Cystic Fibrosis
Conditions
Keywords
Antioxidants, Vitamins, Inflammation, Oxidative stress
Brief summary
The purpose of this study will be to evaluate the effects of a modified formulation of AquADEKs (AquADEKs-2) on markers of inflammation, antioxidant levels and oxidative stress. Cystic Fibrosis (CF) is a disease that affects the organs in the body such as the lungs. Some of the damage to the lungs of CF patients may be caused by something called oxidant/antioxidant imbalance and oxidative stress. Oxidation in the body is kind of what happens to an apple when it turns brown after being cut. And, just as a squeeze of lemon juice stops the oxidation of an apple, antioxidants can stop the rusting (or damage) inside our bodies by unstable oxygen molecules called free radicals. Free radicals can help fight off bacteria and viruses but too many of them do damage instead. Our bodies need antioxidants to keep things in balance so we have the right amount of free radicals. Many CF patients also have trouble digesting food and absorbing nutrients like vitamins. Many of the vitamins we rely on are antioxidants, like vitamins A, D, E, K and beta-carotene. In some people with CF, even though they take multivitamins and pancreatic enzymes, they still have low amounts of antioxidants. The investigators are looking to see if taking more vitamins and antioxidants will help CF patients. AquADEKs-2 is an investigational new drug (a drug that has not received approval by the Food and Drug Administration \[FDA\]). This research study is being done with the AquADEKs-2 compared to a control multivitamin. The study drug, AquADEKs-2 contains standard amounts of fat-soluble vitamins (A, D, E, K) that are contained in typical CF multivitamin supplements plus several antioxidants including beta-carotene, mixed tocopherols (different forms of vitamin E), coenzyme Q10 (CoQ10), mixed carotenoids (lutein, lycopene and zeaxanthin), and the minerals zinc and selenium. The control multivitamin contains standard amounts of vitamins A, B, D, E, and K without additional antioxidant supplementation.
Interventions
DRUGAquADEKs-2
AquADEKs-2 contains standard amounts of fat-soluble vitamins (A, D, E, K) that are contained in typical CF multivitamin supplements plus several antioxidants including beta-carotene, mixed tocopherols (different forms of vitamin E), coenzyme Q10 (CoQ10), mixed carotenoids (lutein, lycopene and zeaxanthin), and the minerals zinc and selenium.
DIETARY_SUPPLEMENTcontrol multivitamin
The control multivitamin contains standard (standard for CF multivitamin supplements) amounts of vitamins A, B, D, E, and K without added antioxidants.
Sponsors
Cystic Fibrosis Foundation
Yasoo Health
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female ≥10 years of age * Documentation of a Cystic Fibrosis (CF) diagnosis as evidenced by 1 or more clinical features consistent with the CF phenotype and 1 or more of the following criteria: * Sweat chloride equal to or greater than 60 milliequivalent (mEq/L) by quantitative pilocarpine iontophoresis test (QPIT) * 2 well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene * Pancreatic insufficiency documented by having a spot fecal elastase-1 (FE-1) ≤ 100μg/g in a stool sample done either historically or at the screening visit * Clinically stable with no significant changes in health status within 2 weeks prior to randomization * Forced expiratory volume over one second (FEV1) ≥ 40 and ≤ 100% of predicted for age based on the Wang (males \< 18 years,females \< 16 years) or Hankinson (males ≥ 18 years, females ≥ 16 years) standardized equations at the screening visit * Weight ≥ 30 kg at the screening visit * Able to perform repeatable, consistent efforts in pulmonary function testing * Able to tolerate sputum induction with 3% hypertonic saline and to expectorate with induction * Written informed consent (and assent when applicable) obtained from subject or subject's legal representative * Ability to swallow softgel capsules
Exclusion criteria
* Subjects being treated with ivacaftor (Kalydeco™) * Liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyl transferase (GGT) \> 3 times the upper limits of normal at the screening visit * Use of antibiotics (oral, iv, and/or inhaled) for acute respiratory symptoms within 2 weeks prior to randomization * Active treatment for allergic bronchopulmonary aspergillosis (ABPA) * Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day * Active treatment for nontuberculous mycobacterial (NTM) infection * Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline,azithromycin,Tobramycin Inhalation solution (TOBI®), Cayston® within 8 weeks prior to randomization * Unwilling to discontinue current oral vitamin and antioxidant supplementation (e.g.,AquADEKs®, another source of β-carotene, vitamin A, vitamin E or tocopherols,vitamins D or K, n-acetylcysteine, glutathione, CoQ10, other over-the-counter antioxidant) for the duration of the study * Use of vitamins (other than control vitamin) or antioxidants within 4 weeks prior to randomization * Daily use of \> 2 cans of Boost or Pulmocare dietary supplement formulas * Known hypersensitivity to oral AquADEKs® * For women of child bearing potential: 1. positive pregnancy test at Visit 1 or at Visit 2, or 2. lactating or 3. unwilling to practice a medically acceptable form of contraception (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent) * Subject unlikely to complete the study as determined by the Investigator * Any condition that the Investigator believes would interfere with the intent of this study or would make participation not in the best interest of the subject * Use of investigational therapies within 4 weeks prior to randomization * Current tobacco smoker * Current use of anticoagulant medications * Severe malnutrition based either on having a BMI less than the 5th percentile for subjects \< 18 years of age or a body mass index (BMI) less than 18 kg/m2 for subjects \> 18 years of age. * Subjects with poorly controlled CF-related diabetes on active insulin therapy, defined as having a Glycosylated Hemoglobin (HgbA1c) ≥ 7.5% at the most recent historic evaluation of HgbA1c
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Sputum Myeloperoxidase (MPO) Level | Baseline (Visit 2) to Week 16 (Visit 4) | The primary outcome is the difference in 16 week mean change in log10 sputum myeloperoxidase levels between the AquADEKs-2 arm and the Control Multivitamin arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 18 weeks follow up | Rate is defined as the number of events per participant follow-up week. |
| Change in Lung Function | Baseline (Visit 2) to Week 16 | Absolute Change in Forced Expiratory Volume over one second (FEV1) % predicted between Baseline and Week 16. Global Lung Initiative equations were used to calculate FEV1 %predicted. |
| Change in Growth Endpoints | Baseline (Visit 2) to Week 16 | Absolute change in Body Mass Index (BMI) (kg/m\^2) between Baseline and Week 16. |
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 18 weeks follow up | Incidence is defined as the number and percentage of participants with at least one event over the 18 week follow-up period. |
| Number of Pulmonary Exacerbations | Baseline (Visit 2) to end of follow up (Week 18) | The total number of PEx between baseline (Visit 2) and end of follow up (Week 18). |
| Number of Participants With Pulmonary Exacerbations | Baseline (Visit 2) to end of follow up (Week 18) | Number (%) with at least one protocol-defined PEx between baseline (Visit 2) and end of follow up (Week 18). |
| Number of Participants Hospitalized | Baseline (Visit 2) to end of followup (Week 18) | Number (%) of participants with at least one hospitalization between Baseline (Visit 2) and end of follow up (Week 18). |
| Time to First Pulmonary Exacerbation | Baseline (Visit 2) to end of follow up (Week 18) | Median time to first pulmonary exacerbation (PEx) between baseline (Visit 2) and end of follow up (Week 18) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AquADEKs-2 Two control multivitamin softgel capsules will be taken orally on a once daily basis with pancreatic enzymes and a glass of milk or fat-containing meal for 4 weeks for the screening run in period. For those subjects randomized to the AquADEKs-2 arm, two AquADEKs-2 softgel capsules will be taken orally on a once daily basis with pancreatic enzymes and a glass of milk or fat-containing meal for 16 weeks.
AquADEKs-2: AquADEKs-2 contains standard amounts of fat-soluble vitamins (A, D, E, K) that are contained in typical CF multivitamin supplements plus several antioxidants including beta-carotene, mixed tocopherols (different forms of vitamin E), coenzyme Q10 (CoQ10), mixed carotenoids (lutein, lycopene and zeaxanthin), and the minerals zinc and selenium.
control multivitamin: The control multivitamin contains standard (standard for CF multivitamin supplements) amounts of vitamins A, B, D, E, and K without added antioxidants. | 36 |
| Control Multivitamin Two control multivitamin softgel capsules will be taken orally on a once daily basis with pancreatic enzymes and a glass of milk or fat-containing meal for 4 weeks for the screening run in period for all participants and for 16 weeks for those randomized to this comparative therapy.
control multivitamin: The control multivitamin contains standard (standard for CF multivitamin supplements) amounts of vitamins A, B, D, E, and K without added antioxidants. | 37 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Insufficient Sputum Collected | 1 | 3 |
| Overall Study | Sample Missing Collection Date | 0 | 1 |
| Overall Study | Shipment Error | 0 | 1 |
| Overall Study | Tube Cracked | 0 | 2 |
Baseline characteristics
| Characteristic | Control Multivitamin | AquADEKs-2 | Total |
|---|---|---|---|
| Age, Continuous | 22.9 years STANDARD_DEVIATION 9.5 | 22.3 years STANDARD_DEVIATION 8.9 | 22.6 years STANDARD_DEVIATION 9.1 |
| Age, Customized Age >=10 - <18 yrs | 16 Participants | 13 Participants | 29 Participants |
| Age, Customized Age >=18 - <30 yrs | 11 Participants | 17 Participants | 28 Participants |
| Age, Customized Age >30 yrs | 10 Participants | 6 Participants | 16 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Heterozygous | 18 Participants | 9 Participants | 27 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Homozygous | 16 Participants | 23 Participants | 39 Participants |
| Cystic Fibrosis (CF) Genotype Not Identified | 0 Participants | 1 Participants | 1 Participants |
| Cystic Fibrosis (CF) Genotype Other | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Race/Ethnicity African-American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Caucasian | 30 Participants | 34 Participants | 64 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Unknown/Other | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 36 | 34 / 37 |
| serious Total, serious adverse events | 8 / 36 | 13 / 37 |
Outcome results
Primary
Change in Sputum Myeloperoxidase (MPO) Level
The primary outcome is the difference in 16 week mean change in log10 sputum myeloperoxidase levels between the AquADEKs-2 arm and the Control Multivitamin arm.
Time frame: Baseline (Visit 2) to Week 16 (Visit 4)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AquADEKs-2 | Change in Sputum Myeloperoxidase (MPO) Level | -0.10 log10 (ng/mL) | Standard Deviation 0.67 |
| Control Multivitamin | Change in Sputum Myeloperoxidase (MPO) Level | 0.03 log10 (ng/mL) | Standard Deviation 0.76 |
Comparison: Two-sample T-testp-value: 0.4695% CI: [-0.49, 0.22]t-test, 2 sided
p-value: 0.32595% CI: [-0.513, 0.173]Regression, Linear
Secondary
Change in Growth Endpoints
Absolute change in Body Mass Index (BMI) (kg/m\^2) between Baseline and Week 16.
Time frame: Baseline (Visit 2) to Week 16
Population: This population includes participants who did not complete the study (i.e., did not have a final analyzable sputum sample) but did have final height and weight assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AquADEKs-2 | Change in Growth Endpoints | 0.16 kg/m^2 | Standard Deviation 0.68 |
| Control Multivitamin | Change in Growth Endpoints | 0.13 kg/m^2 | Standard Deviation 0.96 |
p-value: 0.862395% CI: [-0.37, 0.44]t-test, 2 sided
Secondary
Change in Lung Function
Absolute Change in Forced Expiratory Volume over one second (FEV1) % predicted between Baseline and Week 16. Global Lung Initiative equations were used to calculate FEV1 %predicted.
Time frame: Baseline (Visit 2) to Week 16
Population: This population includes participants who did not complete the study (i.e., did not have a final analyzable sputum sample) but did have a final lung function assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AquADEKs-2 | Change in Lung Function | -0.76 FEV1 %Predicted | Standard Deviation 8 |
| Control Multivitamin | Change in Lung Function | -2.20 FEV1 %Predicted | Standard Deviation 7.53 |
p-value: 0.446395% CI: [-2.3, 5.16]t-test, 2 sided
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 18 week follow-up period.
Time frame: 18 weeks follow up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AquADEKs-2 | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of AEs | 33 Participants |
| AquADEKs-2 | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of SAEs | 8 Participants |
| Control Multivitamin | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of AEs | 34 Participants |
| Control Multivitamin | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of SAEs | 13 Participants |
p-value: 0.30295% CI: [-32.1, 7.8]Fisher Exact
Secondary
Number of Participants Hospitalized
Number (%) of participants with at least one hospitalization between Baseline (Visit 2) and end of follow up (Week 18).
Time frame: Baseline (Visit 2) to end of followup (Week 18)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AquADEKs-2 | Number of Participants Hospitalized | 7 Participants |
| Control Multivitamin | Number of Participants Hospitalized | 13 Participants |
p-value: 0.1995% CI: [-34.5, 4.8]Fisher Exact
Secondary
Number of Participants With Pulmonary Exacerbations
Number (%) with at least one protocol-defined PEx between baseline (Visit 2) and end of follow up (Week 18).
Time frame: Baseline (Visit 2) to end of follow up (Week 18)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AquADEKs-2 | Number of Participants With Pulmonary Exacerbations | 19 Participants |
| Control Multivitamin | Number of Participants With Pulmonary Exacerbations | 25 Participants |
p-value: 0.236395% CI: [-35.1, 7.4]Fisher Exact
Secondary
Number of Pulmonary Exacerbations
The total number of PEx between baseline (Visit 2) and end of follow up (Week 18).
Time frame: Baseline (Visit 2) to end of follow up (Week 18)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AquADEKs-2 | Number of Pulmonary Exacerbations | 28 Pulmonary Exacerbations |
| Control Multivitamin | Number of Pulmonary Exacerbations | 39 Pulmonary Exacerbations |
Comparison: Rate Ratio for PEx calculated using Poisson Regression with an offset for the log of follow-up time in months. The total number of follow-up months in the AquADEKs-2 group was 148 and in the Control group was 147.p-value: 0.173195% CI: [0.44, 1.16]Poisson Model
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: 18 weeks follow up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AquADEKs-2 | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant week | 0.34 events per participant-week |
| AquADEKs-2 | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant week | 0.04 events per participant-week |
| Control Multivitamin | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant week | 0.37 events per participant-week |
| Control Multivitamin | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant week | 0.05 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 in the AquADEKs-2 group was 642 and in the Control group was 639.p-value: 0.48695% CI: [0.78, 1.13]Poisson Model
p-value: 0.26995% CI: [0.43, 1.26]Poisson Regression
Secondary
Time to First Pulmonary Exacerbation
Median time to first pulmonary exacerbation (PEx) between baseline (Visit 2) and end of follow up (Week 18)
Time frame: Baseline (Visit 2) to end of follow up (Week 18)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AquADEKs-2 | Time to First Pulmonary Exacerbation | 102 days |
| Control Multivitamin | Time to First Pulmonary Exacerbation | 96 days |
p-value: 0.053495% CI: [0.284, 1.009]Regression, Cox