.5 
times Upper Limit of Normal (ULN). 
9. EKG with QTc of > 450 ms (if QTc is prolonged on one EKG, repeat 
EKG may be done at the same visit for confirmation, if subsequent 
EKG shows QTc < 450 ms, subject will be eligible for enrollment) 
10. Clinical or laboratory abnormality of Grade III or higher as assessed 
by CTCAE v4.0 which in the view of investigator would compromise 
safety 
11. History of known allergy or hypersensitivity to fresolimumab 
12. Current clinically significant infection. Rescreening will be allowed 
after resolution of infection. 
13. Personal history of basal cell carcinoma, squamous cell carcinoma or 
keratoacanthomas 
14. Any personal history of cancer, recent or remote 
15. Any personal history of precancerous condition or lesions including 
actinic keratosis, atypical moles, Barret’s esophagus, or cervical 
intraepithelial cancer. 
16. Evidence of untreated cavities or planned invasive dental work 
during the study period. 
17. Any history of organ transplantation. 
18. Any known or suspected valvular heart disease. (Valvular heart 
disease will be defined by these criteria: 1) history of 
hemodynamically significant known valvular stenosis or 
regurgitation; OR 2) presence of grade 3 or higher cardiac murmur at 
screening visit; OR 3) any history of valvular replacement; OR 4) 
echocardiographic evidence of any clinically significant valvular 
stenosis or regurgitation). Trace or trivial valvular regurgitation will 
not be considered as an exclusion criterion. 
19. Anticipated skeletal surgery in the study period. 
20. Osteotomy less than 5 months of screening. 
21. Prior treatment 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. 
22. Active treatment with systemic glucocorticoids (equivalent of 
greater than 5 mg of prednisone per day for more than 2 weeks) 
3 weeks before screening visit or anticipated treatment of greater 
than 2 week duration during the study period. 
23. Current and daily treatment with antiplatelet agents (aspirin, 
clopidogrel, dipyridamole, cilostazol, or ticlopidine)   
24. Current treatment with anticoagulant medications (low molecular 
weight heparin analogues, warfarin, dabigatran, rivaroxaban, 
apixaban, or edoxaban) 
25. Documented history of autoimmune disease or immune deficiency. 
Hashimoto’s thyroiditis will not be considered as an exclusion. 
26. Evidence of latent tuberculosis by a positive purified protein derivative 
(PPD) test or Interferon-gamma release assay. 
27. Currently receiving another investigational agent in a research study, 
or less than 30 days since ending treatment on another 


Protocol Version Date: 24Feb17 
7 
 
 
investigational drug study. 
28. Current or planned pregnancy at any time during the study period. 
29. Nursing mothers. 
30. In the opinion of the investigator, inability to fully comply with the 
study requirements or participation in the study exposes the subject 
to undue risk. 
 
Treatment 
Agent: 
GZ402669 or fresolimumab or GC1008, Human Anti-Transforming 
Growth Factor-β 1, 2, 3 Monoclonal Antibody 
Dosage, schedule, route of 
administration:
Single dose study (Stage 1): 
 
Group 1 
• 
4 subjects will receive a single intravenous infusion of 
fresolimumab at a dose of 1 mg/kg body weight. Maximal 
body weight used for calculation of the drug dose is 80 kg; for 
those weighing greater than 80 kg, the drug dose will be 
calculated using a weight of 80 kg. Total duration of study 
participation per subject is 6 months. 
Group 2 
• 
4 subjects will receive a single intravenous infusion of 
fresolimumab at a dose of 4 mg/kg body weight. Maximal 
body weight for calculation of the drug dose is 80 kg; for 
those weighing greater than 80 kg, the drug dose will be 
calculated using a weight of 80 kg. Total duration of study 
participation per subject is 6 months. 
Repeat dose study (Stage 2): 
Group 1 
• 
4 subjects receive four intravenous infusions of fresolimumab 
at months 0, 3, 6, and 9, with a follow up period of 3 months. 
Total duration of study participation 12 months. 
Group 2 
• 
4 subjects receive two intravenous infusions of fresolimumab 
at months 0 and 6, with a follow up period of 6 months. Total 
duration of study participation is 12 months. 
Safety Issues: 
Fresolimumab has been investigated in humans. The investigators 
brochure provides additional safety information. This will be provided to 
investigators as supplemental material to the protocol. 
 Primary Outcome 
Measures: 
Single dose study (Stage 1): 
1) Pharmacokinetics of fresolimumab with single dose administration 
2) To evaluate the safety of single administration of fresolimumab in  
adults with moderate-to-severe OI with respect to: 
• 
Vital signs 
• 
Laboratory variables 
• 
EKG (Corrected QT interval) 
• 
Adverse events and serious adverse events 
Repeat dose study (Stage 2): 
To evaluate the safety of repeat dose administrations of fresolimumab in 
adults with moderate-to-severe OI with respect to: 
• 
Vital signs 
• 
Laboratory variables 
• 
EKG 
• 
Adverse events and serious adverse events 
 


8 
 
 
Secondary Outcome 
Measures:
Single dose study (Stage 1): 
Effect of fresolimumab with respect to: 
• 
Markers of bone turnover in blood (type 1 procollagen, N-terminal 
or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or CTX) 
• 
Areal bone mineral density (aBMD) at the hip or the lumbar spine 
as measured by dual-energy X-ray absorptiometry (DXA) scan 
 
Repeat dose study (Stage 2): 
Effect of fresolimumab with respect to: 
• 
Markers of bone turnover in blood (type 1 procollagen, N-terminal 
or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or CTX) 
• Areal bone mineral density (aBMD) at the hip or the lumbar spine as 
measured by dual-energy X-ray absorptiometry (DXA) scan 
• Bone density and estimated strength by pQCT of forearm 
• Pain score as assessed by Numeric Rating Scale (NRS) 
• Forced expiratory volume in 1 second (FEV1), forced vital 
capacity (FVC) as measured by pulmonary function tests 
• QOL as assessed by PROMIS® 
• Functional capacity as assessed by the 6-minute walk test. 
Statistical Considerations 
(sample size and analysis 
plan): 
This study is designed to assess the safety and tolerability of 
fresolimumab in patients with Osteogenesis Imperfecta. 
Sample Size: No formal sample size calculations will be done for this study. 
The sample size was selected to allow for an initial assessment of safety in 
this population, dose range and feasibility of enrollment in this rare disorder. 
The sample size is 8 for the single dose study and 8 for the repeat dose study. 
Participants enrolled in Stage 1 of this study may be enrolled in Stage 2 of the 
study if they meet eligibility.  T h e  overall enrollment will be 16. If needed, 2 
additional patients will be enrolled in the repeat dose study to account for a 
dropout rate of 20%. 
Treatment-Related Adverse Events will be summarized by dose groups. 
Changes in Vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature), EKG, changes in laboratory assessments and physical 
examination findings, and patient-reported symptoms will be described. These 
variables will assess the primary endpoint of safety. Percent change in bone 
remodeling markers will be analyzed using a mixed model. BMD in the lumbar 
spine and the hip at 6 months for the single dose study and at 12 months for the 
multiple dose study will be compared to pretreatment levels using a Wilcoxon 
Signed Rank test. Percent change in the variables of the pulmonary function 
tests, and changes in the 6-minute walk test and the Numeric Rating Scale 
(NRS) for pain will be evaluated by Wilcoxon Signed Rank test. Values for 
derived pharmacokinetic variables, including Cmax, area under the curve, 
distribution, half-life (T1/2a), elimination half-life (T1/2b), clearance (CL), and 
volume of distribution at steady state (Vss), will be calculated as previously 
described and summarized by dose-group using descriptive statistics. 
Sponsors (federal, 
state, foundation and 
industry support): 
National Institutes of Health (NIH), The Osteogenesis Imperfecta 
Foundation (OIF), Genzyme 
 
 
1.1 Overview 
Osteogenesis imperfecta (OI) refers to a group of heritable disorders of connective 
tissue. Individuals with OI present with predominant involvement of the bone that 
includes low bone mass, increased bone fragility, recurrent fractures, and bone 
deformities. In addition, extraskeletal symptoms like cardiac valvular insufficiency,  
 
 


Protocol Version Date: 24Feb17 
9 
 
 
ligamentous laxity, and lung abnormalities add to the significant morbidity of the 
disorder. The current medical therapy for OI is limited to medications that are FDA- 
approved for treatment of osteoporosis. Bisphosphonates (BPNs), a class of 
antiresorptive medications, are generally considered as standard of care. 
Bisphosphonates increase bone mineral density in children and adults with OI. Evidence 
for reduction of fractures is conflicting and is particularly problematic in adult patients. An 
alternative approach to increase bone density and bone quality is the use of bone 
anabolic agents. A recent trial with teriparatide, a bone anabolic agent approved for 
treatment of osteoporosis, showed that efficacy of such therapy is rather limited in those 
who need therapy the most, i.e., individuals with moderate-to-severe OI. 
 
Transforming growth factor beta (TGFβ) is a cytokine that belongs to a superfamily of 
ligands. Members of the TGFβ family maintain homeostasis in many organ systems. In 
bone, TGFβ acts as a central coordinator of bone remodeling. Recently, it was 
discovered that increased TGFβ activity in the bone matrix is a primary mechanism 
contributing to the decreased bone mass, impaired biomechanical properties, and 
susceptibility to fracture in OI. These data suggest that inhibition of TGFβ could be a 
potential disease-specific therapy in OI. 
 
This is a multi-center interventional study to determine the safety of fresolimumab 
therapy in individuals with moderate-to-severe OI. It will be conducted by the Brittle 
Bone Disorders Consortium, which is part of the Rare Disease Clinical Research 
Network (RDCRN) and comprises  of multiple distinct Rare Disease Clinical Research 
Consortia (RDCRC) and one Data Management & Coordinating Center (DMCC). The 
National Institutes of Health (NIH) and its Office of Rare Diseases Research (ORDR), 
the National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the 
National Institute of Dental and Craniofacial Research (NIDCR) and the National 
Institute of Child Health and Human Development (NICHD) provide oversight for the 
Brittle Bone Disease Clinical Research Consortium.  
 
We propose to: 
1) Evaluate the safety of a single dose injection of fresolimumab in adult patients with OI 
(Stage 1). 
 
2) Evaluate the safety of repeated dose administration of fresolimumab in adult 
patients with OI (Stage 2). 
 
2. Specific Aims (Hypothesis and Objectives) 
 
We propose to conduct a Phase 1 clinical trial of fresolimumab (a human pan-TGFβ- 
neutralizing monoclonal antibody) in patients with moderate-to-severe OI by 
accomplishing the following specific aims: 
 
 
 


10 
 
 
Aim 1. Evaluate the safety of a single administration of fresolimumab in adult patients 
with OI (Stage 1). We will perform a multicenter, dose-ranging, study in adults with 
moderate-to-severe OI. Subjects will be assigned to receive a single-dose of either 1 
mg/kg (group 1) or 4 mg/kg (group 2) of fresolimumab (n=4 per group). The primary 
endpoints will be safety measures that will be assessed over a period of 6 months. 
The secondary endpoints will be changes in markers of bone remodeling and bone 
mineral density as compared to pretreatment values. 
 
Aim 2. Evaluate the safety of repeated dose administration of fresolimumab in adult 
patients with moderate-to-severe OI (Stage 2). This will also be a multicenter wherein 
fresolimumab will be administered every three months (group 1) or every six months 
(group 2) for a total treatment period of 12 months (n=4 patients per group). 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 as assessed by peripheral QCT of the forearm, pulmonary function 
tests, pain as assessed by NRS, QOL as assessed by the PROMIS questionnaire, and 
changes in the 6-minute walk test. 
 
3. Background 
 
3.1 Disease Description 
Osteogenesis imperfecta (OI) refers to a group of heritable disorders of connective 
tissue. Individuals with OI present with predominant involvement of bone that 
includes low bone mass, increased bone fragility, recurrent fractures, and bone 
deformities. In addition, extraskeletal manifestations like cardiac valvular 
insufficiency, ligamentous laxity, and lung abnormalities add to the significant 
morbidity of the disorder. 1 Intrauterine fractures and perinatal mortality are typical in 
the severe forms of the disease. A prevalence of 1 in 15,000–20,000 births and an 
estimated patient population of ~ 25,000 in the United States make OI a prototype 
rare disease. 1,2 The majority of patients with OI have mutations in either COL1A1 or 
COL1A2, which encode components of type I collagen, the major matrix protein in 
bone. More recently, mutations in genes involved in post-translational modification of 
type I collagen, chaperone proteins, signaling molecules, and others have been 
discovered to cause OI as well. 3-9 
 
3.2 Current Therapies Available 
The current medical therapy for OI is limited to medications that are FDA-approved 
for treatment of osteoporosis. Bisphosphonates (BPNs), a class of antiresorptive 
medications, are generally considered as standard of care. The rationale for BPN 
therapy in OI is that this could increase the bone mineral density, and the increased 
bone mass albeit with abnormal matrix could potentially reduce fracture rates. 
Bisphosphonates increase bone mineral density in children and adults with OI; 
however, their efficacy in reducing fractures is still unclear, particularly in adult 
patients. 10,11 More recently, human and murine studies have raised concerns that 
long-term use of BPNs in OI could result in impaired bone quality and adverse effects 
such as atypical fractures. 12-14 An alternative approach to increase bone density and 
bone quality is the use of bone anabolic agents. A recent trial with teriparatide, a 


Protocol Version Date: 24Feb17 
11 
 
 
bone anabolic agent approved for treatment of osteoporosis, showed that efficacy of 
such therapy is rather limited in those who need therapy the most, i.e., individuals 
with moderate-to-severe OI. 15Thus, the current strategy of repurposing approved 
anti-osteoporotic medications for OI has significant limitations as these do not target 
the primary pathogenetic mechanisms involved in the causation of bone fragility. 
Additionally, none of the current therapies are geared towards treatment of 
extraskeletal manifestations such as pulmonary disease. Currently, there are no 
disease-specific therapies for OI, and availability of such modalities would be of 
significant importance to patients. 
 
3.3 TGF-β is a potential therapeutic target in OI 
Transforming growth factor beta (TGFβ) is a cytokine that belongs to a superfamily of 
ligands including bone morphogenetic proteins and activins. Members of the TGFβ 
family maintain homeostasis in many organ systems. In bone, TGFβ acts as a central 
coordinator of bone remodeling by coupling the activity of bone-resorbing osteoclasts 
and bone-forming osteoblasts.16 Recently, it was discovered that increased TGFβ 
activity in the bone matrix is a primary mechanism contributing to the decreased 
bone mass, impaired biomechanical properties, and susceptibility to fracture in OI. 17 
This increased TGFβ signaling was also observed in extraskeletal tissue like the 
lungs further underscoring the central role of TGFβ dysregulation in OI. In mouse 
models of moderate-to-severe OI that recapitulate human disease, inhibiting TGFβ 
with anti-TGFβ antibody (1D11, a murine analog of fresolimumab, Genzyme, USA) 
resulted in increased bone mass, quality, and strength. 17 Additionally, this approach 
also rescued the pulmonary abnormalities. These data suggest that inhibition of 
TGFβ could be a potential disease-specific therapy in OI. 
 
3.4 Fresolimumab, a pan TGFβ neutralizing antibody 
Fresolimumab (Genzyme, USA) is an engineered human IgG4 kappa monoclonal 
antibody capable of neutralizing all mammalian isoforms of TGFβ (i.e., β1, 2, and 3). 
 
3.5 Fresolimumab for inhibition of TGFβ in humans 
The safety of fresolimumab has been evaluated by Genzyme in non-clinical studies 
using rodent and non-human primate models. Fresolimumab has also been used in 
humans with idiopathic pulmonary fibrosis, idiopathic focal segmental 
glomeruolosclerosis 18, advanced renal cell carcinoma and malignant melanoma 19 in 
Genzyme-sponsored clinical studies. The nonclinical and clinical data gathered to 
date support single- and repeat-dose administration of fresolimumab in humans. 
 
The effects of fresolimumab on bone turnover and bone mass have not been studied, 
and the sponsor wishes to conduct a phase I study of fresolimumab in a Mendelian 
skeletal condition with proven over-activity of TGFβ. This would be the first disease- 
specific therapy to be investigated in humans with OI. 


12 
 
 
4. Study Design and Methods 
This is a multicenter, phase I study to evaluate the safety of single and repeat dose 
administration of fresolimumab in adult patients with moderate-to-severe OI. Stage I 
will involve a single dose of fresolimumab wherein those in group 1 will be 
administered a dose of 1 mg/kg body weight and those in group 2 will be 
administered a dose of 4 mg/kg body weight; there will be no randomization in this 
stage. Stage 2 will involve repeat doses of fresolimumab; in this stage, the Data 
Management Coordinating Center will randomize patients into two groups – 
individuals in group 1 will receive 4 doses of fresolimumab at months 0, 3, 6, and 9 
and individuals in group 2 will receive two doses of fresolimumab at months 0 and 6.  
 
Design 
After the four individuals complete the 1 mg/kg dose (group 1, stage 1), an 
independent Data Safety and Monitoring Board appointed by the National Institute of 
Health will review the safety data. The decision to proceed with the 4 mg/kg single 
dose administration (group 2, stage 1) will be determined by the DSMB based on 
adverse events, safety data collected, and discontinuation criteria outlined in 
sections 5.6 and 5.7 of the protocol. 
 
If the study proceeds, the study procedures for the 4 mg/kg (group 2, stage 1) will be 
identical to those for the 1 mg/kg (group 1, stage 1). After completion of the single 
dose infusion of 4 mg/kg (group 2, stage 1), the DSMB will assess the safety profile 
of the dose and provide a decision regarding the repeat dose studies (Stage 2). 
 
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 
baseline. 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. 
Group 1, Stage 1 
Groups 1 and 2, Stage 2 
DSMB Meeting •
Review Safety Data •
Will determine if study shall proceed
forth, based upon adverse events,
safety data collected, and
discontinuation criteria outlined in
sections 5.6/5.7 of the protocol. 
Investigator Review •
Evaluate the effect of the two doses in
Stage 1 •
Determine which dose shows the 
greatest reduction in bone 
turnover markers from baseline. •
If no significant changes 4 mg/kg will 
be selected 
Group 2, Stage 1 
DSMB Meeting •
Review Safety Data •
Will determine if the study shall
proceed forth based upon adverse
events, safety data collected and
discontinuation criteria outlined in
sections 5.6/5.7 of the protocol. 


Protocol Version Date: 24Feb17 
13 
 
 
Study Sites 
The study will be conducted at select clinical sites of the Brittle Bone Disorders 
Consortium (BBD) (https://www.rarediseasesnetwork.org/cms/bbd/). The BBD is a 
part of the National Center for Advancing Translational Sciences (NCATS) Rare 
Disease Clinical Research Network (RDCRN). The study procedures are funded 
through collaboration between the Office of Rare Diseases Research (ORDR), 
NCATS, the National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS), and the National Institute of Dental and Craniofacial Research (NIDCR). 
The Principal Investigators at each site that will conduct the study have significant 
expertise in the management of OI. 
 
4.1 Inclusion Criteria (Stage 1 and Stage 2) 
1. Willing and able to provide signed informed consent. 
2. Age > 18 years 
3. Diagnosis of moderate-to-severe OI based on history of more than 20 fractures in 
lifetime. 
4. 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. Males who enroll in the study and their partners must agree to use an acceptable 
form of birth control for the entire duration of the study. 
 
4.2 Exclusion criteria (Stage 1 and Stage 2) 
1. Long bone fracture less than 3 months of screening. These patients can be 
rescreened after radiologically documented healing of fracture. If an individual 
sustains a fracture in the period after the screening visit but before the day 1 of the 
trial, rescreening will be allowed after 3 months from the date of the fracture. 
2. Instrumentation in the lumbosacral (LS) and both hips that prevents reliable bone 
mineral density (BMD) assessment in at least one site. 
3. Known unhealed fracture involving a long bone (Nonunion or malunion of greater than 1 
year duration will not be considered as unhealed fracture). 
4. Vitamin D < 15 ng/dL; rescreening for vitamin D levels will be allowed after 
supplementation. 
5. Serum albumin-corrected calcium levels below 8 mg/dL. Rescreening will be allowed 
after calcium supplementation. 
6. Hemoglobin < 10 g/dL. 
7. Platelet count < 75,000mm3; rescreening will be allowed to confirm that this is not due 
to a technical error. 
8. Prothrombin time/(PT/INR) international normalized ratio > 1.5 times Upper Limit of 
Normal (ULN).  
9. EKG with QTc of > 450 ms (if QTc is prolonged on one EKG, repeat EKG may be 
done at the same visit for confirmation, if subsequent EKG shows QTc < 450 ms, 
subject will be eligible for enrollment.) 
10. Clinical or laboratory abnormality of Grade III or higher as assessed by CTCAE v4.0 
which in the view of investigator would compromise safety. 
11. History of known allergy or hypersensitivity to fresolimumab. 


14 
 
 
12. Current clinically significant infection. Rescreening will be allowed after resolution of 
infection. 
13. Personal history of basal cell carcinoma, squamous cell carcinoma or 
keratoacanthomas. 
14. Any personal history of cancer, recent or remote. 
15. Any personal history of precancerous condition or lesions including actinic keratosis, 
atypical moles, Barret’s esophagus, or cervical intraepithelial cancer. 
16. Evidence of untreated cavities or planned invasive dental work during the 
study period. 
17. Any history of organ transplantation. 
18. Any known or suspected valvular heart disease. (Valvular heart disease will be 
defined by these criteria: 1) history of hemodynamically significant known valvular 
stenosis or regurgitation; OR 2) presence of grade 3 or higher cardiac murmur at 
screening visit; OR 3) any history of valvular replacement; OR 4) echocardiographic 
evidence of any clinically significant valvular stenosis or regurgitation). Trace or 
trivial valvular regurgitation will not be considered as an exclusion criterion. 
19. Anticipated skeletal surgery in the study period. 
20. Osteotomy less than 5 months of screening. 
21. Prior treatment 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. 
22. Active treatment with systemic glucocorticoids (equivalent of greater than 5 mg of 
prednisone per day for more than 2 weeks) 3 weeks before screening visit or 
anticipated treatment of greater than 2 week duration during the study period. 
23. Current and daily treatment with antiplatelet agents (aspirin, clopidogrel, 
dipyridamole, cilostazol, or ticlopidine)   
24. Current treatment with anticoagulant medications (low molecular weight heparin 
analogues, warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) 
25. Documented history of autoimmune disease or immune deficiency. Hashimoto’s 
thyroiditis will not be considered as an exclusion. 
26. Evidence of latent tuberculosis by a positive purified protein derivative (PPD) test or 
Interferon-gamma release assay. 
27. Currently receiving another investigational agent in a research study, or less than 30 
days since ending treatment on another investigational drug study. 
28. Current or planned pregnancy at any time during the study period. 
29. Nursing mothers. 
30. In the opinion of the investigator, inability to fully comply with the study requirements 
or participation in the study exposes the subject to undue risk. 
 
Women 
If the subject is a female, she will be asked about her menstrual cycle history (including 
date of last period; menses regularity; typical duration and normalcy; any abnormal 
discharges; and excessive bleeding). If she is of childbearing potential and is sexually 
active, she must be non-lactating and have a negative urine pregnancy test at 
Screening and Baseline/Day1. The subject must agree to use one of these acceptable 
methods of contraception until study termination: 
a) Hormonal contraceptive: birth control pills, injection, patch, vaginal ring or implant 
b) Condom or diaphragm, with spermicide 
c) Intrauterine device (IUD) 


Protocol Version Date: 24Feb17 
15 
 
 
d) Sterile male partner (vasectomy performed at least 6 months prior to the 
study) Absolute abstinence from all sexual activity is also acceptable. 
Men 
If the subject is a man who has not had a vasectomy, he and his female partner must 
agree to practice appropriate contraception, as described above, during the study. 
 
4.3 Rescreening 
Rescreening will be allowed in patients initially excluded for these criteria: 
1. Fracture less than 3 months of screening. These patients can be rescreened after 
radiologically documented healing of fracture. If individual sustains fracture in the 
period after the screening visit but before the day 1 of the trial, rescreening will be 
allowed after 3 months from the date of the fracture. 
2. Vitamin D < 15 ng/dL; rescreening for vitamin D levels will be allowed 
after supplementation. 
3. Serum albumin-corrected calcium levels below 8 mg/dL; rescreening will be 
allowed after calcium supplementation. 
4. Current clinically significant infection; rescreening will be allowed after resolution 
of infection. 
5. Platelet count less than 75,000/mm3. Rescreening with a second CBC will be 
allowed. 
 
4.4 Recruitment of Participants 
Recruitment will occur through the clinical practices of each site investigator, through 
the RDCRN Contact Registry, and, as needed, via mailings to appropriate clinicians in 
the investigators’ catchment areas and to the patient members of the Osteogenesis 
Imperfecta Foundation. 
 
Recruitment will occur by physicians, study nurses, and research coordinators. Details 
of the goals of the research and the risk and benefits of the protocol will be reviewed 
with each potential study participant. Strict patient confidentiality will be observed 
throughout all aspects of the study. Potential subjects may be requested to provide 
medical records prior to consenting to the study to establish eligibility. In this case a 
medical records release form will be completed to request clinical lab results such 
as genetic confirmation data and historical X-rays. While medical records will be 
reviewed by members of the research team, no individually identifiable patient data will 
be distributed to non-research or care-giving team members. 
 
4.5 Retention Strategies 
OI is a rare disorder that is managed by a small number of specialists. Most of these 
specialists work regularly with the OIF, participate in scientific and clinical research 
meetings and have the expertise to provide medical and surgical care to individuals 
with OI. These clinical relationships provide an avenue for increased communication 
that can facilitate retention. Furthermore, this study may provide benefit to the 
participants that would enhance retention.  Nurses/genetic counselors/clinical research 
coordinators at each site will work to maintain close contact with participants, including 
regular clinic visits, newsletters and communication by phone, email and web sites. 
Study related testing for this research protocol will be performed at no charge to the 
participant. Finally, we will reimburse families for some travel related costs. 


16 
 
 
 
4.6 Investigational Product(s) 
 
Fresolimumab will be supplied as a sterile lyophilized powder for reconstitution. The 
sterile lyophilized powder is intended to be reconstituted with 5.1 mL (50 mg vial) 
sterile Water for Injection (sWFI). For the vials containing fresolimumab this will 
result in a protein concentration of approximately 10 mg/mL in a 50 mM sodium 
phosphate buffer at pH 7.1, containing 25 mM sodium chloride, 3% mannitol, 1% 
sucrose, and 0.01% Polysorbate-80.  
  
Packaging 
 
Packaging and distribution services will be coordinated by the Sponsor or its 
designee for all study sites.  Fresolimumab is stored in clear glass vials of 5 mL 
capacity (nominal), which meet the USP standard for Type I glass, closed by a 
siliconized butyl rubber stopper.  Each vial contains approximately 50 mg of IP. All 
label text will comply with country specific regulatory requirements. 
  
Storage 
 
Upon receipt by the clinical site, IP must be stored at 2 to 8°C (35.6 to 46.4 °F), in 
a limited-access area until preparation for infusion.  Reconstituted fresolimumab is 
stable for up to 24 hours after reconstitution with sWFI at either room temperature 
or under refrigeration (between 2 to 8° C or 35.6 to 46.4° F).  Although stable for 
up to 24 hours under these conditions, fresolimumab in sWFI should be used 
immediately. All used and unused vials should be stored and organized in a 
secure area for later drug accountability. 
 
4.7 Single Dose Administration Study (Stage 1) 
Primary objective 
1. 
Pharmacokinetics of fresolimumab with a single dose administration 
2. 
To evaluate the safety of a single dose administration of fresolimumab in 
adults with moderate-to-severe OI with respect to: 
• Vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Laboratory variables. 
• EKG (Corrected QT interval). 
• Adverse events and serious adverse events. 
 
Secondary Objectives 
Effect of fresolimumab with respect to: 
• Markers of bone turnover in blood (type 1 procollagen, N-terminal 
or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or 
CTX). 
• Areal bone mineral density (aBMD) at the hip or the lumbar spine as 
measured by dual-energy X-ray absorptiometry (DXA) scan. 
 
Dose 
• 4 subjects will receive a single intravenous infusion of fresolimumab at a dose of 
1 mg/kg body weight. Maximal body weight used for calculation of the drug dose 


Protocol Version Date: 24Feb17 
17 
 
 
is 80 kg; for those weighing greater than 80 kg, the drug dose will be calculated 
using a weight of 80 kg. Total duration of study participation per subject is 6 
months. 
• 4 subjects will receive a single intravenous infusion of fresolimumab at a dose of 
4 mg/kg body weight. Maximal body weight for calculation of the drug dose is 80 
kg; for those weighing greater than 80 kg, the drug dose will be calculated using 
a weight of 80 kg. Total duration of study participation per subject is 6 months. 
 
The two doses have been selected based on safety data from previous studies 
conducted with fresolimumab that have shown that single doses up to 4 mg/kg have 
been well tolerated. 
 
Study Procedures 
This study will require six visits at a participating clinical site of the BBD consortium. 
Laboratory tests, ECGs, and radiographs obtained during this study will be interpreted 
locally by the PIs. 
 
A patient can be enrolled in the study only after an in-person screening visit which will be 
conducted at BCM. Day 1 visit, during which the participant will receive the study medication will 
have to be an in-person visit at BCM.  Participants are expected to come in for the follow up visits 
to the study site at BCM. However if there are unforeseen circumstances, or safety reasons 
(e.g.,  COVID-19) due to which a participant is unable to travel to BCM, for the follow up visits, an 
attempt will be made to accommodate study procedures virtually and/or at a remote site which 
is close to the place of the residence.  
 
 Screening visit procedures 
• Obtain informed consent. 
• Record medical history. 
• Determine if participant has used or is using an exclusionary medication. 
• Determine if participant plans to have invasive dental work or skeletal 
surgery during the period of the study. 
• Perform physical examination. 
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Measure height and weight. 
• Collect blood sample for laboratory tests (Safety: comprehensive 
metabolic panel (CMP), complete blood count (CBC), PT/INR, vitamin D 
testing, bone remodeling markers [serum C-terminal telopeptide of type 1 
collagen (CTX), Osteocalcin (Ocn), and amino-terminal propeptide of type 
I collagen (P1NP)], and lymphoblast culture).  
• Confirm that the subject has a genetic test demonstrating that s/he has a 
Glycine substitution in COL1A1 or COL1A2, or pathogenic variants in 
CRTAP, PPIB, or LEPRE1.  If not present, collect sample for DNA testing. 
• Collect urine sample for laboratory test (Safety: urinalysis OR urine dipstick, 
urine pregnancy test for women of child- bearing age). 
• Perform skeletal survey (if historical x-rays are not available to 
review and ascertain the bony deformities or scoliosis). 
• Perform a 12-lead EKG. 


18 
 
 
•  Perform tuberculosis screening by a positive purified protein derivative 
(PPD) test or Interferon-gamma release assay. 
 
Prior to enrollment (Day 1) screening eligibility criteria for each subject will be 
reviewed by participating investigators.  Individuals who meet the criteria for 
enrollment will have Study Visit 1 within 60 days of screening. 
 
Day 1 visit procedures (Baseline) 
• Review and confirm that the subject meets all criteria for inclusion.  
• Confirm that the subject would not be excluded based on screening 
laboratory tests, a clinically significant infection, a recent fracture or use of 
any medications since the screening visit that would exclude them from 
participation.  
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Collect urine from female subjects to determine pregnancy status. 
• Perform DXA scan of the lumbar spine (test may not be performed if 
there is significant scoliosis or the patient has had spinal 
instrumentation). 
• Perform DXA scan total hip and femoral neck (test may not be performed 
if there are pins or rods in the region of interest). 
• Collect blood for pharmacokinetics prior to infusion of fresolimumab 
• Intravenous Infusion of fresolimumab over 30 minutes. 
• Collect blood for pharmacokinetics after the end of the infusion. 
• Subjects will be monitored for three hours for any infusion-related 
reactions (document adverse events) and will be discharged home. 
 
Day 15 visit procedures 
• Perform a physical exam. 
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Record adverse events assessment including history of any oral or 
mucosal bleeding. 
• Perform a 12-lead EKG. 
• Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Lymphoblast culture). 
• Collect urine sample for laboratory test (Safety: urinalysis OR urine dipstick). 
• Document adverse events. 
 
Day 30 visit procedures 
• Perform a physical exam. 
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers). 
• Collect urine sample for laboratory test (Safety: urinalysis OR urine dipstick). 
• Record adverse events assessment including history of any oral or 


Protocol Version Date: 24Feb17 
19 
 
 
mucosal bleeding. 
 
Day 90 visit procedures 
• Perform a physical exam. 
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Record medical history. 
• Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers). 
• Collect urine sample for laboratory test (Safety: urinalysis OR urine dipstick). 
• Document adverse events. 
 
Day 180 visit procedures 
• Perform a physical exam. 
• Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Record adverse events. 
• Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers). 
• Collect urine sample for laboratory test (Safety: urinalysis OR urine dipstick) 
• Perform a 12-lead EKG. 
• Perform DXA scan of the lumbar spine (test may not be performed if 
there is significant scoliosis or the patient has had spinal 
instrumentation). 
• Perform DXA scan total hip and femoral neck (test may not be performed 
if there are pins or rods in the region of interest). 
• Document adverse events. 
 
4.8 Repeat Dose Administration study (Stage 2) 
Primary objective 
To evaluate the safety of repeat dose administrations of fresolimumab in adults with 
moderate-to-severe OI with respect to: 
• Vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• Laboratory variables. 
• EKG. 
• Adverse events and serious adverse events. 
 
Secondary Objectives 
Effect of fresolimumab with respect to: 
• Markers of bone turnover in blood (type 1 procollagen, N-terminal 
or P1NP, Osteocalcin or Ocn, and C-terminal telopeptide or 
CTX). 
• Areal bone mineral density (aBMD) at the hip or the lumbar spine as 
measured by dual-energy X-ray absorptiometry (DXA) scan. 
• Bone density and estimated strength by pQCT of forearm. 
• Pain score as assessed by Numeric Rating Scale (NRS). 


20 
 
 
• Forced expiratory volume in 1 second (FEV1), forced vital capacity 
(FVC) as measured by pulmonary function tests 
• QOL as assessed by PROMIS®. 
• Functional capacity as assessed by the 6-minute walk test. 
 
Dose 
Group 1 
• 4 subjects receive four intravenous infusions of fresolimumab- months 0, 
3, 6, and 9, with a follow up period of 3 months (total duration of study 
participation 12 months). 
 
Group 2 
• 4 subjects receive two intravenous infusions of fresolimumab- months 0 
and 6, with a follow up period of 6 months (total duration of study 
participation 12 months). 
 
The dose regimen has been selected based on the duration of bone remodeling cycle 
that can vary from 3-6 months. The dose regimen and duration are similar to studies 
that have been conducted with denosumab (Prolia ®), a monoclonal antibody that 
inhibits receptor activator of nuclear factor kappa-B ligand (RANKL), which has been 
approved for the treatment of osteoporosis. 24 Repeat doses of both 1 mg/kg and 4 
mg/kg body weight of fresolimumab, have been studied in a trial titled  “A Phase 2, 
Multicenter, Double-Blind, Parallel Dosing, Randomized Study of Fresolimumab or 
Placebo in Patients with Steroid-Resistant Primary Focal Segmental Glomerulosclerosis” 
under IND 100054. This study had four monthly IV administrations of fresolimumab at 
either 1 mg/kg or 4 mg/kg or placebo with treatment duration of 12 weeks and 
observation duration of 24 weeks after last dose of study medication. The dose and the 
number of doses being proposed for our study are similar but far less frequent than used 
in the study under IND 100054. 
 
Study Procedures 
This study will require up to eight visits at a participating clinical site of the BBD consortium.  
Laboratory tests, ECGs, and radiographs obtained during this study will be interpreted locally by 
the PIs. 
A patient can be enrolled in the study only after an in-person screening visit which will be 
conducted at BCM. Day 1 visit, during which the participant will receive the study medication will 
have to be an in-person visit at BCM.  Participants are expected to come in for the follow up visits 
to the study site at BCM. However if there are unforeseen circumstances, or safety reasons 
(e.g.,  COVID-19) due to which a participant is unable to travel to BCM, for the follow up visits, an 
attempt will be made to accommodate study procedures virtually and/or at a remote site which 
is close to the place of the residence.  
 
 Screening visit procedures 
• 
Obtain informed consent. 
• 
Record medical history. 
•  Determine if participant has used or is using an exclusionary medication. 
• 
Determine if participant plans to have invasive dental work or skeletal 
surgery during the period of the study 
• 
Perform physical examination. 


Protocol Version Date: 24Feb17 
21 
 
 
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Measure height, weight, arm span. 
• 
Collect blood sample for laboratory tests (Safety: comprehensive 
metabolic panel (CMP), complete blood count (CBC), PT/INR, vitamin D 
testing, bone remodeling markers [serum C-terminal telopeptide of type 1 
collagen (CTX), Osteocalcin (Ocn), and amino-terminal propeptide of type 
I collagen, P1NP)], and lymphoblast culture for gene expression studies). 
• 
Confirm that the subject has a genetic test demonstrating that s/he has a 
Glycine substitution in COL1A1 or COL1A2, or pathogenic variants in 
CRTAP, PPIB, or LEPRE1.  If not present, collect sample for DNA testing. 
• 
Collect urine sample for laboratory test (Safety: urinalysis OR urine 
dipstick, urine pregnancy test for women of child-bearing age). 
• 
Perform skeletal survey (if historical x-rays are not available to 
review and ascertain the bony deformities or scoliosis). 
• 
Perform a 12-lead EKG. 
• 
Perform tuberculosis screening by a positive purified protein derivative 
(PPD) test or Interferon-gamma release assay. 
 
Prior to enrollment (Day 1) screening eligibility criteria for each subject will be 
reviewed by participating investigators.  Individuals who meet the criteria for 
enrollment will have Study Visit 1 within 60 days of screening.   
 
Day 1 visit procedures (Baseline) 
• 
Review and confirm that the subject meets all criteria for inclusion.  
• 
Confirm that the subject would not be excluded based on screening 
laboratory tests, a clinically significant infection, a recent fracture or use of 
any medications since the screening visit that would exclude them from 
participation.  
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Collect urine from female subjects to determine pregnancy status. 
• 
Perform DXA scan of the lumbar spine (test may not be performed if 
there is significant scoliosis or the patient has had spinal 
instrumentation). 
• 
Perform DXA scan total hip and femoral neck (test may not be performed 
if there are pins or rods in the region of interest). 
• 
Perform a peripheral quantitative CT (pQCT) of the forearm. 
• 
Perform a pulmonary function test. 
• 
Perform a 6-minute walk test. 
• 
Collect Numeric Rating Scale (NRS) and PROMIS® 29 questionnaire 
responses. 
• 
Collect blood for immunogenicity (measure antibodies against 
fresolimumab) and for pharmacokinetics prior to infusion of fresolimumab. 
• 
Intravenous infusion of fresolimumab over 30 minutes. 
• 
Collect blood for pharmacokinetics after the end of the infusion. 
• 
Subjects will be monitored for three hours for any infusion-related 


22 
 
 
reactions (document adverse events) and will be discharged home. 
 
Day 15 visit procedures 
• 
Perform a physical exam. 
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Perform a 12-lead EKG. 
• 
Collect blood for laboratory tests (Pharmacokinetics; 
Immunogenicity; Lymphoblast culture). 
• 
Document adverse events include bleeding assessment. 
 
Day 30 visit procedures 
• 
Perform a physical exam. 
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers; Immunogenicity; 
Lymphoblast culture). 
• 
Collect urine sample for safety test (urinalysis OR urine dipstick). 
• 
Record adverse events assessment including history of any oral or 
mucosal bleeding. 
 
Day 90 visit procedures 
• 
Perform a physical exam. 
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Collect NRS responses. 
• 
Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers; Immunogenicity; 
Lymphoblast culture). 
• 
Collect urine sample for laboratory test (Safety: urinalysis OR urine 
dipstick, urine pregnancy test for women of child-bearing age). 
• 
Perform a 12-lead EKG. 
• 
The cohort of subjects randomized to receive four infusions of study 
drug will receive second dose of fresolimumab. The cohort of subjects 
randomized to receive two infusions of study drug will not receive any 
drug during this visit. 
• 
Intravenous infusion of fresolimumab over 30 minutes. 
• 
Collect blood for pharmacokinetics after the end of the infusion. 
• 
Document adverse events. 
 
Day 180 visit procedures 
• 
Perform a physical exam. 
• 
Measure vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Collect NRS and PROMIS® 29 responses. 
• 
Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 


Protocol Version Date: 24Feb17 
23 
 
 
Pharmacokinetics Bone remodeling markers; Immunogenicity) 
• 
Collect urine sample for laboratory test (Safety: urinalysis OR urine 
dipstick, urine pregnancy test for women of child-bearing age.) 
• 
The cohort of subjects randomized to receive four infusions of study 
drug will receive the third dose of fresolimumab. The cohort of subjects 
randomized to receive two infusions of study drug will receive the 
second. 
• 
Intravenous Infusion of fresolimumab over 30 minutes. 
• 
Collect blood for pharmacokinetics after the end of the infusion. 
• 
Document adverse events 
 
Day 270 visit procedures 
• 
Perform a physical exam. 
• 
Measure Vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature. 
• 
Collect NRS responses. 
• 
Collect blood for laboratory tests (Pharmacokinetics; Bone remodeling 
markers). 
• 
Collect urine for urine pregnancy test in women. 
• 
The cohort of subjects randomized to receive four infusions of study 
drug will receive fourth dose of fresolimumab. The cohort of subjects 
randomized to receive two infusions of study drug will not receive any 
drug during this visit. 
• 
Intravenous Infusion of fresolimumab over 30 minutes. 
• 
Collect blood for pharmacokinetics after the end of the infusion. 
• 
Document adverse events. 
 
Day 360 visit procedures 
• 
Perform a physical exam 
• 
Measure Vital signs - heart rate, blood pressure, respiratory rate, and body 
temperature (including height, weight, arm span) 
• 
Collect NRS and PROMIS® 29 responses 
• 
Collect blood for laboratory tests (Safety: CBC, CMP, PT/INR; 
Pharmacokinetics; Bone remodeling markers; Immunogenicity; 
Lymphoblast culture) 
• 
Collect urine sample for laboratory test (Safety: urinalysis OR urine 
dipstick, urine pregnancy test for women of child-bearing age.) 
• 
Perform a 12-lead EKG 
• 
Perform DXA scan of the lumbar spine (test may not be performed if 
there is significant scoliosis or the patient has had spinal 
instrumentation) 
• 
Perform DXA scan total hip and femoral neck (test may not be performed 
if there are pins or rods in the region of interest) 
• 
Perform a peripheral QCT 
• 
Perform a pulmonary function test 
• 
Perform a 6-minute walk test 
• 
Document adverse events. 


24 
 
 
• 
Subjects’ participation will conclude when they are discharged home 
following this visit. 
 
4.9 Data Elements 
Once referred for screening, the participant’s diagnostic testing will be reviewed to 
assure that the correct OI classification has been made and eligibility requirements are 
met based on study inclusion and exclusion criteria. Data will be collected at study visits 
per the Schedule of Events for each study group. We will use a variety of methods to 
obtain these data. Certain information will be obtained from a historical review of existing 
charts and laboratory/treatment data. Other data will be obtained from patients or     
their families through a standard interview, examination or laboratory/functional testing. 
The investigators who will perform functional assessments and other critical evaluations 
will be included as investigators on their local institution’s IRB application.   
 
Medical History: Medical history will be recorded on a history and physical examination 
form. 
 
12-lead EKG: EKG at the screening visit then at 2 subsequent study visits for all study 
participants. 
 
Bone mineral density:  A dual-energy x-ray absorptiometry (DXA) at the lumbar spine, 
total hip and femoral neck will be performed. 
 
X-rays of the spine: Standard posterio-anterior and lateral views will be taken, 
preferably in the standing position. If this is not possible, these radiographs will be 
obtained in the sitting position. If participants not able to sit, the X-rays will be taken in 
the supine position. Taking each of the two views on a single film (skull base to sacrum) 
is preferred. All radiographic images will be reviewed at the screening visit to determine 
eligibility.  Historical surveys are acceptable if X-rays taken demonstrate the boney 
abnormalities that are required as inclusion criteria. 
 
Peripheral Quantitative CT of the forearm: A peripheral quantitative CT (pQCT) will 
be performed at Baseline and exit visits for those subjects participating in the 2nd 
stage of the study to determine bone mineral density. Measurements will be 
performed at the non-dominant forearm. In case of recent fracture (< 2 years before) 
or the presence of metal at this measurement site, the contralateral forearm will be 
used. Two sites at the forearm will be analyzed, the metaphysis ('4% site') and the 
diaphysis ('65% site'). Trabecular bone is analyzed at the 4% site, cortical bone is 
analyzed at the 65% site. The main outcome measures of these analyses are 
trabecular volumetric bone mineral density (vBMD, 4% site), cortical vBMD (65% 
site), bone mineral content (both sites) and section modulus (a measure of bone 
strength, 65% site). 
 
Pulmonary function tests: These will be performed in participants enrolled in the 2nd 
stage of the study at baseline and exit visits, according to the American Thoracic 
Society guidelines. Lung volume measurements will be determined by helium dilution. 
Arm span will be measured to obtain a corrected height and will be used for calculating 
predicted lung volumes and flow rates. Vital capacity (VC), residual volume (RV), total 


Protocol Version Date: 24Feb17 
25 
 
 
lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second 
(FEV1), and FEV1/FVC will be calculated for each participant to determine whether 
participants suffer from pulmonary compromise due to an underlying tissue disorder, 
which may go unrecognized without PFT, or if scoliosis is the actual cause for 
pulmonary compromise. Restrictive lung disease will be defined as a reduction in the 
VC and a ratio of FEV1/FVC greater than or equal to 80%. Obstructive lung disease will 
be defined as a reduction in FEV1 and a ratio of FEV1/FVC less than 80%8. 
 
6 Minute Walk Test: A 6 minute walk test will be performed at the baseline and exit 
visits for those subjects enrolled in the 2nd stage of the study to determine the subject’s 
mobility. 
 
Numeric Rating Scale: Pain will be evaluated using the Numeric Rating Scale (NRS). 
This is a self-report assessment scale for patients who are able to use numbers to rate 
the intensity of their pain. 
 
PROMIS® 29: This tool will be assessed at the screening, day 180 and day 360 study 
visits for participants enrolled in the 2nd stage of the study. 
 
All study elements are interpreted locally by the respective PIs. 
All laboratory testing will be performed using local laboratories and will be interpreted 
by the respective PIs.   


26 
 
 
4.10 Schedule of Events 
Single Dose Administration (Stage 1) 
Procedures 
Screening 
Treatment 
1 
15 
30 
90 
180 
-60 d window 
 
+3 d window 
+7 d window 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
Vital signs - heart rate, blood pressure, 
respiratory rate, and body temperature 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
Blood/Urine for Safety labs (CBC, CMP, 
P T / I N R ,  Urinalysis OR Urine Dipstick) 
X 
 
X 
X 
X 
X 
Blood for Bone remodeling markers (P1NP, 
Osteocalcin, CTX) 
X 
 
 
X 
X 
X 
Blood for Vitamin D testing 
X 
 
 
 
 
 
Blood for lymphoblast culture 
X 
 
X 
 
 
 
Urine Pregnancy test (if applicable) 
X 
X 
 
 
 
X 
Blood for Genetic Testing for COL1A1, 
COL1A2, CRTAP, P3H1, or PPIB mutations a 
X 
 
 
 
 
 
Skeletal survey b 
X 
 
 
 
 
 
12 Lead EKG 
X 
 
X 
 
 
X 
DXA Lumbar Spine c 
 
X 
 
 
 
X 
DXA total hip and femoral neck a 
 
X 
 
 
 
X 
Infusion of fresolimumab 
 
X 
 
 
 
 
Pharmacokinetics 
 Xe 
X 
X 
X 
X 
Adverse event documentation 
X 
X 
X 
X 
X 
 
a Genetic testing will be done only if the genotype is not known 
b If skeletal films are available for review to ascertain the bony deformities or scoliosis, this test will not be done 
c Test may not be performed if there is significant scoliosis or the patient has had spinal instrumentation 
d Test may not be done if there are pins or rods in the region of interest 
e For Day 1 of the study, PK samples will be obtained prior to the infusion of fresolimumab and after the end of the infusion. 


Protocol Version Date: 24Feb17 
27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Genetic testing will be done only if the genotype is not known, 
b If skeletal films are available for review to ascertain the bony deformities or scoliosis, this test will not be done 
c this test may not be performed if there is significant scoliosis or the patient has had spinal instrumentation 
d this test may not be done if there are pins or rods in the region of interest 
e Will not be performed if bone deformities preclude assessment 
f Will not be performed if subject is randomized into the study group to receive 2 infusions. 
g Any patient who experiences clinically significant bleeding will be referred to their primary physicians or hematology specialists for appropriate work up 
# PK samples will be obtained prior to the infusion of fresolimumab and after the end of the infusion.  
NOTE: For documentation of AE and safety, specific information regarding including history of bleeding episodes, physical examination for 
peripheral edema, hematomas, and gingival hyperplasia, and urinalysis OR a urine dipstick to evaluate for blood will be conducted. 
Repeat Dose Administration (Stage 2) 
Procedures 
Screening 
Treatment 
1 
15 
30 
90 
180 
270 
360 
- 60 d window 
 
+3 d window 
+ 14 d window 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs - heart rate, blood 
pressure, respiratory rate, and body 
temperature 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
X 
Weight 
X 
 
 
 
 
 
 
X 
Arm-span 
X 
 
 
 
 
 
 
X 
Blood/urine for Safety labs (CBC, 
CMP, PT/INR, Urinalysis OR Urine 
X 
 
X 
X 
X 
X 
 
X 
Blood for Vitamin D testing 
X 
 
 
 
 
 
 
 
Bone remodeling markers (P1NP, 
Ocn, CTX) 
X 
 
 
X 
X 
X 
X 
X 
Blood for PK# 
 
X 
X 
X 
X 
X 
X 
X 
Blood for lymphoblast culture 
X 
 
X 
X 
X 
 
 
X 
Blood for Antibody/Immunogenicity 
testing 
 
X 
X 
X 
X 
X 
 
X 
Blood for Genetic Testing for 
COL1A1, COL1A2, CRTAP, P3H1, 
X 
 
 
 
 
 
 
 
Urine Pregnancy test (if applicable) 
X 
X 
 
 
X 
X 
X 
X 
Skeletal survey b 
X 
 
 
 
 
 
 
 
12-lead EKG 
X 
 
X 
 
X 
 
 
X 
Infusion of fresolimumab 
 
X 
 
 
Xf 
X 
Xf 
 
DXA Lumbar Spine c 
 
X 
 
 
 
 
 
X 
DXA total hip and femoral neck a 
 
X
 
 
 
 
 
X
Peripheral quantitative CT (pQCT) 
of the forearm e 
 
X 
 
 
 
 
 
X 
NRS 
 
X 
 
 
X 
X 
X 
X 
PROMIS® 29 QOL 
 
X 
 
 
 
X 
 
X 
Pulmonary function test 
 
X 
 
 
 
 
 
X 
6-minute Walk test 
 
X 
 
 
 
 
 
X 
Adverse event documentation 
 
X 
X 
X 
X 
X 
X 
X 
Bleeding Assessmentg 
 
 
X 
X 
 
 
 
 


28 
 
 
5. Data and Safety Monitoring Plan 
The study protocol will be reviewed and approved by the National Institutes of Health 
(NIH) before submission to individual center IRBs for approval.  Participant enrollment 
may only begin with IRB approved consent forms. 
 
5.1 Study Oversight 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH 
appointed Data Safety Monitoring Board (DSMB) has oversight responsibility of the 
Data Safety Monitoring Plan (DSMP) for this clinical trial. The DSMB will review accrual, 
patterns and frequencies of all adverse events, and protocol compliance every 6 
months. The DSMB makes recommendations to the NIH regarding the continuation 
status of the protocol. 
 
Each site’s Principal Investigator and their research team (co-Investigators, research 
nurses, clinical trial coordinators, and data managers) are responsible for identifying 
adverse events. Aggregate report- detailed by severity, attribution (expected or 
unexpected), and relationship to the study drug/study procedures – will be available 
from the DMCC for site review.  Adverse events will be reviewed monthly by the 
research team.  A separate report detailing protocol compliance will also be available 
from the DMCC for site review on a monthly basis. The research team will then evaluate 
whether the protocol or informed consent document requires revision based on the 
reports. 
 
5.2 Adverse Event Definitions and Standards 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an 
unfavorable and unintended sign, symptom or disease associated with a participant’s 
participation in a Rare Diseases Clinical Research Network study.” 
 
Serious adverse events include those events that: “result in death; are life-threatening; 
require inpatient hospitalization or prolongation of existing hospitalization; create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.” 
 
An unexpected adverse event is defined as any adverse experience, the specificity or 
severity of which is not consistent with the risks of information described in the protocol. 
 
Expected adverse events are those that are identified in the research protocol as having 
been previously associated with or having the potential to arise as a consequence of 
participation in the study. 
 
All reported adverse events will be classified using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) developed and maintained by CTEP 
at National Cancer Institute. 
 
 
 


Protocol Version Date: 24Feb17 
29 
 
 
5.3 Expected/ Known Risks/ Discomforts/ Adverse Event Associated with 
Study Intervention and Procedures: Definition of Expected Adverse 
Events 
 
Study Drug 
TGFβ is a cytokine that has an important physiological role in the regulation of cell 
proliferation and differentiation, extracellular matrix production, angiogenesis, immune 
regulation and embryonic development. However, sustained overactivity of TGFβ may 
play a pathophysiological role in disease states such as fibrotic diseases such as FSGS, 
IPF, and in oncology. Fresolimumab, a human IgG4 antibody which neutralizes TGFβ1, 
2, and 3, has potential in the treatment of fibrotic and oncologic diseases. Given the 
pleiotropic effects of TGFβ, side effects associated with fresolimumab therapy may be 
observed. The following is a description of potential risks, precautions, and 
contraindications based on the results of preclinical safety studies and clinical data. 
 
Epithelial Changes Including Keratoacanthoma 
Based on the clinical experience to date, the main epithelial adverse reaction to 
fresolimumab appears to be adverse events involving the skin, most notably 
keratoacanthoma (KA) and squamous cell carcinoma (SCC). Keratoacanthomalike 
epithelial lesions developed in 4 patients who received multiple doses of fresolimumab in 
the Phase 1 oncology study of patients with advanced melanoma or RCC. Skin biopsies 
were sent for an independent, blinded pathological analysis from these patients. On 
review, the 2 cases diagnosed at the site as SCC were interpreted as representing KAs, 
and in one case involving a patient with prior SCC, an atypical squamous-epithelial-
proliferation with KA-like features was read as most consistent with SCC. Therefore, 
subjects with personal history of cancer are excluded from this study. 
 
Acceleration of Neoplasia 
Available literature suggests neutralization of TGFβ does not cause de novo 
malignancies. In advanced cancers, TGFβ neutralization may ameliorate cancer 
progression; however, in certain settings such as in the presence of premalignant 
lesions, it is possible that neutralization of TGFβ may contribute to 
premalignant/malignant transformation. 
 
As noted above, 2 melanoma patients in the oncology trial developed SCC. One of the 
2 patients had a history of SCC and the lesions of both patients spontaneously 
regressed as is consistent with the natural history of KAs. However, the development of 
KA/SCC has been mechanistically linked to TGFβ signaling in patients with Ferguson- 
Smith disease. Therefore, the risk of SCC development is likely mechanistically distinct 
from the theoretical risk of acceleration of neoplasia. 
 
One patient with FSGS experienced a primitive neuroectodermal tumor (PNET) 2 years 
after a single 1 mg/kg dose of fresolimumab. The patient died approximately one year 
later from complications of PNET, primarily respiratory failure. The investigator 
assessed the PNET to be unrelated to fresolimumab. The Data Monitoring Committees 
(DMCs) of both the oncology and FSGS Phase 1 studies reviewed this case and 
concluded that the relationship between fresolimumab and PNET was unlikely because 
the patient received a single dose of fresolimumab 2 years prior to identification of 


30 
 
 
the tumor and had prior exposure to multiple immunosuppressive medications. 
 
Patients receiving fresolimumab should be carefully monitored for the development of 
malignancies. 
 
Bleeding and Anemia 
Across the clinical studies, the majority of bleeding adverse events reported have been 
mild, self-limited events of gum bleeding without associated gingival lesions and nose 
bleeding without discrete nasal lesions. Anemia was not seen with these mild, self- 
limited events. Patients should be carefully monitored for the development of anemia 
and bleeding while receiving fresolimumab. 
 
Immune Modulation 
In preclinical studies, there did not appear to be any significant immune-mediated 
toxicity associated with long-term neutralization of TGFβ in normal mice. No evidence of 
significant immune dysregulation has been seen in clinical studies to date. Three 
patients with malignant melanoma and 1 patient with FSGS developed non- 
disseminated herpes zoster. The FSGS patient had a history of herpes zoster. In 1 of 
the 4 patients, the herpes zoster event was considered by the reporting physician to be 
related to therapy. It remains to be determined if fresolimumab increases the risk of 
herpes zoster. Patients should be carefully monitored for the development of herpes 
zoster.  One FSGS patient developed transient vitiligo and 2 oncology patients 
developed hypopigmentation of skin or hair. In all 3 patients, the events were 
considered by the reporting physician to be treatment-related. The mechanism by which 
fresolimumab could be associated with vitiligo/hypopigmentation could potentially be via 
immune modulation however alternative non-immune mechanisms may play a role. 
 
Reproductive Function 
The effects of fresolimumab on male and female reproductive function or fetal growth 
and development have not been investigated in formal toxicity studies. Maternal TGFβ 
levels are elevated during normal pregnancy and may have an important role in 
establishment and preservation of pregnancy. Additionally, TGFβ has a role in 
embryonic development including organogenesis. Fresolimumab is an antibody and is 
expected to be able to cross the placenta and enter the fetal circulation during 
pregnancy. The effects of fresolimumab in this situation are unknown. There is a 
theoretical risk that inhibiting TGFβ during pregnancy may adversely affect the 
establishment and preservation of pregnancy or have adverse effects on embryonic or 
fetal growth and development. Pregnant or lactating women are excluded from clinical 
studies of fresolimumab. Women who become pregnant or start lactating during the 
study will be discontinued from study treatment. Sexually active men or sexually active 
women of childbearing potential (premenopausal and not surgically sterile) must use 
contraception or abstinence when being treated with fresolimumab. 
 
Overdose 
Animal studies have not clearly identified any acute dose related toxic effects. In the 
event of fresolimumab overdose, the administration should be immediately discontinued 
and appropriate precautions should be taken. 
 
 
 


Protocol Version Date: 24Feb17 
31 
 
 
Contraindications and Warnings 
There are no established contraindications to fresolimumab. Patients with significant 
hypersensitivity to fresolimumab or product components are excluded from clinical 
studies with fresolimumab. Continued treatment with fresolimumab should be carefully 
re-evaluated if significant hypersensitivity is observed.  Pregnant or lactating women are 
excluded from clinical studies of fresolimumab. Women who become pregnant or start 
lactating during the study will be discontinued from study treatment. 
 
Study Procedures 
Blood samples will be drawn for safety labs. It is expected that there may be bruising and 
mild discomfort at the site of needle insertion when phlebotomy is performed. Fainting 
may even occur. 
 
Participants will be exposed to radiation during dual-energy X-ray absorptiometry 
scanning and radiographs. The total amount of radiation that the participant will receive 
in this study is about 1.1 mSv or 110 mrem, and is approximately equivalent to a uniform 
whole body exposure of 133 days of exposure to natural background radiation. (Ref 
http://www.doseinfo-radar.com/RADARDoseRiskCalc.html). Though the biological 
effects of diagnostic radiation on humans have not been studied directly, the potential 
risk to an individual associated with techniques used for the assessment of bone status 
is believed to be very small since radiation doses are low. In 2012 the United Nations 
Scientific Committee on the Effects of Atomic Radiation stated that for typical 
background radiation levels (1–13 mSv per year), it is not possible to account for any 
health effects. 
 
Patients may find the pulmonary function testing, function and mobility assessments and 
hearing tests to be tiring. 
 
Protection from Risk: The study will be conducted in the Clinical and Translational 
Science Award (CTSA) Centers or research facilities of our respective institutions 
comprising the BBD Consortium whenever possible. When a CTSA/research facility is 
not available, study visits will be conducted in the investigator’s clinic. 
 
The study implementers will be nursing staff/coordinators of the Centers with a long 
experience in care of individuals with OI. If any participant should incur any unexpected 
and untoward event during the testing procedure, the emergency caregivers, would 
become available on an immediate basis to provide necessary emergent management. 
 
Female participants will have no radiographic procedures while pregnant. 
 
5.4 Adverse Event Reporting Timeline 
• Within 24 hours (of learning of the event), investigators must report any reportable 
Serious Adverse Event (SAE) that: 
o 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
o 
Is Unexpected/Unanticipated 
• Investigators must report all other reportable SAEs within 5 working days (of learning 
of the event). 
• All other (suspected) reportable AEs must be reported to the RDCRN within 20 


32 
 
 
working days of the notification of the event or of the site becoming aware of the 
event. 
 
Local institutional reporting requirements to IRBs, any GCRC oversight committee and 
the FDA, if appropriate, remain the responsibility of the treating physician and the Study 
Chair. 
 
5.5 RDCRN Adverse Event Monitoring System (AEMS) 
The study will utilize the DMCC Adverse Event Monitoring System.  Upon entry of a 
serious adverse event, the DMCC created AEMS will immediately notify the Study 
Chair, site PIs, the Medical Review Officer, and any additional agencies (if applicable- 
industry sponsor, CTEP) of any reported adverse events via email. 
 
Serious adverse events: The NIAMS OSMB/DSMB Safety Officer reviews the causality 
assessment determined by the PI and comment on attribution and recommend any 
needed action. A back-up notification system is in place so that any delays in review by 
the NIAMS OSMB/DSMB Safety Officer beyond a specified period of time are forwarded 
to a secondary reviewer. The DMCC Adverse Event Monitoring  System maintains audit 
trails and stores data (and data updated) and communication related to any adverse 
event in the study. 
 
Non-serious expected adverse events: Except those listed above as immediately 
reportable, non-serious expected adverse events that are reported to or observed by 
the investigator or a member of his/her research team will be submitted to the DMCC in 
a timely fashion (within 20 working days). The events will be presented in tabular form 
and given to the NIAMS OSMB/DSMB Safety Officer on a biannual basis. Local site 
investigators are also required to fulfill all reporting requirements of their local 
institutions. 
 
The DMCC will post aggregate reports of all reported adverse events for site 
investigators and IRBs. 
 
5.6 Unanticipated Problem Reporting 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
Per the definition, only a subset of adverse events would be characterized as 
unanticipated problems. There are other types of incidents, experiences, and outcomes 


Protocol Version Date: 24Feb17 
33 
 
 
that are not considered adverse events, but are characterized as unanticipated problems 
(e.g., breach of confidentiality or other incidents involving social or economic harm). 
Incidents or events that meet the OHRP criteria for unanticipated problems are to be 
reported to the IRB, per local institutional reporting requirements. Local institutional 
reporting requirements to IRBs, any GCRC oversight committee and the FDA, if 
appropriate, remain the responsibility of the treating physician and the Study Chair. 
 
5.7 Study Discontinuation 
The NIH, RDCRN DSMB and local IRBs (at their local site) have the authority to stop or 
suspend this trial at any time. This study may be suspended or closed if: 
• Accrual has been met. 
• The study objectives have been met. 
• The Study Chair / Study Investigators believe it is not safe for the study 
to continue. 
• The RDCRN DSMB suspends or closes the trial. 
• The NIH suspends or closes the trial. 
• The FDA suspends or closes the trial. 
• If 2 or more subjects experience Grade 4 or higher adverse events as defined 
by the CTCAE or life threatening AEs not covered by the CTCAE of the 
same preferred term related to the study medication, excluding conditions 
present at baseline or those directly related to skeletal complications of 
Osteogenesis Imperfecta. 
• If 2 or more subjects develop cancer. 
 
5.8 Subject Discontinuation 
An intent to treat approach will be used. All data acquired prior to termination for 
the reasons outlined below will be included in the primary analysis unless patient 
withdraws consent. Every effort will be made to conduct a final study visit with the 
participant and participants will be followed clinically until, if applicable, all 
adverse events resolve. 
• Withdrawal of consent. 
• Withdrawal by the participant. 
• Withdrawal by the investigator. 
• Intercurrent illness or event that precludes further visits to the study site or ability 
to evaluate disease (e.g.-mental status change, large pleural effusion). 
• Grade 4 or higher adverse events as defined by the CTCAE or life threatening 
AEs not covered by the CTCAE of the same preferred term related to the study 
medication, excluding conditions present at baseline or those directly related to 
skeletal complications of Osteogenesis Imperfecta. 
• Clinically significant allergy or hypersensitivity to fresolimumab. 
• Pregnancy. 
• QTc interval of > 500msec. 
• Clinically significant oral or mucosal bleeding with resulting hemoglobin of < 8g/dL. 
• Development of keratoacanthoma, squamous cell or basal cell carcinoma. 
• Development of any cancer. 
 
 


34 
 
 
5.9 Data Quality and Monitoring Measures 
As much as possible data quality is assessed at the data entry point using intelligent on- 
line data entry via visual basic designed screen forms. Data element constraints, 
whether independent range or format limitations or ‘relative’ referential integrity 
limitations, can be enforced by all methods employed for data input. QA reports assess 
data quality post-data entry. As we note, data quality begins with the design of the data 
collection forms and procedures and incorporates reasonable checks to minimize 
transcription and omission errors.  Of the more important quality assurance measures 
are the internal validity checks for reasonableness and consistency. 
• Data Monitoring: The RDCRN DMCC identifies missing or unclear data and 
generates a data query to the consortium administrator contact. 
• Data Delinquency Tracking: The Data Management and Coordinating Center will 
monitor data delinquency on an ongoing basis. 
 
5.10 Quality Control: Study Related Procedures 
Accurate, consistent and reliable data will be ensured through the use of standard 
practices and procedures. The DMCC will audit the Investigators’ source data against 
eCRF entries and verify that the data are accurate. 
 
6. Statistical Considerations 
This study is designed to assess the safety and tolerability of fresolimumab in patients 
with Osteogenesis Imperfecta. 
 
Sample Size: No formal sample size calculations were done  for this study. The sample 
size was selected to allow for an initial assessment of safety in this population and dose 
range and feasibility of enrollment in this rare disorder. The sample size is 8 for the 
single dose study and 8 for the repeat dose study. The overall enrollment will be 16. 
 
If needed, 2 additional patients will be enrolled in the repeat dose study to account for a 
drop-out rate of 20%. 
 
Treatment-Related Adverse Events will be summarized by dose groups.  Changes in 
vital signs, EKG, shifts in laboratory assessments and physical examinations, and 
patient-reported symptoms will be described. These will assess the primary endpoint of 
safety. Percent change in bone remodeling markers will be analyzed using a mixed 
model. BMD in the lumbar spine and the hip at 6 months for single dose study and 12 
months for the multiple dose study will be compared to pretreatment levels using a 
Wilcoxon Signed Rank test. Percent change in the variables of the pulmonary function 
tests, and change in the 6-minute walk tests, and Numeric Rating Scale (NRS) for     
pain will be evaluated by Wilcoxon Signed Rank test. Values for derived 
pharmacokinetic variables, including Cmax, area under the curve, distribution, half-life 
(T1/2a), elimination half-life (T1/2b), clearance (CL), and volume of distribution at steady 
state (Vss), will be calculated as previously described and summarized by dose-group 
using descriptive statistics. 
 
 
7. Data Management 
The results from Screening and data collected during the study will be recorded in the 


Protocol Version Date: 24Feb17 
35 
 
 
patient’s CRF (either paper or electronic CRF). To maintain confidentiality, the patients 
will be identified only by numbers or initials.  All source documents, records, and reports 
will be retained by the study site in accordance with 21 CFR 312.62(c). All primary data, 
or copies thereof (e.g., laboratory records, CRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and 
activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the study site archives. 
 
All study data will be collected via systems created in collaboration with the RDCRN 
Data Management and Coordinating Center and will comply with all applicable 
guidelines regarding patient confidentiality and data integrity. Biological samples 
collected for safety testing will be shipped to a CLIA certified laboratory for analysis. 
Biological samples collected for pharmacokinetics and drug efficacy will be shipped to 
Genzyme/Sanofi for analysis. 
 
7.1 Registration 
Registration of participants on this protocol will employ an interactive data system in 
which the clinical site will attest to the participant’s eligibility as per protocol criteria and 
obtain appropriate informed consent. IRB approval for the protocol must be on file at the 
DMCC before accrual can occur from the clinical site. 
 
The DMCC will use a system of coded identifiers to protect participant confidentiality and 
safety.  Each participant enrolled will be assigned a local identifier by the enrollment site.  
This number can be a combination of the site identifier (location code) and a serial 
accession number.  Only the registering site will have access to the linkage between this 
number and the personal identifier of the subject. When the participant is registered to 
participate in the study, using the DMCC provided web-based registration system, the 
system will assign a participant ID number. Thus each participant will have two codes: 
the local one that can be used by the registering site to obtain personal identifiers and a 
second code assigned by the DMCC.  For all data transfers to the DMCC both numbers 
will be required to uniquely identify the subject.  In this fashion, it is possible to protect 
against data keying errors, digit transposition or other mistakes when identifying a 
participant for data entry since the numbers should match to properly identify the 
participant. 
 
 
7.2 Data Entry 
Data collection for this study will be accomplished with online electronic case report 
forms. Using encrypted communication links, on-line forms will be developed that 
contain the requisite data fields. 
 
7.3 Laboratory Data Flow 
The DMCC will provide the study with a specimen database that allows tracking of 
the colletion, storage, and transfer of biological specimens, their submission to 
laboratories for testing, and the incorporation of laboratory results in the study 
database. 
 
7.4 Study Records Retention 
Patient files and other source data shall be kept for the maximum period of time to meet 


36 
 
 
all regulatory requirements, including those of the hospital or institution.  
 
Additional requirements for record retention are those required by the Food and Drug 
Administration for studies conducted under IND. The investigator shall retain records 
required to be maintained under this part for a period of 2 years following the date a 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.  
 
To fulfill requirements of the National Institutes of Health, grantees must retain the 
records pertinent to all studies supported by the award for three years from the date the 
final Federal Financial Report is submitted to NIH. 
 
7.5 Protocol Deviations 
The following protocol deviations will be recorded and summarized in the final report: 
1) eligibility (inclusion/exclusion) violations,  
2) study drug dosing violations,  
3) excluded medication violations,  
4) procedures performed outside the protocol-specified window, 
5) procedures not done,  
6) subject non-compliance and  
7) other, to be specified by the Investigator. 
 
8. Human Subjects 
 
8.1 GCP Statement 
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki, and that are consistent with Good Clinical 
Practice and all applicable regulatory requirements. 
 
8.2 Benefits 
The potential benefits of this study are: Severe osteogenesis imperfecta is both 
debilitating and progressive, and, as discussed previously, treatment options for adults 
with severe OI are limited. This work will have a direct impact on the treatment of these 
patients if it is found that therapy to decrease TGFβ activity in humans with severe OI is 
safe and has beneficial effects on bone as assessed by biochemical markers and a 
BMD. If successful, such therapy may be of significant benefit in reducing the fracture 
rates and pain, and improving the quality of life of individual study participants. In 
addition, participants will have access to routine medical care and follow-up. 
 
Severe osteogenesis imperfecta not only takes its toll on individuals who have the 
disease, but it also impacts society as a whole through the devastating loss of human 
potential resulting from the disorder. In addition, medical care for a person with type III 
or IV OI requires a variety of interventions, many of which are expensive and place an 
increased burden on our already overextended health care system. This phase I clinical 
trial should provide important information about a possible new therapy for patients with 
OI. If successful, such therapy may be of significant benefit in reducing the morbidity 
and improving the quality of life in these patients. As well as reducing the suffering of 


Protocol Version Date: 24Feb17 
37 
 
 
those with the most severe forms of OI, a beneficial therapy might decrease the 
frequency of medical interventions now required to manage the disease. No matter what 
the outcome of the trial, the information to be learned could be useful in optimizing 
therapy and clinical management of patients with this disorder. 
 
8.3 Risks 
 
The potential risks of this study are: 
 
Blood samples will be drawn for safety labs. It is expected that there may be bruising and 
mild discomfort at the site of needle insertion when phlebotomy is performed. Fainting 
may even occur. 
 
Participants will be exposed to radiation during dual-energy X-ray absorptiometry 
scanning and radiographs. The total amount of radiation that the participant will receive 
in this study is about 1.1 mSv or 110 mrem, and is approximately equivalent to a uniform 
whole body exposure of 133 days of exposure to natural background radiation. (Ref 
http://www.doseinfo-radar.com/RADARDoseRiskCalc.html). Though the biological 
effects of diagnostic radiation on humans have not been studied directly, the potential 
risk to an individual associated with techniques used for the assessment of bone status 
is believed to be very small since radiation doses are low. In 2012 the United Nations 
Scientific Committee on the Effects of Atomic Radiation stated that for typical 
background radiation levels (1–13 mSv per year), it is not possible to account for any 
health effects. 
 
Patients may find the pulmonary function testing, function and mobility assessments and 
hearing tests to be tiring. 
 
Protection from Risk: The study will be conducted in the Clinical and Translational 
Science Award (CTSA) Centers or research facilities of our respective institutions 
comprising the BBD Consortium whenever possible. When a CTSA/research facility is 
not available, study visits will be conducted in the investigator’s clinic. 
 
The study implementers will be nursing staff/coordinators of the Centers with a long 
experience in care of individuals with OI. If any participant should incur any unexpected 
and untoward event during the testing procedure, the emergency caregivers, would 
become available on an immediate basis to provide necessary emergent management. 
 
Female participants will have no radiographic procedures while pregnant. 
 
8.4 Written Informed Consent 
Written informed consent will be obtained from each participant before any study- 
specific procedures or assessments are done and after the aims, methods, anticipated 
benefits, and potential hazards are explained. The participant’s willingness to 
participate in the study will be documented in writing in a consent form, which will be 
signed by the participant with the date of that signature indicated. The investigator will 
keep the original consent forms and signed copies will be given to the participants.  It 
will also be explained to the participants that they are free to refuse entry into the study 
and free to withdraw from the study at any time without prejudice to future treatment. 


38 
 
 
Written or oral information about the study in a language understandable by the 
participant will be given to all participants. 
 
8.5 Process of Consent 
Consent forms will be given to potential participants prior to enrollment so that they have 
ample time to review the information and ask questions about the study. Forms can     
be mailed to the individuals in advance of their participation so that can read and ask 
questions before considering participating. If participation is proposed during a clinic 
appointment, a copy of the consent form may be sent home with the patient along with 
study staff contact information. Potential enrollees will be encouraged to take their time 
in reviewing the consent, call with questions, and contact study staff if interested in 
enrolling. 
 
 Anytime consent is obtained, it is incumbent on the individual obtaining the consent to 
ascertain whether the potential participant and his/her legal representative understand 
all aspects of the study. Obtaining informed consent is an unhurried, interactive process 
with questions asked of both the Investigator and potential participant. 
 
 For non-English speaking subjects, a translator will be available to aid in the 
explanation of the protocol and consent and to answer questions. A short consent form 
in the subject’s language will be used in addition to the full English consent form. 
 
 We will follow the usual consent procedures with those 18 years and over signing 
consent forms. All prospective participants will be asked to sign a medical records 
release form along with the study consent form. Medical records may be obtained to 
confirm OI diagnosis and affirm that none of the exclusionary conditions are present. 
Results from medical history and laboratory testing may be recorded. 
 
8.6 Certificate of Confidentiality 
To help protect participant privacy, a Letter of Confidentiality has been obtained from 
the National Institutes of Health (NIH). With this Certificate, the researchers cannot be 
forced to disclose information that may identify a study participant, even by a court 
subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings. The researchers will use the Certificate to resist any demands for 
information that would identify a participant, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of 
the United States Government that is used for auditing or evaluation of federally 
funded projects or for information that must be disclosed to meet the requirements of 
the federal Food and Drug Administration (FDA). 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical 
obligations to report child abuse or neglect and to prevent an individual from carrying 
out any threats to do serious harm to themselves or others. If keeping information 
private would immediately put the study participant or someone else in danger, the 
investigators would release information to protect the participant or another person. 
 
Department of Health and Human Services (DHHS) personnel may request identifying 


Protocol Version Date: 24Feb17 
39 
 
 
information for purposes of performing audits, carrying out investigations of DHHS grant 
recipients, or evaluating DHHS funded research projects. 
 
9. References 
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Barnes, A.M. et al. Deficiency of cartilage-associated protein in recessive lethal 
osteogenesis imperfecta. N Engl J Med 355, 2757-64 (2006). 
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Cabral, W.A. et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive 
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Dwan, K., et al. Bisphosphonate therapy for osteogenesis imperfecta. 
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12. 
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Uveges, T.E. et al. Alendronate treatment of the brtl osteogenesis imperfecta 
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couples bone resorption with formation. Nat Med 15, 757-65 (2009). 
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Grafe, I. et al. Excessive transforming growth factor-beta signaling is a common 
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beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. 
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Morris, J.C. et al. Phase I study of GC1008 (fresolimumab): a human anti- 
transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with 
advanced malignant melanoma or renal cell carcinoma. PLoS One 9, e90353 


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(2014). 
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Erlebacher, A. & Derynck, R. Increased expression of TGF-beta 2 in osteoblasts 
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