Use of ACTIMMUNE in Patients With ADO2

Phase 2a Study of Interferon Gamma-1b for the Treatment of Autosomal Dominant Type 2 Osteopetrosis

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.

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Osteopetrosis Type 2
• Intervention / Treatment: Drug: ACTIMMUNE

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; ACTIMMUNE 50 µg/m2 subcutaneously three times per week (TIW) for 8 weeks	Drug: ACTIMMUNE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	baseline, 14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6-12 weeks

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Investigators: Principal Investigator: Michael J Econs, MD, Indiana University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): November 12, 2019
• Study Completion (Actual): November 12, 2019

Study Registration Dates

• First Submitted: October 20, 2015
• First Submitted That Met QC Criteria: October 21, 2015
• First Posted (Estimate): October 22, 2015

Study Record Updates

• Last Update Posted (Actual): January 8, 2021
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Osteosclerosis; Osteopetrosis; Anti-Infective Agents; Antiviral Agents; Interferon-gamma
• Other Study ID Numbers: 1510340687