Idiopathic Pulmonary Fibrosis
Conditions
Keywords
pulmonary, fibrosis
Brief summary
The aims of the study are to assess safety, tolerability, the pharmacokinetic profile, and the pharmacodynamic profile of multiple doses of PRM-151 administered IV to IPF patients.
Detailed description
Idiopathic pulmonary fibrosis (IPF) is a diffuse lung disease with a histological picture of usual interstitial pneumonia and a deteriorating clinical course. The prognosis is poor. Chronic alveolar inflammation with associated parenchymal remodeling is theorized to promote an ongoing abnormal fibrogenic repair response. Corticosteroids and immunomodulatory agents have not been shown to benefit IPF patients. Recently several published clinical studies have indicated a strong correlation between IPF severity and/or disease progression and the levels of specific plasma biomarker proteins related to epithelial cell health and extracellular matrix turnover. PRM-151 is being developed for potential therapeutic uses to prevent, treat, and reduce fibrosis. This study is the first intravenous multiple-dose study in humans, and will be conducted in patients with IPF. Patients will be randomized to receive either PRM-151 or placebo.
Interventions
BIOLOGICALPRM-151
Intravenous PRM-151 administered over 30 minutes on study days 1, 3, 5, 8, and 15 at doses of 1.0, 5.0, or 10.0 mg/kg.
OTHERPlacebo
Intravenous 0.9% normal saline administered over 30 minutes on study days 1, 3, 5, 8, and 15.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Men or women of non-childbearing potential aged 40 to 80 years at screening. * Diagnosis of idiopathic pulmonary fibrosis (IPF) as determined by high resolution computerized tomography (HRCT) and pulmonary function tests.
Exclusion criteria
* History or presence of connective tissue disorder, tuberculosis (TB), cystic fibrosis, sarcoidosis, amyloidosis or other pulmonary disease except idiopathic pulmonary fibrosis (IPF). * History or presence of chronic pulmonary obstructive disease, severe pulmonary hypertension, drug-induced pulmonary toxicity, other forms of idiopathic pneumonia, or interstitial lung diseases associated with environmental exposure medication or systemic disease. * High resolution computerized tomography (HRCT) findings inconsistent with idiopathic pulmonary fibrosis(IPF).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | From first dose on Day 1 through Day 57 | Number of subjects with Dose Limiting Toxicities, Number of Treatment Emergent Serious Adverse Events and Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | Day 15 | Time of Maximum observed concentration |
| AUC48 | Day 15 | Area under the curve from 0 to 48 hrs post dose, with samples collected at 0.5, 0.75, 1, 1.5, 2, 3,4,6,8,12,16, 24 and 48 hours post Day 15 dose. |
| Terminal Elimination Half Life | Day 15 | — |
| Total Body Clearance | Day 15 | — |
| Vss | Day 15 | Volume of Distribution at Steady State |
| Cmax | Day 15 | Maximum concentration |
| FVC (Forced Vital Capacity) % Predicted Change From Baseline | Day 1 (Baseline) and Day 57 | — |
| DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline | Day 1 (Baseline) and Day 57 | — |
| FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline | Day 1 (Baseline) and Day 57 | — |
| 6MWT (6 Minute Walk Test) Distance Walked Change From Baseline | Screening (between Day -35 and Day 1) and Day 57 | Change from baseline (measured during screening period) in distance walked during a 6 minute walk test |
| SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline | Day 1 (Baseline) and Day 57 | St. George's Respiratory Questionnaire Total Score. Scores range from 0 (no impairment) to 100 (maximum impairment). A decrease in score represents a decrease in disease related symptoms. The SGRQ is not validated for IPF. |
| FVC (Forced Vital Capacity) Change From Baseline to Day 57 | Change from Day 1 (Baseline) to Day 57 | — |
Countries
Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo 0.9% saline administered as a 30 minute IV infusion Days 1, 3, 5, 8 and 15 | 6 |
| PRM-151 1 mg/kg PRM-151 1 mg/kg administered as a 30 minute IV infusion Days 1, 3, 5, 8 and 15 | 6 |
| PRM-151 5 mg/kg PRM-151 5 mg/kg administered as a 30 minute IV infusion Days 1, 3, 5, 8 and 15 | 5 |
| PRM-151 10 mg/kg PRM-151 10 mg/kg administered as a 30 minute IV infusion Days 1, 3, 5, 8 and 15 | 4 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | PRM-151 10 mg/kg | PRM-151 5 mg/kg | PRM-151 1 mg/kg |
|---|---|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 12.88 | 66.4 years STANDARD_DEVIATION 9.21 | 66.5 years STANDARD_DEVIATION 5.69 | 70.6 years STANDARD_DEVIATION 8.26 | 63.7 years STANDARD_DEVIATION 8.45 |
| DLCO | 35.2 percent STANDARD_DEVIATION 8.4 | 43.3 percent STANDARD_DEVIATION 10.9 | 46.0 percent STANDARD_DEVIATION 7.2 | 52.8 percent STANDARD_DEVIATION 9.8 | 41.2 percent STANDARD_DEVIATION 10.5 |
| FEV1 % Predicted | 68.8 percent STANDARD_DEVIATION 17.7 | 78.5 percent STANDARD_DEVIATION 16.2 | 73.0 percent STANDARD_DEVIATION 12.1 | 87.0 percent STANDARD_DEVIATION 11.9 | 85.8 percent STANDARD_DEVIATION 16.8 |
| FVC | 2.15 liters STANDARD_DEVIATION 0.64 | 2.67 liters STANDARD_DEVIATION 0.76 | 2.97 liters STANDARD_DEVIATION 0.71 | 2.78 liters STANDARD_DEVIATION 0.73 | 2.96 liters STANDARD_DEVIATION 0.85 |
| FVC % Predicted | 63.2 percent STANDARD_DEVIATION 16.7 | 74.1 percent STANDARD_DEVIATION 15.3 | 72.8 percent STANDARD_DEVIATION 14.3 | 80.0 percent STANDARD_DEVIATION 7.8 | 82.4 percent STANDARD_DEVIATION 15.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 20 Participants | 4 Participants | 5 Participants | 6 Participants |
| Region of Enrollment Netherlands | 4 participants | 12 participants | 0 participants | 3 participants | 5 participants |
| Region of Enrollment United States | 2 participants | 9 participants | 4 participants | 2 participants | 1 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 17 Participants | 4 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 4 |
Outcome results
Primary
Safety and Tolerability
Number of subjects with Dose Limiting Toxicities, Number of Treatment Emergent Serious Adverse Events and Adverse Events
Time frame: From first dose on Day 1 through Day 57
Population: All subjects who received at least one dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety and Tolerability | Dose Limiting Toxicities | 0 participants |
| Placebo | Safety and Tolerability | Adverse Events | 6 participants |
| Placebo | Safety and Tolerability | Serious Adverse Events | 0 participants |
| PRM-151 1 mg/kg | Safety and Tolerability | Dose Limiting Toxicities | 0 participants |
| PRM-151 1 mg/kg | Safety and Tolerability | Adverse Events | 6 participants |
| PRM-151 1 mg/kg | Safety and Tolerability | Serious Adverse Events | 0 participants |
| PRM-151 5 mg/kg | Safety and Tolerability | Serious Adverse Events | 0 participants |
| PRM-151 5 mg/kg | Safety and Tolerability | Dose Limiting Toxicities | 0 participants |
| PRM-151 5 mg/kg | Safety and Tolerability | Adverse Events | 5 participants |
| PRM-151 10 mg/kg | Safety and Tolerability | Dose Limiting Toxicities | 0 participants |
| PRM-151 10 mg/kg | Safety and Tolerability | Adverse Events | 4 participants |
| PRM-151 10 mg/kg | Safety and Tolerability | Serious Adverse Events | 0 participants |
Secondary
6MWT (6 Minute Walk Test) Distance Walked Change From Baseline
Change from baseline (measured during screening period) in distance walked during a 6 minute walk test
Time frame: Screening (between Day -35 and Day 1) and Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 6MWT (6 Minute Walk Test) Distance Walked Change From Baseline | -11 meters | Standard Deviation 51 |
| PRM-151 1 mg/kg | 6MWT (6 Minute Walk Test) Distance Walked Change From Baseline | -11 meters | Standard Deviation 63 |
| PRM-151 5 mg/kg | 6MWT (6 Minute Walk Test) Distance Walked Change From Baseline | 6 meters | Standard Deviation 43 |
| PRM-151 10 mg/kg | 6MWT (6 Minute Walk Test) Distance Walked Change From Baseline | 35 meters | Standard Deviation 45 |
Secondary
AUC48
Area under the curve from 0 to 48 hrs post dose, with samples collected at 0.5, 0.75, 1, 1.5, 2, 3,4,6,8,12,16, 24 and 48 hours post Day 15 dose.
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC48 | 446 µg*hr/mL | Standard Deviation 118 |
| PRM-151 1 mg/kg | AUC48 | 2190 µg*hr/mL | Standard Deviation 1140 |
| PRM-151 5 mg/kg | AUC48 | 4710 µg*hr/mL | Standard Deviation 1180 |
Secondary
Cmax
Maximum concentration
Time frame: Day 15
Population: Subjects who received all doses of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax | 25.5 µg/mL | Standard Deviation 7.9 |
| PRM-151 1 mg/kg | Cmax | 145 µg/mL | Standard Deviation 41.9 |
| PRM-151 5 mg/kg | Cmax | 225 µg/mL | Standard Deviation 43.7 |
Secondary
DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline
Time frame: Day 1 (Baseline) and Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline | -2.3 Absolute change in % predicted DLCO | Standard Deviation 2.1 |
| PRM-151 1 mg/kg | DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline | 0.2 Absolute change in % predicted DLCO | Standard Deviation 3.3 |
| PRM-151 5 mg/kg | DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline | -4.0 Absolute change in % predicted DLCO | Standard Deviation 6.8 |
| PRM-151 10 mg/kg | DLCO (%) (Diffusing Capacity of Carbon Monoxide) Change From Baseline | -1.5 Absolute change in % predicted DLCO | Standard Deviation 3.8 |
Secondary
FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline
Time frame: Day 1 (Baseline) and Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline | -1.7 Absolute change in FEV1 % predicted | Standard Deviation 4.3 |
| PRM-151 1 mg/kg | FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline | 2.6 Absolute change in FEV1 % predicted | Standard Deviation 4.3 |
| PRM-151 5 mg/kg | FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline | 2.4 Absolute change in FEV1 % predicted | Standard Deviation 1.1 |
| PRM-151 10 mg/kg | FEV1 (Forced Expiratory Volume 1sec )(%) Change From Baseline | 0.3 Absolute change in FEV1 % predicted | Standard Deviation 3.8 |
Secondary
FVC (Forced Vital Capacity) Change From Baseline to Day 57
Time frame: Change from Day 1 (Baseline) to Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC (Forced Vital Capacity) Change From Baseline to Day 57 | -0.063 liters | Standard Deviation 0.116 |
| PRM-151 1 mg/kg | FVC (Forced Vital Capacity) Change From Baseline to Day 57 | 0.058 liters | Standard Deviation 0.164 |
| PRM-151 5 mg/kg | FVC (Forced Vital Capacity) Change From Baseline to Day 57 | 0.060 liters | Standard Deviation 0.074 |
| PRM-151 10 mg/kg | FVC (Forced Vital Capacity) Change From Baseline to Day 57 | 0.078 liters | Standard Deviation 0.21 |
Secondary
FVC (Forced Vital Capacity) % Predicted Change From Baseline
Time frame: Day 1 (Baseline) and Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC (Forced Vital Capacity) % Predicted Change From Baseline | -1.5 absolute change in % predicted FVC | Standard Deviation 3.3 |
| PRM-151 1 mg/kg | FVC (Forced Vital Capacity) % Predicted Change From Baseline | 2.4 absolute change in % predicted FVC | Standard Deviation 4.6 |
| PRM-151 5 mg/kg | FVC (Forced Vital Capacity) % Predicted Change From Baseline | 2.8 absolute change in % predicted FVC | Standard Deviation 3 |
| PRM-151 10 mg/kg | FVC (Forced Vital Capacity) % Predicted Change From Baseline | 1.8 absolute change in % predicted FVC | Standard Deviation 5.3 |
Secondary
SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline
St. George's Respiratory Questionnaire Total Score. Scores range from 0 (no impairment) to 100 (maximum impairment). A decrease in score represents a decrease in disease related symptoms. The SGRQ is not validated for IPF.
Time frame: Day 1 (Baseline) and Day 57
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline | -0.5 units on a scale | Standard Deviation 6.2 |
| PRM-151 1 mg/kg | SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline | 2.3 units on a scale | Standard Deviation 17.9 |
| PRM-151 5 mg/kg | SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline | 7.1 units on a scale | Standard Deviation 12 |
| PRM-151 10 mg/kg | SGRQ (St. George's Respiratory Questionnaire) Total Score Change From Baseline | -6.3 units on a scale | Standard Deviation 6.6 |
Secondary
Terminal Elimination Half Life
Time frame: Day 15
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Terminal Elimination Half Life | 21.7 hour |
| PRM-151 1 mg/kg | Terminal Elimination Half Life | 43.6 hour |
| PRM-151 5 mg/kg | Terminal Elimination Half Life | 71.6 hour |
Secondary
Tmax
Time of Maximum observed concentration
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Tmax | 5.35 hours | Standard Deviation 10.4 |
| PRM-151 1 mg/kg | Tmax | 1.30 hours | Standard Deviation 1.51 |
| PRM-151 5 mg/kg | Tmax | 0.69 hours | Standard Deviation 1.25 |
Secondary
Total Body Clearance
Time frame: Day 15
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Total Body Clearance | 2.33 ml/hr/kg |
| PRM-151 1 mg/kg | Total Body Clearance | 1.59 ml/hr/kg |
| PRM-151 5 mg/kg | Total Body Clearance | 1.09 ml/hr/kg |
Secondary
Vss
Volume of Distribution at Steady State
Time frame: Day 15
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Vss | 53.9 mL/kg |
| PRM-151 1 mg/kg | Vss | 73.9 mL/kg |
| PRM-151 5 mg/kg | Vss | 72.0 mL/kg |