Autosomal Dominant Osteopetrosis Type 2
Conditions
Brief summary
This study is an open label use of ACTIMMUNE for patients with Autosomal Dominant Osteopetrosis Type 2(ADO2). Effects of treatment will be evaluated after 14 weeks on ACTIMMUNE by bone resorption markers. This study will treat 12 patients with ADO2 recruited from Indiana University and Riley Hospital for Children at Indiana University Health.
Detailed description
This is a single center, open-label, dose-escalation study evaluating the efficacy, as defined by biochemical endpoints, and safety profiles of ACTIMMUNE in ADO2 subject. The investigators will treat 12 ADO2 subjects (children or adults age 3-65) with Actimmune® via a dose escalation protocol to a dose of 50 µg/m2 subcutaneously three times per week (TIW) for 8 weeks. If serum CTX does not increase by more than 25% by week 8, the dose will be increased to 100 µg/m2 subcutaneously TIW. Individual subjects in whom ACTIMMUNE administration increases bone resorption markers during the 14 weeks of this trial will be eligible for a 1 year extension trial.
Interventions
DRUGACTIMMUNE
Sponsors
Horizon Pharma Ireland, Ltd., Dublin Ireland
Indiana University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is diagnosed with clinically significant ADO2 as determined by the investigator. Individuals will be screened who have either been diagnosed with osteopetrosis and have a clinical phenotype and/or family history that is consistent with ADO2, have been told that they have an abnormally high bone density (\>3SD above mean for age and sex), or a clinical presentation consistent with ADO2. Initial contact will be with members of ADO2 kindreds who have known disease. 2. Provide written informed consent for competent adults and for minors provide written assent (if appropriate) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures 3. Ages 3 to 65 years inclusive. 4. Willing to use reliable method of contraception \[i.e. oral or patch hormonal contraceptives, intrauterine device, physical barrier methods, tubal ligation or hysterectomy, vasectomy (partner) or abstinence\] throughout the study and for 30 days after the last dose of study drug.
Exclusion criteria
1. Any unstable illness that in the investigator's opinion precludes participation in the study. 2. Serum calcium \>10.6 mg/dl at screening. 3. eGFR using the MDRD equation in adults (or the modified Schwartz equation for children) of \< 35 ml/min/1.73m2. 4. Nephrocalcinosis on screening ultrasound Grade 3 or higher \[18\]. Subjects with grade 3 or higher nephrocalcinosis will be excluded because we anticipate that use of study drug will increase bone resorption, resulting in increased urinary calcium excretion, which could, potentially, lead to worsening nephrocalcinosis. The grading scale is listed below: 0 = Normal 1. = Faint hyperechogenic rim around the sides and tip of the medullary pyramids 2. = More intense echogenic rim with echoes faintly filling the entire medullary pyramid 3. = Intense echoes throughout the medullary pyramid 4. = Solitary focus of echoes at the tip of the medullary pyramid/nephrolithiasis 5\. Use of any investigational product (drug or device) within 30 days prior to randomization. 6\. Subject reported history of hepatitis C. 7\. A recent (past 5 years) history of alcoholism or intravenous drug abuse. 8\. History of hypersensitivity to IFN-ɣ or E. coli-derived products. 9\. History of liver disease as evidenced by laboratory results at Screening (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\] \>2x the upper limit of normal), except when in the opinion of the investigator the liver disease is caused by extra medullary hematopoiesis. 10\. Pregnant or nursing women or those who plan on becoming pregnant during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Bone Resorption Markers From Baseline to 14 Weeks. | baseline, 14 weeks | Evaluate for changes in bone resorption markers including CTX, NTX/creatinine ratio between baseline and 14 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment | 6-12 weeks | Evaluate for changes in bone turnover markers including TRAP5b, NTX, CTX/TRAP5b ratio after 6-12 weeks of treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment ACTIMMUNE 50 µg/m2 subcutaneously three times per week (TIW) for 8 weeks
ACTIMMUNE | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous Total | 30.48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 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 | 0 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 | 11 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 10 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Changes in Bone Resorption Markers From Baseline to 14 Weeks.
Evaluate for changes in bone resorption markers including CTX, NTX/creatinine ratio between baseline and 14 weeks
Time frame: baseline, 14 weeks
Population: All subjects
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment | Changes in Bone Resorption Markers From Baseline to 14 Weeks. | Percent change of CTX | 2.2 percentage of change |
| Treatment | Changes in Bone Resorption Markers From Baseline to 14 Weeks. | Percent change of NTX/creatinine ratio | -2.1 percentage of change |
Secondary
Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment
Evaluate for changes in bone turnover markers including TRAP5b, NTX, CTX/TRAP5b ratio after 6-12 weeks of treatment.
Time frame: 6-12 weeks
Population: all subjects
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment | Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment | TRAP5B | -15.34 percentage of change |
| Treatment | Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment | NTX | -2.09 percentage of change |
| Treatment | Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment | CTX/TRAP5b ratio | 26.31 percentage of change |