Prevention of Cystic Fibrosis Diabetes

NCT00967798 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: IRB000127241R01FD003527-01
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 3

Brief Summary

Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The pro-inflammatory cytokines induced by hyperglycemia are toxic to islet insulin producing cells, and thus worsen glucose intolerance. Patients with cystic fibrosis (CF) have a high prevalence of CF related diabetes (CFRD) and up to 40% of CF adults develop CFRD. During the prediabetic phase in CF, there is progression from normal glucose homeostasis to high risk prediabetes characterized by episodes of acute hyperglycemia after meals and during respiratory exacerbations. The mild hyperglycemia seen in CF patients with high risk prediabetes following a meal would be expected to induce a degree of systemic inflammation and oxidative stress. These repetitive episodes, if left unchecked, could lead to progression of glucose impairment, worsening severity of oxidative stress and inflammation, and ultimately the development of CFRD, all via hyperglycemia-induced toxicity to beta cells. Furthermore, this process may be accelerated in CF because lung disease and resultant respiratory exacerbations are associated with oxidative stress and inflammation and this will further contribute to beta cell damage. Sitagliptin is a recently approved agent for type 2 diabetes and markedly enhances insulin secretion in the presence of hyperglycemia and has been shown to be effective in preventing postprandial hyperglycemia. The hypothesis to be tested in this project is that sitagliptin will prevent the development of CFRD in CF subjects with high risk prediabetes by blocking postprandial hyperglycemia. The investigators propose a randomized, double-blind, placebo-controlled, multicenter, 15-month longitudinal study in 118 CF subjects with high risk prediabetes to test this hypothesis. Specifically, the investigators aim to show that chronic treatment with sitagliptin: prevents the conversion to diabetes; results in preservation of beta cell function; reduces systemic measures of oxidative stress and inflammation; and slows the rate of progression of lung disease. Funding Source - FDA Office of Orphan Products Development

Conditions

Cystic Fibrosis; Prediabetes

Keywords

cystic fibrosis; diabetes; inflammation; oxidative stress; redox balance; lung disease

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Conversion to Cystic Fibrosis Related Diabetes

  The number of participants with conversion to cystic fibrosis related diabetes was determined.

  Month 15

Secondary Outcomes (4)

• Change in Beta-cell Disposition Index

  Baseline through Month 15

• Change in Redox Couples Glutathione/Glutathione Disulfide and Cysteine/Cystine

  Baseline through Month 12

• Change in Inflammatory Cytokines

  Baseline through Month 12

• Change in Percent Predicted FEV1

  Baseline, end of treatment (Month 12 or Month 24)

Study Arms (2)

Sitagliptin

EXPERIMENTAL

CF patients receiving Sitagliptin. Intervention: Dose is 100 mg taken orally once a day in the morning with breakfast. Duration is one year or until converted to CF diabetes, whichever comes sooner.

Drug: Sitagliptin

Sugar pill

PLACEBO COMPARATOR

CF patients receiving placebo. Intervention: Placebo is taken orally once a day in the morning with breakfast. Duration is one year or until converted to CF diabetes, whichever comes sooner.

Drug: Sitagliptin

Interventions

Sitagliptin DRUG

100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.

Also known as: Januvia

Sitagliptin; Sugar pill

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 13 years of age or older at the time of enrollment
• Diagnosis of cystic fibrosis (CF) confirmed by pilocarpine iontophoresis sweat chloride measurements and/or genotyping
• Clinically stable with no lower respiratory tract exacerbation requiring intravenous antibiotics in the three weeks prior to enrollment
• On a stable clinical treatment regimen for at least three weeks prior to enrollment
• Male or female. If female, is not lactating and has a negative pregnancy test at screening. If female of child bearing potential, willing to practice effective birth control (i.e. a method known to decrease the risk of pregnancy to less than 1%)
• Able to understand and provide informed consent
• Willing and able to comply with the study schedule and testing
• High risk prediabetes as defined by high-risk impaired fasting glucose levels of 110-125 mg/dl and/or a 2-hour plasma glucose level of 140 to 199 mg/dl found on an Oral Glucose Tolerance Test performed at screening 8 weeks or less before enrollment
• Available by telephone
• Has literacy and language skills required to fill out study material

You may not qualify if:

• Diagnosed with CF related diabetes
• Chronic heart failure with New York Heart Association (NYHA) class III/IV, ejection fraction less than 25%, or receiving digoxin
• Liver disease as defined by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times above the upper limit of normal.
• Serum creatinine greater than 1.3 mg/dl for males and greater than 1.1 mg/dl for females or receiving chronic dialysis
• Taking chronic oral or intravenous glucocorticosteroids during the past month
• On insulin therapy during the past month
• CF lung disease severe enough to require daytime chronic oxygen therapy via nasal cannula during the past month
• Unable to perform pulmonary function testing
• History of any illness or condition that, in the opinion of the sponsor might confound the results of the study or pose an additional risk in administering study drug to the subject
• Post lung or liver transplant
• Listed and awaiting organ transplant
• Current drug or alcohol dependency
• Participating in another clinical drug trial or past participant within 30 days of enrollment
• Pancreatic sufficient
• History of acute pancreatitis as documented by characteristic clinical manifestations and elevation of serum amylase and lipase within the last 2 years.

Sponsors & Collaborators

• Emory University: lead

Study Sites (3)

Emory University and Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, 30322, United States

Location

Children's Healthcare of Atlanta at Scottish Rite

Atlanta, Georgia, 30342, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

MeSH Terms

Conditions

Cystic Fibrosis; Prediabetic State; Diabetes Mellitus; Inflammation; Lung Diseases

Interventions

Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Limitations and Caveats

Poor enrollment lead to early termination of the study and a small sample size for analyses. Equipment failure resulted in loss of serum samples for some of the secondary outcomes.

Results Point of Contact

• Title: Arlene Stecenko, MD
• Organization: Emory University

astecen@emory.edu

404-712-2657

Study Officials

• Arlene A Stecenko, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 27, 2009
• First Posted: August 28, 2009
• Study Start: May 1, 2010
• Primary Completion: March 31, 2017
• Study Completion: December 31, 2017
• Last Updated: June 25, 2018
• Results First Posted: June 25, 2018

Record last verified: 2018-04

Locations

US (3)