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

• ClinicalTrials.gov Identifier: NCT01859390
• Recruitment Status: Completed
• First Posted: May 21, 2013
• Results First Posted: June 8, 2017
• Last Update Posted: July 14, 2017
• Sponsor: University of Colorado, Denver
• Collaborators: Cystic Fibrosis Foundation; Yasoo Health
• Information provided by (Responsible Party): University of Colorado, Denver

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 (Clinical Trial)
• 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: June 2013
• Actual Primary Completion Date: April 2015
• Actual Study Completion Date: July 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 Name: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 18 weeks follow up ]
   Rate is defined as the number of events per participant follow-up week.
3. Change in Lung Function [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 10 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Arizona

University Medical Center

Tucson, Arizona, United States, 85724

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Florida

The Nemours Children's Clinic

Orlando, Florida, United States, 32806

United States, Michigan

Children's Hospital of Michigan

Detroit, Michigan, United States, 48201

United States, Minnesota

University of Minnesota Children's Hospital

Minneapolis, Minnesota, United States, 55455

United States, New York

Women and Children's Hospital of Buffalo

Buffalo, New York, United States, 14222

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232-5735

United States, Texas

The University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75390

United States, Wisconsin

University of Wisconsin Hospital Center

Madison, Wisconsin, United States, 53792

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

More Information

Publications:

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.

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. doi: 10.1016/j.jcf.2007.05.001. Epub 2007 Jun 13.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jain R, Baines A, Khan U, Wagner BD, Sagel SD. Evaluation of airway and circulating inflammatory biomarkers for cystic fibrosis drug development. J Cyst Fibros. 2021 Jan;20(1):50-56. doi: 10.1016/j.jcf.2020.06.017. Epub 2020 Jul 1.

Sagel SD, Khan U, Jain R, Graff G, Daines CL, Dunitz JM, Borowitz D, Orenstein DM, Abdulhamid I, Noe J, Clancy JP, Slovis B, Rock MJ, McCoy KS, Strausbaugh S, Livingston FR, Papas KA, Shaffer ML. Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial. Am J Respir Crit Care Med. 2018 Sep 1;198(5):639-647. doi: 10.1164/rccm.201801-0105OC.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01859390
• Other Study ID Numbers: 13-1557; AQUADEK12K1 ( Other Identifier: Medic )
• First Posted: May 21, 2013
• Results First Posted: June 8, 2017
• Last Update Posted: July 14, 2017
• Last Verified: June 2017

Individual Participant Data (IPD) Sharing Statement:

• 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; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs