ACTIMMUNE in Intermediate Osteopetrosis

• ClinicalTrials.gov Identifier: NCT02666768
• Recruitment Status: Completed
• First Posted: January 28, 2016
• Last Update Posted: July 2, 2019
• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Collaborators: University of Minnesota; Horizon Pharma Ireland, Ltd., Dublin Ireland
• Information provided by (Responsible Party): Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Osteopetrosis	Drug: Interferon gamma-1b	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label Early Phase 2 Study With a Single Arm of Interferon Gamma-1b Treatment of Osteopetrosis
• Actual Study Start Date: February 22, 2016
• Actual Primary Completion Date: March 11, 2019
• Actual Study Completion Date: April 11, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: gamma interferon-1b; Gamma interferon-1b 100 mcg 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 Name: ACTIMMUNE

Outcome Measures

Primary Outcome Measures :

1. Number of participants with treatment related adverse events CTCAE v4.0 Grade 3 or higher [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Change in Bone Mineral Density (BMD) [ Time Frame: 12 months ]
   BMD measured by peripheral quantitative computed tomography (pQCT)
2. Change in white blood cell count (WBC) [ Time Frame: 12 months ]
3. Change in pain score [ Time Frame: 4 weeks ]
   Self reported pain intensity over the last 4 weeks

Eligibility Criteria

• Ages Eligible for Study: 1 Year and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

Torrance, California, United States, 90502

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55454

Sponsors and Collaborators

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• ClinicalTrials.gov Identifier: NCT02666768
• Other Study ID Numbers: 21549-01
• First Posted: January 28, 2016
• Last Update Posted: July 2, 2019
• Last Verified: June 2019

Additional relevant MeSH terms:

Osteopetrosis; Osteosclerosis; Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Interferons; Interferon-gamma; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents