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Chronic Granulomatous DiseasePhase 1NCT02609932

Effect of IFN-γ on Innate Immune Cells

A Phase 1 study testing Administration of drug (Interferon-gamma 1-b) subcutaneously in people with Chronic Granulomatous Disease, run by University of Colorado, Denver at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The investigators hypothesize that neutrophils and monocytes developed under the influence of Interferon- gamma-1b (IFN-γ-1b, Actimmune*) in vivo will display enhanced function across a broad range of activities related in large part to the transcriptional activation effects of this cytokine. Read more about this study

Who is it for?
Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for
Chronic Granulomatous Disease
What is being tested?
Administration of drug (Interferon-gamma 1-b) subcutaneously
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteUnited States
Study dates
Jul 2016to Feb 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy adults over the age of 18 years up to 60 years.
  • At time of screening subject is well and healthy;
  • Acute infections resolved;
  • Subject off treatment medications;
  • No diagnosis of chronic conditions or active health care issues for which the subject is actively followed by a health care provider or is on chronic medications.
  • Non-prescription medications for mild inter-current illnesses will be allowed at the discretion of the principal investigator.

Who cannot join

  • Pregnancy.
  • History of current infection;
  • Two weeks from most recent intercurrent infection;
  • History of recurrent infections or immunodeficiency.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of Colorado Denver, Anschutz Medical Campus

    Aurora, Colorado, 80045

Other trials in United States

About this study

Official title: Effect of Interferon-gamma 1-b on Innate Immune Cells

The investigators hypothesize that neutrophils and monocytes developed under the influence of Interferon- gamma-1b (IFN-γ-1b, Actimmune*) in vivo will display enhanced function across a broad range of activities related in large part to the transcriptional activation effects of this cytokine. The investigators will evaluate the effects of IFN-γ in healthy human subjects in vivo on gene expression, biologic activity markers, and functional activity of myeloid cells in single dose studies and in steady state studies.

Read the detailed description

Named for their potent ability to interfere and protect against viral infections, interferons (IFNs) have many regulatory effects on the immune system.1 Of the members of the two classes of these compounds, IFN-γ has the most diverse and powerful immune effects. Studies have mostly evaluated IFN-γ interactions with cells of adaptive immunity, including macrophages and lymphocytes. Effects on innate immunity, particularly polymorphonuclear leukocytes or neutrophils and monocytes are less well studied. However, investigations have suggested that IFN-γ may be involved in signal transduction, gene expression, the respiratory burst and neutrophil NADPH oxidase (Nox2) activity, phagocytosis, motility, microbicidal activity, and apoptosis. Not all of these functions are enhanced by IFN-γ; but the clinical use of this cytokine has been driven, in part by these results. For example, the primary motivation for initiating investigation of its beneficial clinical effects in Chronic Granulomatous Disease (CGD) was its effects on Nox2 activity.2 Most data in this area was based on studies using differentiated neutrophils from peripheral blood.1 However, the phenotype of neutrophils developed under the influence of this cytokine, not just changes expressed by exposure of differentiated cells to IFN-γ, is critical to understanding the physiologic effects of IFN-γ and the broad applications for its use in treatment of a range of human diseases. To expand their understanding of the role of IFN-γ in the development and functional integrity of the neutrophil, the investigators have completed a series of studies with PLB-985 cells in an in vitro culture system of myeloid cells. In this proposal, the investigators will evaluate innate immune activation and phagocyte function in healthy adult volunteers who are receiving IFN-γ.

Being tested
Administration of drug (Interferon-gamma 1-b) subcutaneously
Keywords
Interferon-gamma, innate immunity
Medical subject headings
Granulomatous Disease, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Administration of drug (Interferon-gamma 1-b) subcutaneouslyDrug

    Also called Actimmune

    SD = group who has received a single dose of IFN-gamma (10, 25, 50, and 100 mcg/m2) given once with subsequent analysis of effects (serum IL-10, Neuropterin, and IFN levels as well as neutrophil Nox2 activity and gene expression by Affimetrics Chip analysis). One month is allowed between doses. SS = administration of four doses (50 mcg/m2) of IFN-gamma given on Monday, Wednesday Friday schedule with neutrophil or monocyte function studies performed before the first and after the fourth dose to determine steady state effects.

Study groups in NCT02609932
Study groupRoleWhat they receive
SD or SSOtherIn this study, IFN- γ-1b will be subcutaneously administered a total of 30 subjects in one of two cohorts; Single Dose (SD) or Steady State (SS) dosing. Dosing of IFN- γ-1b will be based upon the time subject became eligible and started study. In this non-randomized, open-label study, subjects will be enrolled on the SD cohort first, and once that cohort has been filled, enrollment to the SS cohort will begin. Although not required, subjects in the SD cohort may also volunteer to participate in the SS cohort if they still meet eligibility criteria. Separate consents will be used for the SD and SS cohorts. In the event not all the SD subjects choose to continue onto the SS cohort, we will plan to recruit new participants from our local campus community.
Receives: Drug: Administration of drug (Interferon-gamma 1-b) subcutaneously

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Neutrophil Nox2 activity.

    Nox2 activity will be measured by DHR oxidation or Sod inhibitable cytochrome c reduction.

    Measured: Determine the change in Nox2 activity at baseline compared to results for 8,24,48,72,96 hours after each IFN dose for the SD cohort.

  2. Change in Plasma IL-10 and Neuropterin concentration.

    IL-10nd Neuropterin will be measured by ELISA.

    Measured: Determine the change in IL-10 and neuropterin concentration at baseline compared to 4, 8, 12, 24, 36, 48, 72, and 96 hours after each IFN dose, SD cohort.

  3. Change in Neutrophil Gene Expression Analysis.

    RNA will be extracted and gene expression will be determined by Affimetrix Gene Chip assay.

    Measured: Determine the change in gene expression at baseline compared to 4, 8, 12, 24, 36, 48, 72, and 96 hours after each IFN dose, SD cohort.

  4. Change in IFN concentration and detection of anti-IFN antibody

    IFN levels and anti-drug antibody will be completed by standard assays.

    Measured: Determine the change in IFN level at baseline compared to 4, 8, 12, and 24 hours after administration of each dose of IFN-gamma in the SD cohort. Determine the change in IFN antibody at baseline compared to day 7-10 and day 30 after IFN

Secondary outcomes (4)

  1. Change in Neutrophil Function studies.

    Neutrophil chemotaxis, bactericidal activity,ingestion, degranulation, f-Actin expression, CD11b/18 expression, Nox2 activity to a variety of agonists.

    Measured: Determine the change in neutrophil function at baseline compared to results on Day 8 after the 4th dose of IFN.

  2. Change in Anti-IFN antibody.

    Anti-drug antibody to be determined by standard assay.

    Measured: Determine the change in IFN antibody at baseline compared to results for 7-10 da. and 30 da. after IFN.

  3. Change in Monocyte function studies.

    Monocyte chemotaxis, bactericidal activity,ingestion, Expression of monocyte specific surface determinants, CD11b/18 expression, Nox2 activity to a variety of agonists, cell content of specific proteins, and antibody dependent cellular cytotoxicity.

    Measured: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.

  4. Change in Neutrophil and Monocyte Gene Expression Analysis.

    RNA will be extracted and gene expression will be determined by Affimetrix Gene Chip assay.

    Measured: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2015 (estimated)
  2. Study startJul 2016
  3. Primary completionAug 2018
  4. Study completionFeb 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02609932
Sponsor's protocol ID
15-1643
Other IDs
UL1TR001082
Status last verified
Feb 2019
First submitted
11 Nov 2015
Last updated
15 Feb 2019
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Ellison MA, Thurman G, Gearheart CM, Seewald RH, Porter CC, Ambruso DR. INF-gamma Enhances Nox2 Activity by Upregulating phox Proteins When Applied to Differentiating PLB-985 Cells but Does Not Induce Nox2 Activity by Itself. PLoS One. 2015 Aug 28;10(8):e0136766. doi: 10.1371/journal.pone.0136766. eCollection 2015.

    PubMed 26317224

  • Ambruso DR, Briones NJ, Baroffio AF, Murphy JR, Tran AD, Gowan K, Sanford B, Ellison M, Jones KL. In vivo interferon-gamma induced changes in gene expression dramatically alter neutrophil phenotype. PLoS One. 2022 Feb 3;17(2):e0263370. doi: 10.1371/journal.pone.0263370. eCollection 2022.

    PubMed 35113934

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Administration of drug (Interferon-gamma 1-b) subcutaneously in people with Chronic Granulomatous Disease, run by University of Colorado, Denver at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Neutrophil Nox2 activity. (time frame: Determine the change in Nox2 activity at baseline compared to results for 8,24,48,72,96 hours after each IFN dose for the SD cohort.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02609932, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2019.

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