Idiopathic Pulmonary Fibrosis
Conditions
Keywords
IPF, Herpesvirus, Valganciclovir
Brief summary
The investigators will conduct a single-center, prospective, randomized, placebo-controlled, double-blind pilot study of anti-herpesvirus therapy in patients with idiopathic pulmonary fibrosis (IPF). Patients with mild, moderate or severe IPF with serologic evidence of current or past Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) infection. Randomization will be to pirfenidone plus placebo or pirfenidone plus valganciclovir. Thirty subjects will be enrolled and randomized to treatment with pirfenidone plus valganciclovir (20 subjects) or pirfenidone plus placebo (10 subjects) for 12 weeks. The primary outcome will be safety and tolerability will be determined by type, frequency and duration of adverse events (AEs) and serious adverse events (SAEs) after 12 weeks of study drug treatment. All study subjects will be offered bronchoscopy with bronchoalveolar lavage (BAL) at study initiation and upon completion of treatment (12 weeks). Subjects will then be followed up at routine clinic visits at 6, 9 and 12 months for data collection.
Interventions
DRUGValganciclovir
Subjects with IPF currently tolerating pirfenidone treatment who have evidence of prior EBV or CMV infection will be randomized to valganciclovir or placebo for 12 weeks.
DRUGPlacebo
Subjects with IPF currently tolerating pirfenidone treatment who have evidence of prior EBV or CMV infection will be randomized to valganciclovir or placebo for 12 weeks.
Sponsors
Genentech, Inc.
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. age \>21 and \<80 years 2. ability to provided informed consent 3. diagnosis of probable or definite IPF according to American Thoracic Society (ATS) criteria 4. tolerance of full-dose (2403 mg/day) pirfenidone 5. Positive serology for EBV or CMV
Exclusion criteria
1. FVC \< 40% predicted 2. Diffusing capacity for carbon monoxide (DLCO) \< 35% predicted (Crapo) 3. Forced expiratory volume (FEV)1/FVC \<0.7 4. Significant centrilobular emphysema (\>40% by HRCT) 5. Active tobacco use (cigarette or cigar smoking) 6. Resting oxygen saturation (SpO2) on room air \<89% 7. Listed for lung transplantation defined as being assigned a lung allocation score 8. environmental exposure (occupational, environmental, drug, etc.) felt by the principal investigator (PI) to be the etiology of the interstitial disease 9. diagnosis of collagen-vascular conditions (according to the published American College of Rheumatology criteria) 10. history of unstable or deteriorating cardiac disease 11. acute coronary syndrome, coronary artery bypass, or angioplasty within 3 months of screening 12. uncontrolled arrhythmia 13. uncontrolled hypertension 14. known HIV or hepatitis C 15. known cirrhosis or chronic active hepatitis 16. active substance or alcohol abuse 17. pregnancy or lactation 18. Women of childbearing potential who are not using a medically approved means of contraception. Subjects will be considered of childbearing potential if they are not surgically sterile or have not been postmenopausal for at least 2 years \[any subject who is postmenopausal for \< 2 years will be required to have a follicle-stimulating hormone (FSH) level to assess her potential to become pregnant 19. clinically relevant lab abnormalities (obtained within 30 days before enrollment), including: 1. creatinine \> 2 x upper limit of normal (ULN) 2. hematology outside of specified limits: white blood cells (WBCs) \< 3,500/mm3; hematocrit \< 25% or \> 59%; platelets \< 100,000/mm3; 3. total bilirubin \> 2 x ULN 4. Aspartate (AST) or alanine aminotransferases (ALT)/ serum glutamic-oxaloacetic; transaminase (SGOT), or serum glutamic pyruvic transaminase (SGPT) \> 2.0 x ULN 5. alkaline phosphatase \> 3 x ULN 6. albumin \< 3.0 mg/dL at screening 20. known hypersensitivity to study medication 21. any condition that, in the judgment of the PI, might cause participation in this study to be detrimental to the subject or that the PI deems makes the subject a poor candidate 22. any therapy with immunosuppressants such as prednisone, azathioprine, or mycophenolate currently or anticipated to be needed during the study period (subjects on these drugs prior to the study will require a 30-day washout period before randomization) 23. participation in another IPF clinical treatment trial during the study period (if completing another IPF clinical treatment trial, then a 30-day washout period is required before randomization) 24. requirement for chronic suppressive therapy with valacyclovir for recurrent herpes virus infection 25. History of myelodysplasia, aplastic anemia, refractory anemia, or multiple myeloma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Who Discontinue Study Drug Due to Adverse Events | 12 weeks | Proportion of study subjects who discontinue study drug due to adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events - Number | 12 weeks | Number of subjects with each reported adverse event |
| Serious Adverse Events | 12 weeks | Number of subjects with each serious adverse event |
| Total # Adverse Events | Randomization to 16 weeks | Total number of adverse events |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Forced Vital Capacity (FVC) | Baseline vs. 12 weeks, 1 year | Change in FVC percent predicted compared to baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valganciclovir Valganciclovir 450 mg, 2 pills by mouth one time per day x 12 weeks
Valganciclovir: Subjects with IPF currently tolerating pirfenidone treatment who have evidence of prior EBV or CMV infection will be randomized to valganciclovir or placebo for 12 weeks. | 20 |
| Placebo Placebo, 2 pills by mouth one time per day x 12 weeks
Placebo: Subjects with IPF currently tolerating pirfenidone treatment who have evidence of prior EBV or CMV infection will be randomized to valganciclovir or placebo for 12 weeks. | 11 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Valganciclovir |
|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 8 | 68.2 years STANDARD_DEVIATION 7.1 | 67.9 years STANDARD_DEVIATION 6.8 |
| Diffusion capacity for carbon monoxide (DLCO) % predicted for age | 41.0 % STANDARD_DEVIATION 8.9 | 45.0 % STANDARD_DEVIATION 10.1 | 47.3 % STANDARD_DEVIATION 10.2 |
| Forced expiratory volume in 1 second (FEV1) % predicted for age | 79.7 % STANDARD_DEVIATION 10.8 | 77.9 % STANDARD_DEVIATION 17.5 | 76.9 % STANDARD_DEVIATION 20.5 |
| Forced vital capacity (FVC) % predicted for age | 69.4 % STANDARD_DEVIATION 7.7 | 69.4 % STANDARD_DEVIATION 15.8 | 69.4 % STANDARD_DEVIATION 19 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 31 Participants | 20 Participants |
| Region of Enrollment United States | 11 participants | 31 participants | 20 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 25 Participants | 16 Participants |
| Total Lung Capacity (TLC) % predicted for age | 62.1 % STANDARD_DEVIATION 7.2 | 62.2 % STANDARD_DEVIATION 14.4 | 62.2 % STANDARD_DEVIATION 17.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 11 |
| other Total, other adverse events | 14 / 20 | 4 / 11 |
| serious Total, serious adverse events | 2 / 20 | 1 / 11 |
Outcome results
Primary
Proportion of Subjects Who Discontinue Study Drug Due to Adverse Events
Proportion of study subjects who discontinue study drug due to adverse events
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Valganciclovir | Proportion of Subjects Who Discontinue Study Drug Due to Adverse Events | 1 Participants |
| Placebo | Proportion of Subjects Who Discontinue Study Drug Due to Adverse Events | 0 Participants |
Secondary
Adverse Events - Number
Number of subjects with each reported adverse event
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Valganciclovir | Adverse Events - Number | Jaw pain | 0 participants |
| Valganciclovir | Adverse Events - Number | Pneumonia | 2 participants |
| Valganciclovir | Adverse Events - Number | Lymphopenia | 1 participants |
| Valganciclovir | Adverse Events - Number | Bilateral arm swelling | 1 participants |
| Valganciclovir | Adverse Events - Number | Nausea | 0 participants |
| Valganciclovir | Adverse Events - Number | Diarrhea | 2 participants |
| Valganciclovir | Adverse Events - Number | Nephrolithiasis | 1 participants |
| Valganciclovir | Adverse Events - Number | Bilateral lower leg edema | 1 participants |
| Valganciclovir | Adverse Events - Number | Pain in back | 0 participants |
| Valganciclovir | Adverse Events - Number | Worsened dyspnea | 0 participants |
| Valganciclovir | Adverse Events - Number | Paroxysmal atrial fibrillation | 1 participants |
| Valganciclovir | Adverse Events - Number | Carbuncle on face | 1 participants |
| Valganciclovir | Adverse Events - Number | Prostate cancer recurrence | 0 participants |
| Valganciclovir | Adverse Events - Number | Leukocytosis | 1 participants |
| Valganciclovir | Adverse Events - Number | Rash | 1 participants |
| Valganciclovir | Adverse Events - Number | Depression | 0 participants |
| Valganciclovir | Adverse Events - Number | Respiratory tract infection | 1 participants |
| Valganciclovir | Adverse Events - Number | Acute pain of shoulder | 1 participants |
| Valganciclovir | Adverse Events - Number | Sore throat | 1 participants |
| Valganciclovir | Adverse Events - Number | Dyspepsia | 0 participants |
| Valganciclovir | Adverse Events - Number | Thrombocytopenia | 1 participants |
| Valganciclovir | Adverse Events - Number | Elevated liver enzymes | 2 participants |
| Valganciclovir | Adverse Events - Number | Tooth pain | 1 participants |
| Valganciclovir | Adverse Events - Number | Hoarseness | 0 participants |
| Valganciclovir | Adverse Events - Number | Upper respiratory tract infection | 1 participants |
| Valganciclovir | Adverse Events - Number | Acute respiratory failure | 1 participants |
| Valganciclovir | Adverse Events - Number | Vertigo | 1 participants |
| Valganciclovir | Adverse Events - Number | Hypertension | 0 participants |
| Valganciclovir | Adverse Events - Number | Weakness | 1 participants |
| Valganciclovir | Adverse Events - Number | Cough | 3 participants |
| Valganciclovir | Adverse Events - Number | Weight loss | 1 participants |
| Valganciclovir | Adverse Events - Number | Hypoxia during flight | 0 participants |
| Valganciclovir | Adverse Events - Number | Worsening anemia | 0 participants |
| Valganciclovir | Adverse Events - Number | Acute sinusitis | 1 participants |
| Valganciclovir | Adverse Events - Number | Worsening hypertension | 1 participants |
| Valganciclovir | Adverse Events - Number | At least 1 AE | 14 participants |
| Placebo | Adverse Events - Number | Worsening hypertension | 0 participants |
| Placebo | Adverse Events - Number | At least 1 AE | 4 participants |
| Placebo | Adverse Events - Number | Cough | 1 participants |
| Placebo | Adverse Events - Number | Leukocytosis | 3 participants |
| Placebo | Adverse Events - Number | Diarrhea | 0 participants |
| Placebo | Adverse Events - Number | Elevated liver enzymes | 0 participants |
| Placebo | Adverse Events - Number | Pneumonia | 0 participants |
| Placebo | Adverse Events - Number | Worsened dyspnea | 2 participants |
| Placebo | Adverse Events - Number | Acute pain of shoulder | 0 participants |
| Placebo | Adverse Events - Number | Acute respiratory failure | 0 participants |
| Placebo | Adverse Events - Number | Acute sinusitis | 0 participants |
| Placebo | Adverse Events - Number | Bilateral arm swelling | 0 participants |
| Placebo | Adverse Events - Number | Bilateral lower leg edema | 0 participants |
| Placebo | Adverse Events - Number | Carbuncle on face | 0 participants |
| Placebo | Adverse Events - Number | Depression | 1 participants |
| Placebo | Adverse Events - Number | Dyspepsia | 1 participants |
| Placebo | Adverse Events - Number | Hoarseness | 1 participants |
| Placebo | Adverse Events - Number | Hypertension | 1 participants |
| Placebo | Adverse Events - Number | Hypoxia during flight | 1 participants |
| Placebo | Adverse Events - Number | Jaw pain | 1 participants |
| Placebo | Adverse Events - Number | Lymphopenia | 0 participants |
| Placebo | Adverse Events - Number | Nausea | 1 participants |
| Placebo | Adverse Events - Number | Nephrolithiasis | 0 participants |
| Placebo | Adverse Events - Number | Pain in back | 1 participants |
| Placebo | Adverse Events - Number | Paroxysmal atrial fibrillation | 0 participants |
| Placebo | Adverse Events - Number | Prostate cancer recurrence | 1 participants |
| Placebo | Adverse Events - Number | Rash | 0 participants |
| Placebo | Adverse Events - Number | Respiratory tract infection | 0 participants |
| Placebo | Adverse Events - Number | Sore throat | 1 participants |
| Placebo | Adverse Events - Number | Thrombocytopenia | 0 participants |
| Placebo | Adverse Events - Number | Tooth pain | 0 participants |
| Placebo | Adverse Events - Number | Upper respiratory tract infection | 0 participants |
| Placebo | Adverse Events - Number | Vertigo | 0 participants |
| Placebo | Adverse Events - Number | Weakness | 0 participants |
| Placebo | Adverse Events - Number | Weight loss | 0 participants |
| Placebo | Adverse Events - Number | Worsening anemia | 1 participants |
Secondary
Serious Adverse Events
Number of subjects with each serious adverse event
Time frame: 12 weeks
Population: Serious adverse events
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valganciclovir | Serious Adverse Events | 2 events |
| Placebo | Serious Adverse Events | 1 events |
Secondary
Total # Adverse Events
Total number of adverse events
Time frame: Randomization to 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valganciclovir | Total # Adverse Events | 33 events |
| Placebo | Total # Adverse Events | 13 events |
Other Pre-specified
Change in Forced Vital Capacity (FVC)
Change in FVC percent predicted compared to baseline
Time frame: Baseline vs. 12 weeks, 1 year
Population: PFT data not available at 1 year (obtained per standard of-care at clinical visit) for 5 subjects.~Reasons for missing data: Decreased (n=1), moved out of region and lost to follow-up (n=1), PFT's not obtained at visit (n=3).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Valganciclovir | Change in Forced Vital Capacity (FVC) | Baseline to 12 weeks | 0 percentage predicted |
| Valganciclovir | Change in Forced Vital Capacity (FVC) | Baseline to 12 months | -1 percentage predicted |
| Placebo | Change in Forced Vital Capacity (FVC) | Baseline to 12 weeks | -2 percentage predicted |
| Placebo | Change in Forced Vital Capacity (FVC) | Baseline to 12 months | -5 percentage predicted |