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

Cystic Fibrosis Clinical Trial

— AquADEKs-2  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01859390
• Other study ID #: 13-1557
• Secondary ID: AQUADEK12K1
• Status: Completed
• Phase: Phase 2
• First received: May 17, 2013
• Last updated: July 12, 2016
• Start date: June 2013
• Est. completion date: July 2016

Study information

• Verified date: July 2016
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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. We 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: July 2016
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 10 Years and older

Eligibility

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

• 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 ß-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 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Inflammation

Intervention

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.

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.

Locations

Country	Name	City	State
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Women and Children's Hospital of Buffalo	Buffalo	New York
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	The University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	University of Wisconsin Hospital Center	Madison	Wisconsin
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota Children's Hospital	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	The Nemours Children's Clinic	Orlando	Florida
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	University Medical Center	Tucson	Arizona

Sponsors (3)

Lead Sponsor	Collaborator
University of Colorado, Denver	Cystic Fibrosis Foundation Therapeutics, Yasoo Health

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Sputum Myeloperoxidase (MPO) Level	The primary outcome in the study is the change in the sputum levels of MPO between baseline and week 16.	Between Baseline (Visit 2) and Week 16 (Visit 4)	No
Secondary	Number of Adverse Events	Incidence of adverse events including clinically significant changes in clinical safety lab values	22 weeks for each participant	Yes
Secondary	Change in Systemic Antioxidant Levels	Changes in plasma levels of carotenoids (ß-carotene, lutein, zeaxanthin and lycopene), CoQ10, ?-tocopherol, and erythrocyte glutathione peroxidase activity between Baseline and Weeks 4 and 16. Analyses will be performed for absolute values and values corrected for total lipids.	Between baseline (Visit 2) and Weeks 4 and 16	No
Secondary	Change in Systemic Markers of Inflammation and Oxidative Stress	Changes in absolute neutrophil counts, high sensitivity C-reactive protein (hs-CRP), calprotectin, serum amyloid A (SAA), and myeloperoxidase (MPO) measured in plasma between Baseline and Weeks 4 and 16; Changes in malondialdehyde, protein carbonyls, and total antioxidant capacity measured in plasma between Baseline and Weeks 4 and 16; Change in 8-iso-PGF2a measured in urine between Baseline and Week 16	Between Baseline (Visit 2) and weeks 4 and 16	No
Secondary	Change in Sputum Markers of Inflammation and Oxidative Stress	Changes in sputum levels of free neutrophil elastase activity, alpha1 antitrypsin (A1AT), secretory leukoprotease inhibitor (SLPI), Interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-a) between Baseline and Week 16; Changes in levels of 8-iso-PGF2a and 8-Oxo-2'-deoxyguanosine(8-OHdG) between Baseline and Week 16	Between Baseline (Visit 2) and Week 16	No
Secondary	Change in Systemic Vitamin Levels	• Changes in plasma levels of retinol (vitamin A), 25-hydroxy vitamin D, a- tocopherol (vitamin E), and PIVKA-II between Baseline and Weeks 4 and 16. Analyses will be performed for absolute values and values corrected for total lipids.	Between Baseline (Visit 2) and Weeks 4 and 16	No
Secondary	Changes in Lung Function Endpoints	Change in forced expiratory volume over one second (FEV1) % predicted between Baseline and Weeks 4 and 16; Change in FEV1 (Liters) between Baseline and Weeks 4 and 16	Between Baseline (Visit 2) and Weeks 4 and 16	No
Secondary	Change in Growth Endpoints	Change in weight (kg and z-score) and BMI (kg/m2 and z-score) between Baseline and Week 16	Between Baseline (Visit 2) and Week 16	No
Secondary	Time to Pulmonary Exacerbation	• Time to first acute protocol-defined pulmonary exacerbation between Baseline and end of follow up	Between Baseline (Visit 2) and End of Follow-Up	No
Secondary	Number of Pulmonary Exacerbations	Number of acute pulmonary exacerbations between Baseline and end of follow up	Baseline to end of follow up	No
Secondary	Number of hospitalizations	Number of hospitalizations between baseline and end of follow up	Baseline to end of followup	No