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

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

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

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 Summary:

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 sargramosti
Sponsor: Children's Hospital Medical Center, Cincinnati

Current Primary Outcome: Occurrence of any treatment-emergent adverse events and serious adverse events [ Time Frame: 1 year ]

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Maximum plasma GM-CSF Concentration (Cmax) [ Time Frame: 1 year ]
    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 Frame: 1 year ]
    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) [ Time Frame: 1 year ]
    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) [ Time Frame: 1 year ]
    Half-life of GM-CSF following a single administration of inhaled sargramostim
  • Complete cell counts and differentials in blood and BAL fluid [ Time Frame: 1 year ]
    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 [ Time Frame: 1 year ]
    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 [ Time Frame: 1 year ]
    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)


Original Secondary Outcome: Same as current

Information By: Children's Hospital Medical Center, Cincinnati

Dates:
Date Received: November 28, 2016
Date Started: January 2017
Date Completion: March 2018
Last Updated: December 29, 2016
Last Verified: December 2016