Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Gallium Nitrate, IV Gallium, Pseudomonas aeruginosa
Brief summary
The purpose of this study is to assess the efficacy of IV gallium to improve pulmonary function as measured by a 5% or greater relative improvement in forced expiratory volume in one second (FEV1) from baseline to Day 28. Funding Source - FDA OOPD
Detailed description
This is a phase 2, multi-center, randomized, placebo-controlled trial in adults with CF chronically infected with P. aeruginosa. The study will evaluate the safety and clinical efficacy of a five day infusion of IV gallium nitrate (IV gallium). The purpose of this study is to assess the efficacy of IV gallium to improve pulmonary function as measured by a 5% or greater relative improvement in forced expiratory volume in one second (FEV1) from baseline to Day 28.
Interventions
DRUGGallium nitrate
Study subjects will receive an infusion of either placebo or gallium nitrate.
DRUGNormal Saline
Study subjects will receive an infusion of either placebo (normal saline) or gallium nitrate.
Sponsors
Cystic Fibrosis Foundation
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Greater than or equal to 18 years of age at Screening * Documented chronic colonization with P. aeruginosa defined as dentification in two sputum or oropharyngeal cultures within the year prior to Day 1 * Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria: 1. sweat chloride ≥ 60 mEq/liter by quantitative pilocarpine iontophoresis test (QPIT) 2. two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 3. Abnormal nasal potential difference (NPD; change in NPD in response to a low chloride solution and isoproteronol of less than -5 mV) * FEV1 ≥ 25 % of predicted value at Screening * Able to expectorate sputum * Serum liver function tests ≤ 2.5 x upper limit of normal at Screening * Serum urea nitrogen (BUN) ≤ 1.5 x upper limit of normal at Screening * Serum creatinine ≤ 2.0 mg/dl and ≤ 1.5 x upper limit of normal at Screening * Hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/mm3, and white blood cells (WBC) ≥ 4,500/mm3 at Screening * Ionized calcium ≥ lower limit of normal at Screening * Written informed consent obtained from subject or subject's legal representative * Able to communicate with the Investigator and comply with the requirements of the protocol * If female and of childbearing potential, must have a negative pregnancy test on Day 1 prior to receiving study drug * If female and of childbearing potential, is willing to use adequate contraception for the duration of the study through Visit 5, as determined by the investigator * If male and able to father a child, is willing to use adequate contraception for the duration of the study through Visit 5, as determined by the investigator * Clinically stable with no significant changes in health status within 14 days prior to Day 1
Exclusion criteria
* Use of inhaled antibiotics within seven days prior to Day 1 * Unable or unwilling to withhold use of chronic inhaled antibiotics through Day 28 * Use of intravenous, inhaled, or oral antibiotics for an acute indication within 14 days prior to Day 1 * Use of bisphosphonates within seven days prior to Day 1 * History of osteoporosis (defined as the most recent dexa scan with a T-score ≤ -2.5 with the dexa scan performed within the five years prior to Screening) * Lactating female * Known sensitivity to gallium
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 5% or Greater Relative Change in FEV1 (Liters) From Baseline to Day 28 | Baseline to Day 28 | Difference between treatment groups in the proportion of subjects with 5% or greater relative change in FEV1 (liters) from baseline to Day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 to Day 56 | Incidence is defined as the number and percentage of participants with at least one event over the 56 day follow-up period. |
| Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 to Day 56 | Rate is defined as the number of events per participant follow-up week. |
| Relative Change in FEV1 (Liters) From Baseline to Day 56 | Day 1 to Day 56 | Difference between treatment groups in the relative change in FEV1 (liters) from Baseline to Day 56 |
| Absolute Change in P. Aeruginosa Sputum Density (log10 (CFU)) From Baseline to Day 56 | Day 1 to Day 56 | Difference between treatment groups in the absolute change in P. aeruginosa sputum density (log10 (CFU)) from Baseline to Day 56 based on quantitative cultures. |
| Absolute Change in Respiratory Symptoms, as Measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), From Baseline to Day 56 | Day 1 to Day 56 | Difference between treatment groups in the absolute change in respiratory symptoms, as measured by the the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from Baseline to Day 56. The Cystic Fibrosis Respiratory Symptoms Daily Diary asks a participant to state the extent of their 8 respiratory symptoms : difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gallium Gallium nitrate will be infused continuously over 5 days at 200 mg/m2/day. Study drug will be administered via a peripheral IV catheter, a peripherally inserted central catheter (PICC) line, midline catheter, or a chronic indwelling vascular access device () using an ambulatory infusion pump infused over 24 hours for 5 sequential days.
Gallium nitrate: Study subjects will receive an infusion of either placebo or gallium nitrate. | 60 |
| Placebo Placebo with be dispensed as 1,000 milliliters of 0.9% sodium chloride to match the reconstitution volume of the IV Ga
Normal Saline: Study subjects will receive an infusion of either placebo (normal saline) or gallium nitrate. | 59 |
| Total | 119 |
Baseline characteristics
| Characteristic | Gallium | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 10.25 | 33.8 years STANDARD_DEVIATION 9.62 | 32.8 years STANDARD_DEVIATION 9.96 |
| Age, Customized Age Distribution >= 30 years | 30 Participants | 36 Participants | 66 Participants |
| Age, Customized Age Distribution Between 18 and 30 years | 30 Participants | 23 Participants | 53 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Heterozygous | 21 Participants | 18 Participants | 39 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Homozygous | 34 Participants | 38 Participants | 72 Participants |
| Cystic Fibrosis (CF) Genotype Not Available | 0 Participants | 1 Participants | 1 Participants |
| Cystic Fibrosis (CF) Genotype Other | 5 Participants | 2 Participants | 7 Participants |
| Cystic Fibrosis (CF) Genotype Unidentified | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 58 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1 (% Predicted) Distribution < 50% | 28 Participants | 29 Participants | 57 Participants |
| FEV1 (% Predicted) Distribution > 70% | 17 Participants | 18 Participants | 35 Participants |
| FEV1 (% Predicted) Distribution Between 50 and 70% | 15 Participants | 12 Participants | 27 Participants |
| Forced Expiratory Volume in 1 second (FEV1) | 2.0 liters STANDARD_DEVIATION 0.95 | 2.0 liters STANDARD_DEVIATION 0.79 | 2.0 liters STANDARD_DEVIATION 0.87 |
| 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 | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 58 Participants | 58 Participants | 116 Participants |
| Region of Enrollment United States | 60 participants | 59 participants | 119 participants |
| Sex: Female, Male Female | 31 Participants | 24 Participants | 55 Participants |
| Sex: Female, Male Male | 29 Participants | 35 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 59 |
| other Total, other adverse events | 53 / 60 | 55 / 59 |
| serious Total, serious adverse events | 11 / 60 | 9 / 59 |
Outcome results
Primary
Number of Participants With 5% or Greater Relative Change in FEV1 (Liters) From Baseline to Day 28
Difference between treatment groups in the proportion of subjects with 5% or greater relative change in FEV1 (liters) from baseline to Day 28.
Time frame: Baseline to Day 28
Population: Includes only treated participants with FEV1 measurements at Baseline and Day 28.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gallium | Number of Participants With 5% or Greater Relative Change in FEV1 (Liters) From Baseline to Day 28 | 22 Participants |
| Placebo | Number of Participants With 5% or Greater Relative Change in FEV1 (Liters) From Baseline to Day 28 | 17 Participants |
p-value: 0.81195% CI: [-11.2, 22.4]Cochran-Mantel-Haenszel
Secondary
Absolute Change in P. Aeruginosa Sputum Density (log10 (CFU)) From Baseline to Day 56
Difference between treatment groups in the absolute change in P. aeruginosa sputum density (log10 (CFU)) from Baseline to Day 56 based on quantitative cultures.
Time frame: Day 1 to Day 56
Population: Includes only participants with a positive P. aeruginosa (Pa) culture at Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gallium | Absolute Change in P. Aeruginosa Sputum Density (log10 (CFU)) From Baseline to Day 56 | -1.06 log10 (CFU) | Standard Error 1.97 |
| Placebo | Absolute Change in P. Aeruginosa Sputum Density (log10 (CFU)) From Baseline to Day 56 | -0.33 log10 (CFU) | Standard Error 1.52 |
p-value: 0.05495% CI: [-1.49, 0.01]Mixed Models Analysis
Secondary
Absolute Change in Respiratory Symptoms, as Measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), From Baseline to Day 56
Difference between treatment groups in the absolute change in respiratory symptoms, as measured by the the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from Baseline to Day 56. The Cystic Fibrosis Respiratory Symptoms Daily Diary asks a participant to state the extent of their 8 respiratory symptoms : difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.
Time frame: Day 1 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gallium | Absolute Change in Respiratory Symptoms, as Measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), From Baseline to Day 56 | 3.03 score on a scale | Standard Error 13.66 |
| Placebo | Absolute Change in Respiratory Symptoms, as Measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), From Baseline to Day 56 | -0.98 score on a scale | Standard Error 10.75 |
p-value: 0.05395% CI: [-0.06, 8.53]Mixed Models Analysis
Secondary
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Incidence is defined as the number and percentage of participants with at least one event over the 56 day follow-up period.
Time frame: Day 1 to Day 56
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gallium | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of AEs | 57 Participants |
| Gallium | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of SAEs | 11 Participants |
| Placebo | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of AEs | 57 Participants |
| Placebo | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of SAEs | 9 Participants |
p-value: 0.80795% CI: [-10.6, 16.6]Fisher Exact
Secondary
Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Rate is defined as the number of events per participant follow-up week.
Time frame: Day 1 to Day 56
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gallium | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant week | 0.84 events per participant-week |
| Gallium | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant week | 0.02 events per participant-week |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant week | 1.03 events per participant-week |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant week | 0.03 events per participant-week |
Comparison: Rate Ratio for Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in weeks. The total number of follow-up weeks of all participants (not per participant) in the trial was as follows: in the IV Gallium group was 486.86 and in the Placebo group was 473.57.p-value: 0.00295% CI: [0.71, 0.93]Poisson Regression
Comparison: Rate Ratio for Serious Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in weeks. The total number of follow-up weeks in the IV Gallium group was 486.86 and in the Placebo group was 473.57.p-value: 0.78395% CI: [0.39, 2.03]Poisson Regression
Secondary
Relative Change in FEV1 (Liters) From Baseline to Day 56
Difference between treatment groups in the relative change in FEV1 (liters) from Baseline to Day 56
Time frame: Day 1 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gallium | Relative Change in FEV1 (Liters) From Baseline to Day 56 | 1.89 percentage change | Standard Error 16.99 |
| Placebo | Relative Change in FEV1 (Liters) From Baseline to Day 56 | -0.05 percentage change | Standard Error 14.14 |
p-value: 0.47995% CI: [-3.66, 7.77]Mixed Models Analysis