Osteopetrosis
Conditions
Brief summary
This study evaluates the effects of ACTIMMUNE (IFN-γ1b) in children and adults with intermediate osteoporosis. All participants will receive treatment with ACTIMMUNE for 12 months. The investigators hypothesize that ACTIMMUNE will be tolerated by participants for the full 12 months and result in decreased disease severity.
Detailed description
Osteopetrosis is a rare inherited metabolic bone disease characterized by impaired osteoclast function resulting in defective bone resorption and generalized high bone mass and mineral density (BMD). In patients with severe disease, this high bone mass compromises bone marrow space leading to marrow failure and frequent infections, along with hepatosplenomegaly from extramedullary hematopoiesis. Currently, the only treatment for individuals with severe forms of osteopetrosis is hematopoietic cell transplantation (HCT), however survival in patients with osteopetrosis treated with HCT is only around 55%. Therefore, this treatment is only indicated in select individuals with life-threatening complications of their disease. Thus additional treatments for osteopetrosis are needed both for individuals who are not candidates for HCT and to prolong the time until HCT is needed. Interferon gamma (IFN-γ) is a naturally occurring cytokine that has been shown to have anti-microbial and anti-viral immunomodulatory effects, and is a potent stimulator of superoxide anion production which in turn promotes the formation and activation of osteoclasts. Two previous studies of IFN-γ1b in a small group of individuals with osteopetrosis found a decrease in trabecular bone area, an increase in marrow space, a decrease in the number of severe infections requiring antibiotic therapy, and an increase in superoxide generation by granulocyte-macrophage colonies. Therefore, the investigators will conduct an early phase 2, multi-center, open-label, 12-month clinical trial of ACTIMMUNE (IFN-γ1b) treatment of patients with intermediate osteopetrosis to determine the following: 1. The feasibility and tolerability of interferon gamma-1b treatment for 1 year in patients with intermediate osteopetrosis. Specifically, i) the ability to enroll patients, and ii) continued treatment throughout the 1-year observational period. 2. Change in immunologic and hematologic function, bone mineral density and osteoclast function, physical function and quality of life.
Interventions
DRUGInterferon gamma-1b
gamma interferon-1b dose escalation over first 4 weeks of study to 100 mcg SC 3 times weekly
Sponsors
University of Minnesota
Horizon Pharma Ireland, Ltd., Dublin Ireland
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of osteopetrosis; and * Anemia (Hemoglobin \<12 g/dL) not related to iron deficiency, or * Neutropenia (Neutrophil count \<1000 neutrophils/ul unsupported with cytokines), or * Thrombocytopenia (Platelet count \<50,000 cells x 109/L), or * History of impaired bone healing, or * ≥ 1 serious infection over prior year defined as requiring hospitalization and/or IV antibiotics, and * Age \> 1 year; and * Ability to travel to a study center for every 3-6 month study visits; and * Patient or parent/legal guardian is able and willing to provide informed consent. For patients 7 to 17 years of age, assent must also be provided.
Exclusion criteria
* 12 months or fewer following HCT; * Pregnancy or breastfeeding; * Known or suspected allergy to interferon gamma-1b or related products; * Participation in simultaneous therapeutic study that involves an investigational study drug or agent within 4 weeks of study enrollment; * ALT greater than 3 fold higher than normal; or * Any other social or medical condition that the Investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated or be detrimental to the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Adverse Events CTCAE v4.0 Grade 3 or Higher | 12 months | Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 defines a Grade 4 event as having life-threatening consequences, and/or urgent intervention indicated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Bone Mineral Density (BMD) | 6 months | BMD measured by peripheral quantitative computed tomography (pQCT) in bone area w/ BMD\<169mg/m3 |
| Change From Baseline in White Blood Cell Count (WBC) | 6 months | — |
| Change From Baseline in Pain | 6 months | Survey name: RAND 36-Item Health Survey (Version 1.0) Scale name: Pain Scale range: 0-100; Higher score means less pain |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gamma Interferon-1b Gamma interferon-1b 100 micrograms (mcg) subcutaneously (SC) 3 times weekly for 12 months
Interferon gamma-1b: gamma interferon-1b dose escalation over first 4 weeks of study to 100 mcg SC 3 times weekly | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Gamma Interferon-1b |
|---|---|
| Age, Continuous | 36.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Genotype Chloride Voltage-Gated Channel 7 (CLCN7) mutation | 3 Participants |
| Genotype T cell immune regulator 1 (TCIRG) mutation | 1 Participants |
| Genotype Unknown | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Number of Participants With Treatment Related Adverse Events CTCAE v4.0 Grade 3 or Higher
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 defines a Grade 4 event as having life-threatening consequences, and/or urgent intervention indicated.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gamma Interferon-1b | Number of Participants With Treatment Related Adverse Events CTCAE v4.0 Grade 3 or Higher | 0 Participants |
Secondary
Change From Baseline in Pain
Survey name: RAND 36-Item Health Survey (Version 1.0) Scale name: Pain Scale range: 0-100; Higher score means less pain
Time frame: 6 months
Population: One participant was \<18 years old so did not complete the RAND 36-Item Health Survey
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Gamma Interferon-1b | Change From Baseline in Pain | -0.8 change in units on the pain scale |
Secondary
Change From Baseline in White Blood Cell Count (WBC)
Time frame: 6 months
Population: Only 1 participant completed study to 12 months, so 6 month data are reported here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gamma Interferon-1b | Change From Baseline in White Blood Cell Count (WBC) | -0.5 x1000 cells/uL |
Secondary
Percent Change From Baseline in Bone Mineral Density (BMD)
BMD measured by peripheral quantitative computed tomography (pQCT) in bone area w/ BMD\<169mg/m3
Time frame: 6 months
Population: 1 participants withdrew due to flu-like side effects prior to 2nd pQCT measurement.~1 participant has no data for this measurement due to size of pQCT gantry.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gamma Interferon-1b | Percent Change From Baseline in Bone Mineral Density (BMD) | 0 percent change |