Pilot and Feasibility Study for the Treatment of Pre-diabetes in Patients With Cystic Fibrosis

• Sponsor: Arbelaez, Ana Maria (Other)
• Overall Status: Completed
• CT.gov ID: NCT00763412
• Collaborator: Washington University School of Medicine (Other), National Institutes of Health (NIH) (NIH), Novo Nordisk A/S (Industry), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 74
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to provide the necessary data and experience to design a larger, full scale clinical trial to determine if a certain medicine (repaglinide), which increases the amount of insulin secreted by the pancreas, can improve the nutritional status and pulmonary function of adolescents and young adults with cystic fibrosis and prediabetes by improving blood glucose control. The investigators are also trying to determine the relationship between systemic inflammatory factors and glucose impairment.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis Related Diabetes; Pancreatic Insufficiency	Drug: placebo; Drug: repaglinide	N/A

Detailed Description

As people with Cystic Fibrosis (CF) are living well into adulthood new complications are arising. CF-Related Diabetes (CFRD) has emerged as a major complication. Years prior to the diagnosis of CFRD, patients have decreasing insulin secretion, glucose intolerance, deteriorating pulmonary function, and nutritional impairment. There are no current standard recommendations for the treatment of CF patients with prediabetes, and there is little evidence that treatment of this prediabetic state in CF patients will prevent the deterioration of the lung function, nutritional status and potentially slow the progression to manifest CFRD.

To determine the feasibility of testing this hypothesis, we will perform a pilot, double-blinded, randomized controlled trial in 20 CF pancreatic insufficient patients ages of 12 to 24 years old with impaired glucose tolerance test (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) and assign them to either placebo or Repaglinide 0.5 mg PO 3 - 4 times a day before meals for two years. Patients will monitor their blood glucose daily and will be followed every 3 months for 2 years to determine changes in nutritional status by BMI and DEXA, lung function tests, frequency of hospitalizations, antibiotic courses, and degree of glucose tolerance, insulin secretion and insulin sensitivity.

In addition, based on the evidence of increased inflammation in type 2 diabetes, correlation of systemic inflammatory response at different degrees of glucose tolerance and after treatment, will be assessed in these subjects, as well as in another 20 CF pancreatic insufficient matched patients with normal glucose tolerance who will be studied once without intervention

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Pilot and Feasibility Study for the Treatment of Pre-diabetes in Patients With Cystic Fibrosis
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 Placebo 1 pill before each meal 3-4 times a day for 2 years. All subjects had abnormal glucose tolerance. Subjects were randomized to placebo or drug.	Drug: placebo; CF pancreatic insufficient patients with impaired glucose tolerance (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Experimental: 2. repaglinide repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. All subjects had abnormal glucose tolerance.Subjects were randomized to placebo or drug.	Drug: repaglinide; CF pancreatic insufficient patients with impaired glucose tolerance (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.; Other Names: Prandin

Outcome Measures

Primary Outcome Measures

1. BMI [2 year/end of study]

2. Body Composition [2 year/end of study]

   Reporting % of Fat and Lean body mass

3. CRP [2 year/end of study]

Secondary Outcome Measures

1. Glucose Tolerance [2-year]

   We completed the OGTT at the 2 year/end of study visit.

2. Inflammatory Markers [2 year/end of study]

3. Wt Z Score [2 year/end of study]

4. Tanner Stage [2 year/end of study]

   Puberty scale measuring 1-5, 1 being least development, 5 being most development.

5. FEV 1 [2 year/end of study]

   % of lung function

6. C-Peptide [2 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 24 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or females 12 -24 years old

• Diagnosis of Cystic Fibrosis by sweat test with exocrine pancreatic insufficiency

• Must have a glucose pattern by Oral Glucose Tolerance Test with fasting blood glucose <126 mg/dl and 2 hour: 140 - 199 mg/dl or >200 mg/dl.

• Weight must be stable within 5% for 3 months prior to initiation visit

• Must be able to reproducibly perform spirometry based on American Thoracic Society guidelines

Exclusion Criteria:

• Patients receiving growth hormone therapy or taking insulin

• Patients with evidence of liver dysfunction

• Patients who are status-post lung or liver transplantation

• Patients who have received systemic steroids for more than 28 days during the 6 months prior to the study

• Patients with active ABPA on steroids

• Patients taking medications that affect glucose metabolism or contraindicated with repaglinide

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Arbelaez, Ana Maria
• Washington University School of Medicine
• National Institutes of Health (NIH)
• Novo Nordisk A/S
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Study Chair: Neil H White, M.D., Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ana Maria Arbelaez, Assistant Professor in Pediatrics, Arbelaez, Ana Maria
• ClinicalTrials.gov Identifier: NCT00763412
• Other Study ID Numbers: 05-1109; P60DK020579
• First Posted: Oct 1, 2008
• Last Update Posted: Jun 5, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ana Maria Arbelaez, Assistant Professor in Pediatrics, Arbelaez, Ana Maria: Cystic Fibrosis; Diabetes; Cystic Fibrosis Related Diabetes; Pre-diabetes; oral hypoglycemic agents; Repaglinide; treatment; inflammatory markers; Lung function; nutrition
• Additional relevant MeSH terms: Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Diabetes Mellitus; Prediabetic State; Glucose Intolerance; Fibrosis; Repaglinide

Study Results

Participant Flow

Arm/Group Title	Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Period Title: Overall Study
STARTED	8	8
COMPLETED	4	4
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Patients Who Received Placebo	Patients Who Received Repaglinide	Total
Arm/Group Description	All participants were receiving ADEK vitamins and pancreatic enzyme replacement. Patients were required to be clinically stable, without evidence of deterioration from previous pulmonary function tests (PFTs) for 3-months prior to the study and without CF exacerbation or hospitalization for 2-months prior to the study. Additionally, patients were required to have maintained stable weight within 5% variance for 3-months prior to participation. Exclusion criteria included fasting blood glucose levels >126 mg/dL on study day, IV antibiotic or systemic steroid use within two months, oral corticosteroid usage for more than 28-days over the past 6-months, history of lung or liver transplant, elevated transaminases, allergic bronchopulmonary aspergillosis, or the inability to perform spirometry.	All participants were receiving ADEK vitamins and pancreatic enzyme replacement. Patients were required to be clinically stable, without evidence of deterioration from previous pulmonary function tests (PFTs) for 3-months prior to the study and without CF exacerbation or hospitalization for 2-months prior to the study. Additionally, patients were required to have maintained stable weight within 5% variance for 3-months prior to participation. Exclusion criteria included fasting blood glucose levels >126 mg/dL on study day, IV antibiotic or systemic steroid use within two months, oral corticosteroid usage for more than 28-days over the past 6-months, history of lung or liver transplant, elevated transaminases, allergic bronchopulmonary aspergillosis, or the inability to perform spirometry.	Total of all reporting groups
Overall Participants	4	4	8
Age (Count of Participants)
<=18 years	3 75%	3 75%	6 75%
Between 18 and 65 years	1 25%	1 25%	2 25%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	16	15	15.5
Sex: Female, Male (Count of Participants)
Female	2 50%	3 75%	5 62.5%
Male	2 50%	1 25%	3 37.5%
Region of Enrollment (participants) [Number]
United States	8 200%	8 200%	16 200%
BMI (Kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [Kg/m^2]	19.45	18.38	18.94
Wt Z score (Z score) [Mean (Full Range) ]
Mean (Full Range) [Z score]	-1.11	-0.29	-0.7
Fat % (% Fat mass) [Mean (Full Range) ]
Mean (Full Range) [% Fat mass]	20.34	22.06	21.2
Lean % (% Lean mass) [Mean (Full Range) ]
Mean (Full Range) [% Lean mass]	76.71	75	75.9
Tanner stage (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	3.75	3.25	3.5
FEV 1 (% of lung function) [Mean (Full Range) ]
Mean (Full Range) [% of lung function]	97.75	92.75	95.25
Fasting Glucose (mg/dl) [Mean (Full Range) ]
Mean (Full Range) [mg/dl]	99.1	100	99.6
2 hour glucose (mg/dl) [Mean (Full Range) ]
Mean (Full Range) [mg/dl]	182.4	183	182.7
Fasting C-Peptide (mg/dl) [Mean (Full Range) ]
Mean (Full Range) [mg/dl]	1.2	1.7	1.45
2 hour c-peptide (mg/dl) [Mean (Full Range) ]
Mean (Full Range) [mg/dl]	9.7	9.5	9.6
Inflammatory marker (pg/ml) [Mean (Full Range) ]
IL1	0.1	0.9	0.5
IL6	8.3	12.6	10.5
IL8	7	8.5	7.75
TNF Alpha	7.3	4.5	5.9
CRP (mg/L) [Mean (Full Range) ]
Mean (Full Range) [mg/L]	1.8	2.1	1.95

Outcome Measures

1. Primary Outcome

Title	BMI
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Mean (Full Range) [Kg/m^2]	19.63	21.19

2. Primary Outcome

Title	Body Composition
Description	Reporting % of Fat and Lean body mass
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Fat	19.82	26.21
Lean	77.15	70.83

3. Primary Outcome

Title	CRP
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Mean (Full Range) [mg/L]	9.6	2

4. Secondary Outcome

Title	Glucose Tolerance
Description	We completed the OGTT at the 2 year/end of study visit.
Time Frame	2-year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
fasting glucose	101.5	94.5
2 hour glucose	185.75	184

5. Secondary Outcome

Title	Inflammatory Markers
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
IL1	0.14	0.34
IL6	10.4	6
IL8	5.8	5.2
TNF alpha	5.1	3.6

6. Secondary Outcome

Title	Wt Z Score
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Mean (Full Range) [Z score]	-1.21	-0.26

7. Secondary Outcome

Title	Tanner Stage
Description	Puberty scale measuring 1-5, 1 being least development, 5 being most development.
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Mean (Full Range) [units on a scale]	4.25	5

8. Secondary Outcome

Title	FEV 1
Description	% of lung function
Time Frame	2 year/end of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
Mean (Full Range) [% lung function]	90.5	91.5

9. Secondary Outcome

Title	C-Peptide
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Placebo	2. Repaglinide
Arm/Group Description	1 pill before each meal 3-4 times a day for 2 years. placebo: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.	repaglinide 0.5 mg before each meal 3-4 times a day for 2 years. repaglinide: CF pancreatic insufficient patients with prediabetes by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Measure Participants	4	4
fasting	1.5	1.6
2 hour	7.5	7.7

Adverse Events

Time Frame	This pilot study was designed to collect data over a 2 year time period.
Adverse Event Reporting Description	Glucose diaries, and food diaries were reviewed, and safety labs were collected at each visit. Physical assessments by the PI were completed as well.
Arm/Group Title	Placebo		Repaglinide
Arm/Group Description	Placebo group of CF pancreatic insufficient patients ages 12-24 years old with impaired glucose tolerance test (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH).		Repaglinide intervention group of CF pancreatic insufficient patients ages 12-24 years old with impaired glucose tolerance test (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH).
All Cause Mortality
	Placebo		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Placebo		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)

Limitations/Caveats

A limitation of the study was the very small sample size.

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.