Combined PEX, Rituximab and Steroids in Acute Idiopathic Pulmonary Fibrosis Exacerbations

• Sponsor: Michael Donahoe (Other)
• Overall Status: Completed
• CT.gov ID: NCT01266317
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 52
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is an open-label Phase I/II trial to assess the feasibility and safety of combined plasma exchange (PEX), rituximab, and conventional corticosteroid administration on the outcome of hospitalized patients with acute IPF exacerbations. The specific aims of this study are:

1. To assess the feasibility and safety of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations by monitoring indices of respiratory (PaO2) and cardiovascular function during the treatment interval.

2. To assess the efficacy of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations on patient survival in comparison to historical controls. Patient survival for this investigation will be defined using the composite outcome of 60 day survival and/or survival to lung transplantation.

Subjects between 18 and 80 years of age who have a confirmed diagnosis of IPF, and meet all the study requirements will be enrolled in this study. A total of 10 subjects of both genders and all ethnic backgrounds with acute IPF exacerbations hospitalized at University of Pittsburgh Medical Center will be enrolled in this study.

Condition or Disease	Intervention/Treatment	Phase
IPF	Drug: Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids	Phase 1/Phase 2

Detailed Description

This is a prospective, open-label Phase II, non-randomized clinical trial to assess the feasibility and safety of combined plasma exchange (PEX), rituximab, and conventional corticosteroid administration in patients with acute IPF exacerbations.

INCLUSION CRITERIA:

1. A diagnosis of idiopathic pulmonary fibrosis that fulfills American Thoracic Society Consensus Criteria.

2. Unexplained worsening or development of dyspnea or hypoxemia within 30 days leading to the current hospitalization.

3. Radiographic imaging showing ground-glass abnormality and/or consolidation superimposed on a background of reticular or honeycomb pattern consistent with UIP.

4. Intent on the part of the treating physician to use high dose steroid therapy as a therapeutic effort to treat a diagnosis of acute IPF exacerbation.

EXCLUSION CRITERIA

1. Diagnosis of documented infection based upon clinical evaluation and microbial testing.

2. Diagnosis of thromboembolic disease by clinical assessment.

3. Diagnosis of an additional etiology for ALI/ARDS based upon clinical assessment to include sepsis, aspiration, trauma, inhalational injury, acute pancreatitis, drug toxicity, blood product transfusion reaction, or stem cell transplantation.

4. Diagnosis of congestive heart failure that accounts for the hypoxemia.

5. Presence of active hepatitis B infection.

6. Coagulopathy defined as an INR > 1.8, PTT > 2 x control, and platelet count < 50K.

7. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes mellitus or uncontrolled hypertension (systolic BP > 160 mm Hg and diastolic BP > 100 mm Hg) which would contraindicated the use of corticosteroids.

8. Hemodynamic instability defined as a vasopressor requirement which would contraindicate the use of plasmapheresis.

9. History of reaction to blood products, murine-derived products, or prior exposures to human-murine chimeric antibodies,

10. History of malignancy.

11. Inability or unwillingness to accept a blood transfusion.

12. Inability or unwillingness to complete post- treatment surveillance for 60 days.

13. Diagnosis of major comorbidities expected to interfere with subjects study participation for 60 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label, Feasibility Study of Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids in Patients With Acute Idiopathic Pulmonary Fibrosis Exacerbations
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combined PEX, Rituximab and Steroids Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13.

Drug: Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids; Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Respiratory and/or Hemodynamic Deteriorations [28 days]

   To assess the feasibility and safety of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations by monitoring indices of respiratory (PaO2) and cardiovascular function during the treatment interval. Respiratory deterioration was defined by a compilations of respiratory deteriorations (deteriorating gas exchange) and hemodynamic deteriorations (defined as a need for medical intervention).

Secondary Outcome Measures

1. Number of Participants Survived to 60 Days or to Transplantation [60 days]

   The secondary outcome measures a composite outcome defined as survival to 60 days or survival to transplantation at any time post therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A diagnosis of idiopathic pulmonary fibrosis that fulfills American Thoracic Society Consensus Criteria.

• Unexplained worsening or development of dyspnea or hypoxemia within 30 days leading to the current hospitalization.

• Radiographic imaging showing ground-glass abnormality and/or consolidation superimposed on a background of reticular or honeycomb pattern consistent with usual interstitial pneumonia.

• Intent on the part of the treating physician to use high dose steroid therapy as a therapeutic effort to treat a diagnosis of acute IPF exacerbation.

Exclusion Criteria:

• Diagnosis of documented infection based upon clinical evaluation and microbial testing.

• Diagnosis of thromboembolic disease by clinical assessment.

• Diagnosis of an additional etiology for Acute Lung Injury/Acute Respiratory Distress Syndrome based upon clinical assessment to include sepsis, aspiration, trauma, inhalational injury, acute pancreatitis, drug toxicity, blood product transfusion reaction, or stem cell transplantation.

• Diagnosis of congestive heart failure that accounts for the hypoxemia.

• Presence of active hepatitis B infection.

• Coagulopathy defined as an International Normalized Ratio > 1.8, Partial Thromboplastin Time > 2 x control, and platelet count < 50,000.

• Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes mellitus or uncontrolled hypertension (systolic BP > 160 mm Hg and diastolic BP > 100 mm Hg) which would contraindicated the use of corticosteroids.

• Hemodynamic instability defined as a vasopressor requirement which would contraindicate the use of plasmapheresis.

• History of reaction to blood products, murine-derived products, or prior exposures to human-murine chimeric antibodies,

• History of malignancy.

• Inability or unwillingness to accept a blood transfusion.

• Inability or unwillingness to complete post- treatment surveillance for 60 days.

• Diagnosis of major comorbidities expected to interfere with subjects study participation for 60 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Michael Donahoe

Investigators

• Principal Investigator: Michael Donahoe, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michael Donahoe, Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01266317
• Other Study ID Numbers: PRO10110151
• First Posted: Dec 24, 2010
• Last Update Posted: Mar 14, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Rituximab

Study Results

Participant Flow

Arm/Group Title	Combined PEX, Rituximab and Steroids
Arm/Group Description	Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids: Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab
Period Title: Overall Study
STARTED	9
COMPLETED	7
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Combined PEX, Rituximab and Steroids
Arm/Group Description	Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids: Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab
Overall Participants	9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 33.3%
>=65 years	6 66.7%
Sex: Female, Male (Count of Participants)
Female	3 33.3%
Male	6 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	9 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Respiratory and/or Hemodynamic Deteriorations
Description	To assess the feasibility and safety of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations by monitoring indices of respiratory (PaO2) and cardiovascular function during the treatment interval. Respiratory deterioration was defined by a compilations of respiratory deteriorations (deteriorating gas exchange) and hemodynamic deteriorations (defined as a need for medical intervention).
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined PEX, Rituximab and Steroids
Arm/Group Description	Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids: Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab
Measure Participants	7
Respiratory Deterioration	1 11.1%
Hemodynamic Deterioration	3 33.3%

2. Secondary Outcome

Title	Number of Participants Survived to 60 Days or to Transplantation
Description	The secondary outcome measures a composite outcome defined as survival to 60 days or survival to transplantation at any time post therapy.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined PEX, Rituximab and Steroids
Arm/Group Description	Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids: Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab
Measure Participants	7
Count of Participants [Participants]	3 33.3%

Adverse Events

Time Frame	60 days
Arm/Group Title	Combined PEX, Rituximab and Steroids
Arm/Group Description	Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids: Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab
All Cause Mortality
	Combined PEX, Rituximab and Steroids
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combined PEX, Rituximab and Steroids
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Hypoxemia	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Combined PEX, Rituximab and Steroids
	Affected / at Risk (%)	# Events
Total	4/10 (40%)
Endocrine disorders
Hyperglycemia	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxemia	4/10 (40%)	4
Skin and subcutaneous tissue disorders
Rash	1/10 (10%)	1
Infection	1/10 (10%)	1
Vascular disorders
Hypotension	1/10 (10%)	1

Limitations/Caveats

This was a pilot, open-label trial of an unprecedented regimen for a highly lethal disease and, as such, included only small numbers of subjects and historical controls.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.