ACTIMMUNE in Intermediate Osteopetrosis

Open-label Early Phase 2 Study With a Single Arm of Interferon Gamma-1b Treatment of Osteopetrosis

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.

Study Overview

• Status: Completed
• Conditions: Osteopetrosis
• Intervention / Treatment: Drug: Interferon gamma-1b

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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: gamma interferon-1b; Gamma interferon-1b 100 mcg subcutaneous (SC) 3 times weekly for 12 months	Drug: Interferon gamma-1b; gamma interferon-1b dose escalation over first 4 weeks of study to 100 mcg SC 3 times weekly; Other Names: ACTIMMUNE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Bone Mineral Density (BMD)	BMD measured by peripheral quantitative computed tomography (pQCT) in bone area w/ BMD<169mg/m3	6 months
Change From Baseline in White Blood Cell Count (WBC)		6 months
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	6 months

Collaborators and Investigators

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Collaborators: University of Minnesota; Horizon Pharma Ireland, Ltd., Dublin Ireland
• Investigators: Principal Investigator: Lynda E Polgreen, MD, MS, Los Angeles BioMedical Research Center at Harbor-UCLA

Publications and helpful links

General Publications

• Lertwilaiwittaya P, Suktitipat B, Khongthon P, Pongsapich W, Limwongse C, Pithukpakorn M. Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis. Mol Genet Genomic Med. 2021 Jul;9(7):e1727. doi: 10.1002/mgg3.1727. Epub 2021 May 30.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2016
• Primary Completion (Actual): March 11, 2019
• Study Completion (Actual): April 11, 2019

Study Registration Dates

• First Submitted: June 23, 2015
• First Submitted That Met QC Criteria: January 25, 2016
• First Posted (Estimated): January 28, 2016

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: March 1, 2023

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; Antineoplastic Agents; Interferons; Interferon-gamma
• Other Study ID Numbers: 21549-01