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Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis

Primary Purpose

Autoimmune Pulmonary Alveolar Proteinosis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sargramostim
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Autoimmune Pulmonary Alveolar Proteinosis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female

Age ≥ 18 years and ≤ 80 years

Able to understand and willing to sign a written informed consent document

Able and willing to use hand held nebulizer

Able and willing to adhere to study visit schedule and study procedures

Diagnosis of autoimmune PAP determined by:

  • History of a diagnosis of PAP with or without supporting lung histology or BAL/cytology

and

  • Abnormal serum GM-CSF autoantibody test (GMAb ELISA Test)

and

  • Chest CT findings compatible with a diagnosis of autoimmune PAP

Evidence of impaired GM-CSF signaling demonstrated by an abnormal STAT5 phosphorylation index (STAT5-PI) test measured in heparinized whole blood at the time screening

A-aDO2 ≥ 15 mm Hg

Exclusion Criteria:

Diagnosis of any other PAP-causing disease

Autoimmune PAP complicated by:

  • Severe disease at screening/enrollment (A-aD02<50)
  • Clinically significant pulmonary fibrosis

History of any clinically significant:

  • Other lung disease
  • Cardiovascular disease
  • Disease requiring use of systemic steroids in past year
  • Coagulopathy or other hematologic disease
  • Active / serious lung or systemic infection
  • Persistent or unexplained fever >101oF within 2 months of study
  • Use of any immunosuppressive medication within 3-6 months of screening
  • Women who are pregnant or plan to become pregnant
  • History of active tobacco/e-cig/marijuana use
  • Concomitant or recent use of specific medicines

Sites / Locations

  • University of California, Los Angeles
  • Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sargramostim

Arm Description

Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)

Outcomes

Primary Outcome Measures

Occurrence of any treatment-emergent adverse events and serious adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures

Maximum plasma GM-CSF Concentration (Cmax)
Maximum concentration of free and toal GM-CSF in the plasma following a single administration of inhaled sargramostim
Time to maximum plasma GM-CSF concentration (TMax)
Time to maximum plasma concentrations of free and total GM-CSF following a single administration of inhaled sargramostim
GM-CSF Area Under the Curve (AUC)
Systemic exposure to GM-CSF in plasma samples collected at regular intervals following a single administration of inhaled sargramostim
Half-life of inhaled GM-CSF (t1/2)
Half-life of GM-CSF following a single administration of inhaled sargramostim
Complete cell counts and differentials in blood and BAL fluid
Cell Counts and differentials in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
GM-CSF autoantibody levels in blood and BAL fluid
GM-CSF autoantibody concentrations in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
GM-CSF signaling levels in blood and BAL fluid
Responsiveness of blood and BAL cells to in vitro stimulation with GM-CSF in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)

Full Information

First Posted
November 28, 2016
Last Updated
August 2, 2021
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Rare Diseases Clinical Research Network, National Center for Advancing Translational Sciences (NCATS)
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1. Study Identification

Unique Protocol Identification Number
NCT03006146
Brief Title
Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis
Official Title
Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
July 13, 2017 (Actual)
Primary Completion Date
June 7, 2021 (Actual)
Study Completion Date
June 7, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Rare Diseases Clinical Research Network, National Center for Advancing Translational Sciences (NCATS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Autoimmune PAP is a rare lung disease affecting less than 5,000 individuals in US with no FDA-approved pharmacologic therapy. Results from "off-label" use in case reports and clinical studies completed outside of the US indicate that inhaled rhGM-CSF may be a safe and effective thera-py for autoimmune PAP. Preliminary clinical trials of inhaled rhGM-CSF in autoimmune PAP patients show promising results, 62%-96% therapeutic response rate without any identifiable drug-related adverse effects in at least 73 autoimmune PAP patients. However, the pharmacokinetics (PK), pharmacodynamics (PD), optimal dose, and treatment duration to maximize efficacy are unknown. The goal is to begin to address these knowledge gaps for inhaled sargramostim for autoimmune PAP patients with a pilot safety and PK/PD study (TPSC-110). TPSC-110, PharmPAP, which is a self-controlled open-label, phase I study to evaluate the safety, PK, and PD of inhaled sargra-mostim in autoimmune PAP patients. These results will impact the field by 1) confirming existing published data, 2) monitoring the local effects of inhaled sargramostim in autoimmune PAP patients, 3) potentially demonstrating a safe starting dose for a later trial to evaluate the therapeutic efficacy of inhaled sargramostim for autoimmune PAP.
Detailed Description
PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure that occurs in a number of diseases classified pathogenically into three groups: primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP), secondary PAP (caused by reduction in alveolar macrophage numbers and/or functions), and surfactant dysfunction-related PAP (caused by mutations in genes required for normal surfactant production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an approach that is not able to identify the etiology of the PAP. Current therapy involves the physical removal of surfactant by a procedure in which the lungs are repeatedly filled with saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely available, especially for children. Importantly, research advances have elucidated the pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing disease in about 95% of patients. Further, several promising potential disease-specific therapies are currently in development. Preliminary clinical trials of inhaled rhGM-CSF in autoimmune PAP patients show promising results, 62%-96% therapeutic response rate at two doses (250 and 500 mcg/day) without any identified safety concerns. At least 73 people with autoimmune PAP have been reported to have received inhaled sargramostim with no identified drug-related adverse effects. However, the PK, PD, optimal dose, and treatment duration needed to maximize efficacy are unknown. The short-term goal is to address knowledge gaps for inhaled sargramostim for autoimmune PAP patients in the following clinical study: a pilot safety and PK/PD study (TPSC-110). A major goal of this protocol is to evaluate the local and systemic safety, PK, and PD one dose of inhaled sargramostim in autoimmune PAP. The central hypothesis is that in patients with autoimmune PAP, aerosol inhalation of sargramostim will be well-tolerated and safe because the GM-CSF autoantibody will limit detection of free GM-CSF thereby preventing local and systemic toxicity. The specific objectives of this study are to: 1) evaluate the safety profile of one dose of inhaled sargramostim in patients with autoimmune PAP 2) estimate the PK profile of inhaled sargramostim following single dose administration in patients with autoimmune PAP 3) measure the PD effects of inhaled sargramostim following single dose administration in patients with autoimmune PAP. The target population is adults with autoimmune PAP who have measurable, clinically significant disease satisfying all of the inclusion and exclusion criteria. The study design will involve recruitment, screening, and enrollment of participants into a phase I, open-label, multi-site study. Sargramostim will be administered to autoimmune PAP patients via aerosol inhalation one time at a dose of 125 mcg or 250 mcg. Adverse events (AEs), serious AEs (SAEs), PK, and PD parameters will be evaluated (see Appendix 3 Schedule of Events). The experimental approach will evaluate 1) safety of inhaled sargramostim by documenting occurrence of treatment-emergent AEs and SAEs, 2) PK profile of GM-CSF in serum and BAL fluid, 3) local and systemic PD effects of inhaled GM-CSF and 4) effects of inhaled GM-CSF on the quality of life for participants. Anticipated results will determine the safety profile of inhaled sargramostim in patients with autoimmune PAP, will evaluate total and free GM-CSF levels in blood and lung, effects of sargramostim on blood and BAL cell counts, differentials, baseline- and GM-CSF-responsiveness of blood leukocytes and BAL cells, and biomarkers of PAP in patients with autoimmune PAP after single dose administration. These results will impact the field by 1) confirming existing published data, 2) monitoring local effects of inhaled sargramostim in autoimmune PAP patients, 3) demonstrating a safe starting dose to evaluate the efficacy of inhaled sargramostim for autoimmune PAP.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autoimmune Pulmonary Alveolar Proteinosis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sargramostim
Arm Type
Experimental
Arm Description
Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)
Intervention Type
Drug
Intervention Name(s)
Sargramostim
Other Intervention Name(s)
Leukine, recombinant human GM-CSF
Intervention Description
Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)
Primary Outcome Measure Information:
Title
Occurrence of any treatment-emergent adverse events and serious adverse events
Description
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Maximum plasma GM-CSF Concentration (Cmax)
Description
Maximum concentration of free and toal GM-CSF in the plasma following a single administration of inhaled sargramostim
Time Frame
1 year
Title
Time to maximum plasma GM-CSF concentration (TMax)
Description
Time to maximum plasma concentrations of free and total GM-CSF following a single administration of inhaled sargramostim
Time Frame
1 year
Title
GM-CSF Area Under the Curve (AUC)
Description
Systemic exposure to GM-CSF in plasma samples collected at regular intervals following a single administration of inhaled sargramostim
Time Frame
1 year
Title
Half-life of inhaled GM-CSF (t1/2)
Description
Half-life of GM-CSF following a single administration of inhaled sargramostim
Time Frame
1 year
Title
Complete cell counts and differentials in blood and BAL fluid
Description
Cell Counts and differentials in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
Time Frame
1 year
Title
GM-CSF autoantibody levels in blood and BAL fluid
Description
GM-CSF autoantibody concentrations in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
Time Frame
1 year
Title
GM-CSF signaling levels in blood and BAL fluid
Description
Responsiveness of blood and BAL cells to in vitro stimulation with GM-CSF in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female Age ≥ 18 years and ≤ 80 years Able to understand and willing to sign a written informed consent document Able and willing to use hand held nebulizer Able and willing to adhere to study visit schedule and study procedures Diagnosis of autoimmune PAP determined by: History of a diagnosis of PAP with or without supporting lung histology or BAL/cytology and Abnormal serum GM-CSF autoantibody test (GMAb ELISA Test) and Chest CT findings compatible with a diagnosis of autoimmune PAP Evidence of impaired GM-CSF signaling demonstrated by an abnormal STAT5 phosphorylation index (STAT5-PI) test measured in heparinized whole blood at the time screening A-aDO2 ≥ 15 mm Hg Exclusion Criteria: Diagnosis of any other PAP-causing disease Autoimmune PAP complicated by: Severe disease at screening/enrollment (A-aD02<50) Clinically significant pulmonary fibrosis History of any clinically significant: Other lung disease Cardiovascular disease Disease requiring use of systemic steroids in past year Coagulopathy or other hematologic disease Active / serious lung or systemic infection Persistent or unexplained fever >101oF within 2 months of study Use of any immunosuppressive medication within 3-6 months of screening Women who are pregnant or plan to become pregnant History of active tobacco/e-cig/marijuana use Concomitant or recent use of specific medicines
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce Trapnell
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Study Chair
Facility Information:
Facility Name
University of California, Los Angeles
City
Los Altos
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis

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