AquADEKs-2: Effects of an Antioxidant-Enriched Multivitamin Supplement on Inflammation and Oxidative Stress in Cystic Fibrosis

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01859390
• Collaborator: Cystic Fibrosis Foundation (Other), Yasoo Health (Industry)
• Enrollment: 73
• Locations: 15
• Arms: 2
• Duration (Months): 37
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: AquADEKs-2; Dietary Supplement: control multivitamin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Randomized, Controlled, Double-Blind Study of the Effects of an Antioxidant-Enriched Multivitamin Supplement on Inflammation and Oxidative Stress in Cystic Fibrosis Patients
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.; Other Names: Antioxidant-enriched multivitamin supplement ; Dietary Supplement: control multivitamin; The control multivitamin contains standard (standard for CF multivitamin supplements) amounts of vitamins A, B, D, E, and K without added antioxidants.
Active Comparator: 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.	Dietary Supplement: control multivitamin; The control multivitamin contains standard (standard for CF multivitamin supplements) amounts of vitamins A, B, D, E, and K without added antioxidants.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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)

6. 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).

7. 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).

8. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Medical Center	Tucson	Arizona	United States	85724
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	The Nemours Children's Clinic	Orlando	Florida	United States	32806
4	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
5	University of Minnesota Children's Hospital	Minneapolis	Minnesota	United States	55455
6	Women and Children's Hospital of Buffalo	Buffalo	New York	United States	14222
7	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
8	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
9	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
10	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
11	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
12	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-5735
13	The University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
14	University of Wisconsin Hospital Center	Madison	Wisconsin	United States	53792
15	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• University of Colorado, Denver
• Cystic Fibrosis Foundation
• Yasoo Health

Investigators

• Principal Investigator: Scott Sagel, MD, PhD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

• Papas KA, Sontag MK, Pardee C, Sokol RJ, Sagel SD, Accurso FJ, Wagener JS. A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis. J Cyst Fibros. 2008 Jan;7(1):60-7. Epub 2007 Jun 13.
• Sagel SD, Sontag MK, Anthony MM, Emmett P, Papas KA. Effect of an antioxidant-rich multivitamin supplement in cystic fibrosis. J Cyst Fibros. 2011 Jan;10(1):31-6. doi: 10.1016/j.jcf.2010.09.005. Epub 2010 Oct 20.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01859390
• Other Study ID Numbers: 13-1557; AQUADEK12K1
• First Posted: May 21, 2013
• Last Update Posted: Jul 14, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: Antioxidants; Vitamins; Inflammation; Oxidative stress
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Inflammation; Antioxidants

Study Results

Participant Flow

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	36	37
Withdrawals	2	2
COMPLETED	35	30
NOT COMPLETED	1	7

Baseline Characteristics

Arm/Group Title	AquADEKs-2	Control Multivitamin	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	36	37	73
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.3 (8.9)	22.9 (9.5)	22.6 (9.1)
Age, Customized (Count of Participants)
Age >=10 - <18 yrs	13 36.1%	16 43.2%	29 39.7%
Age >=18 - <30 yrs	17 47.2%	11 29.7%	28 38.4%
Age >30 yrs	6 16.7%	10 27%	16 21.9%
Sex: Female, Male (Count of Participants)
Female	20 55.6%	20 54.1%	40 54.8%
Male	16 44.4%	17 45.9%	33 45.2%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	34 94.4%	30 81.1%	64 87.7%
Hispanic	1 2.8%	5 13.5%	6 8.2%
African-American	1 2.8%	1 2.7%	2 2.7%
Unknown/Other	0 0%	1 2.7%	1 1.4%
Cystic Fibrosis (CF) Genotype (Count of Participants)
Delta F508 Homozygous	23 63.9%	16 43.2%	39 53.4%
Delta F508 Heterozygous	9 25%	18 48.6%	27 37%
Other	3 8.3%	3 8.1%	6 8.2%
Not Identified	1 2.8%	0 0%	1 1.4%

Outcome Measures

1. Primary Outcome

Title	Change in Sputum Myeloperoxidase (MPO) Level
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	35	30
Mean (Standard Deviation) [log10 (ng/mL)]	-0.10 (0.67)	0.03 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments	Two-sample T-test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.325
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.170
	Confidence Interval	(2-Sided) 95%; -0.513 to 0.173
	Parameter Dispersion	Type: Value:
	Estimation Comments	Regression Model predictors include: AquADEKs-2 arm, Age >=18 years, Sex, Screening FEV1%Predicted >70%, Chronic use of Inhaled Antibiotics and Azithromycin. The estimated value is the mean difference between groups for 16 week change in log10 MPO.

2. Secondary Outcome

Title	Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Incidence of AEs	33 91.7%	34 91.9%
Incidence of SAEs	8 22.2%	13 35.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.302
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions-SAE incidence
	Estimated Value	-12.9
	Confidence Interval	(2-Sided) 95%; -32.1 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Rate is defined as the number of events per participant follow-up week.
Time Frame	18 weeks follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Number of AEs per participant week	0.34	0.37
Number of SAEs per participant week	0.04	0.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments
	Method	Poisson Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments	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 AquADEKs-2 group was 642 and in the Control group was 639.
Statistical Test of Hypothesis	p-Value	0.269
	Comments
	Method	Poisson Regression
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Lung Function
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	34	35
Mean (Standard Deviation) [FEV1 %Predicted]	-0.76 (8.00)	-2.20 (7.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments	Two sample T-test
Statistical Test of Hypothesis	p-Value	0.4463
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; -2.30 to 5.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Growth Endpoints
Description	Absolute change in Body Mass Index (BMI) (kg/m^2) between Baseline and Week 16.
Time Frame	Baseline (Visit 2) to Week 16

Outcome Measure Data

Analysis Population Description

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/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	34	34
Mean (Standard Deviation) [kg/m^2]	0.16 (0.68)	0.13 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8623
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to First Pulmonary Exacerbation
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Median (95% Confidence Interval) [days]	102	96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0534
	Comments	Not adjusted for multiple comparisons. Alpha at 0.05.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.536
	Confidence Interval	(2-Sided) 95%; 0.284 to 1.009
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox model parameters include: AquADEKs-2 arm, Age >=18 years, Sex, Screening FEV1 % Predicted >70%, Chronic use of Inhaled Antibiotics and Azithromycin. The parameter of interest is the Hazard Ratio comparing the AquADEKs-2 arm to the control arm.

7. Secondary Outcome

Title	Number of Pulmonary Exacerbations
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Number [Pulmonary Exacerbations]	28	39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1731
	Comments
	Method	Poisson Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With Pulmonary Exacerbations
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Count of Participants [Participants]	19 52.8%	25 67.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AquADEKs-2, Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments	Difference in Proportions
Statistical Test of Hypothesis	p-Value	0.2363
	Comments	Not adjusted for multiple comparisons. Alpha at 0.05.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.8
	Confidence Interval	(2-Sided) 95%; -35.1 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants Hospitalized
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AquADEKs-2	Control Multivitamin
Arm/Group Description	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.	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.
Measure Participants	36	37
Count of Participants [Participants]	7 19.4%	13 35.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments	Difference in Proportions
Statistical Test of Hypothesis	p-Value	0.1900
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-15.7
	Confidence Interval	(2-Sided) 95%; -34.5 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Participant adverse event data was collected for the 4 months that subjects were on study drug.
Arm/Group Title	AquADEKs-2		Control Multivitamin
Arm/Group Description	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.		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.
All Cause Mortality
	AquADEKs-2		Control Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AquADEKs-2		Control Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/36 (22.2%)		13/37 (35.1%)
Cardiac disorders
Palpitations	1/36 (2.8%)	1	0/37 (0%)	0
Eye disorders
Eye swelling	1/36 (2.8%)	1	0/37 (0%)	0
General disorders
Asthenia	0/36 (0%)	0	1/37 (2.7%)	1
Chest discomfort	0/36 (0%)	0	1/37 (2.7%)	1
Chest pain	1/36 (2.8%)	1	0/37 (0%)	0
Fatigue	1/36 (2.8%)	1	0/37 (0%)	0
Pyrexia	0/36 (0%)	0	1/37 (2.7%)	1
Investigations
Breath sounds abnormal	0/36 (0%)	0	1/37 (2.7%)	1
Chest X-ray abnormal	0/36 (0%)	0	1/37 (2.7%)	2
Forced expiratory volume decreased	2/36 (5.6%)	2	1/37 (2.7%)	1
Pulmonary function test decreased	2/36 (5.6%)	2	3/37 (8.1%)	3
Weight decreased	1/36 (2.8%)	1	2/37 (5.4%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/36 (0%)	0	1/37 (2.7%)	1
Renal and urinary disorders
Nephrolithiasis	1/36 (2.8%)	1	0/37 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial wall thickening	1/36 (2.8%)	1	0/37 (0%)	0
Cough	3/36 (8.3%)	3	6/37 (16.2%)	6
Dyspnoea	2/36 (5.6%)	2	2/37 (5.4%)	2
Dyspnoea exertional	1/36 (2.8%)	1	0/37 (0%)	0
Haemoptysis	0/36 (0%)	0	2/37 (5.4%)	2
Hypoxia	0/36 (0%)	0	1/37 (2.7%)	1
Nasal congestion	0/36 (0%)	0	1/37 (2.7%)	1
Pneumothorax	0/36 (0%)	0	1/37 (2.7%)	1
Respiratory distress	0/36 (0%)	0	1/37 (2.7%)	1
Respiratory tract congestion	0/36 (0%)	0	1/37 (2.7%)	1
Sputum increased	3/36 (8.3%)	3	3/37 (8.1%)	3
Throat tightness	1/36 (2.8%)	1	0/37 (0%)	0
Skin and subcutaneous tissue disorders
Swelling face	1/36 (2.8%)	1	0/37 (0%)	0
Vascular disorders
Flushing	1/36 (2.8%)	1	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	AquADEKs-2		Control Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/36 (91.7%)		34/37 (91.9%)
Gastrointestinal disorders
Abdominal pain	4/36 (11.1%)	5	8/37 (21.6%)	11
Constipation	1/36 (2.8%)	2	4/37 (10.8%)	4
Diarrhoea	4/36 (11.1%)	4	2/37 (5.4%)	3
Flatulence	3/36 (8.3%)	3	2/37 (5.4%)	5
Nausea	0/36 (0%)	0	2/37 (5.4%)	2
Toothache	2/36 (5.6%)	2	0/37 (0%)	0
Vomiting	4/36 (11.1%)	5	0/37 (0%)	0
General disorders
Asthenia	2/36 (5.6%)	2	1/37 (2.7%)	1
Chest pain	0/36 (0%)	0	2/37 (5.4%)	2
Fatigue	4/36 (11.1%)	4	5/37 (13.5%)	7
Pyrexia	2/36 (5.6%)	2	5/37 (13.5%)	6
Infections and infestations
Pharyngitis	2/36 (5.6%)	2	0/37 (0%)	0
Investigations
Forced expiratory volume decreased	2/36 (5.6%)	3	1/37 (2.7%)	1
Pseudomonas test positive	0/36 (0%)	0	2/37 (5.4%)	2
Pulmonary function test decreased	6/36 (16.7%)	9	9/37 (24.3%)	10
Weight decreased	3/36 (8.3%)	3	3/37 (8.1%)	3
Nervous system disorders
Headache	4/36 (11.1%)	7	5/37 (13.5%)	5
Sinus headache	2/36 (5.6%)	2	1/37 (2.7%)	1
Psychiatric disorders
Anxiety	2/36 (5.6%)	2	0/37 (0%)	0
Decreased activity	2/36 (5.6%)	2	1/37 (2.7%)	1
Depression	1/36 (2.8%)	1	3/37 (8.1%)	3
Respiratory, thoracic and mediastinal disorders
Cough	22/36 (61.1%)	30	19/37 (51.4%)	30
Dyspnoea	4/36 (11.1%)	5	8/37 (21.6%)	8
Haemoptysis	4/36 (11.1%)	4	5/37 (13.5%)	6
Nasal congestion	7/36 (19.4%)	11	8/37 (21.6%)	8
Oropharyngeal pain	4/36 (11.1%)	6	1/37 (2.7%)	1
Rales	3/36 (8.3%)	4	7/37 (18.9%)	8
Respiratory tract congestion	4/36 (11.1%)	4	8/37 (21.6%)	8
Rhinorrhoea	4/36 (11.1%)	5	4/37 (10.8%)	5
Sinus congestion	4/36 (11.1%)	4	3/37 (8.1%)	3
Sputum discoloured	3/36 (8.3%)	3	1/37 (2.7%)	2
Sputum increased	11/36 (30.6%)	14	10/37 (27%)	12
Wheezing	2/36 (5.6%)	2	1/37 (2.7%)	1

Limitations/Caveats

We did not meet the complete enrollment of 80 subjects due to the expiration dates of the antioxidant-enriched and control multivitamins produced for the study.

More Information

Certain Agreements

Principal Investigators are NOT 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.