Clinical trial NCT02584608: Use of ACTIMMUNE in Patients With ADO2
Official title: Phase 2a Study of Interferon Gamma-1b for the Treatment of Autosomal Dominant Type 2 Osteopetrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Osteopetrosis Type 2
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: Horizon Pharma Ireland, Ltd., Dublin Ireland
First posted: 2015-10-22
Enrollment: 12
Sex: ALL
Minimum age (years): 3
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Changes in Bone Resorption Markers From Baseline to 14 Weeks.
timeFrame: baseline, 14 weeks
Secondary outcomes:
measure: Change in Bone Turnover Markers Between After Completion of 6-12 Weeks of Treatment
timeFrame: 6-12 weeks
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
Study officials:
affiliation: Indiana University
name: Michael J Econs, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Imel EA, Liu Z, Acton D, Coffman M, Gebregziabher N, Tong Y, Econs MJ. Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis. J Bone Miner Res. 2019 Aug;34(8):1436-1445. doi: 10.1002/jbmr.3715. Epub 2019 May 13.