Prevention of Cystic Fibrosis Diabetes

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00967798
• Collaborator: (none)
• Enrollment: 33
• Locations: 3
• Arms: 2
• Duration (Months): 92
• Patients Per Site: 11
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis; Prediabetes	Drug: Sitagliptin	Phase 3

Detailed Description

This was a double-blind, placebo-controlled, multicenter study intending to enroll 118 CF subjects aged 13 years of age or older who have high risk prediabetes. High risk prediabetes was defined during the screening visit by performing an oral glucose tolerance test (OGTT) and finding that the fasting plasma glucose level is between 110-125 mg/dl and/or the 2-hour plasma glucose level is between 140 and 199 mg/dl. Upon enrollment, subjects were randomized to receive either sitagliptin or placebo. Each subject was to be followed for 15 months to determine if sitagliptin prevented the conversion to frank diabetes.

The following was to be done at enrollment and every 6 months: an OGTT with collection of blood at 0, 1/2, and 2 hours for measurement of glucose and insulin in order to determine progression of glucose intolerance; collection of blood at time 0 and 2 hours during the OGTT and measurement of systemic redox status, oxidative stress, and degree of inflammation to determine the degree of basal oxidative stress and inflammation as well as the degree of hyperglycemia-induced oxidative stress and inflammation; collection of exhaled breath condensate in a subset of subjects at selected sites at time 0 and 2 hours during the OGTT and measurement of airway redox status, degree of inflammation, and glucose levels to determine basal respiratory tract redox status and inflammation, the degree of hyperglycemia-induced changes in redox status and inflammation, and correlation between plasma and airway glucose levels; collection of blood to determine safety of the study medication (liver and renal function, complete blood count, electrolyte concentrations); and determination of progression of lung disease as defined by the number of respiratory exacerbations severe enough to require hospitalization and the rate of decline in lung function.

The results of two OGTTs performed at least one week apart was used to determine whether the subject had converted from high risk prediabetes to frank diabetes (primary objective). Conversion to CFRD was defined when both OGTTs were abnormal (abnormal is defined as a fasting plasma glucose level greater than 125 mg/dl and/or a 2 hour glucose level greater than 199 mg/dl). The results of measures of redox balance, oxidant stress and inflammation (secondary objectives) would provide biologic plausibility to our concept on the mechanism of action of sitagliptin in preventing the development of CF diabetes.

Hemoglobin-specific A1c fraction (HbA1c) was to be measured half-way between the 6-monthly visits and a rise of more than 0.5% from the enrollment value would result in two OGTT tests done at least one week apart to determine if diabetes has developed. At these interval study visits, blood was also collected to assess the safety of the study drug and, if the subject was female, to determine if pregnancy had occurred.

In the event that diabetes did develop, the study drug (or placebo) was to be stopped and the subject would have completed the study.

In summary, this was a double-blind, placebo-controlled clinical trial to determine whether sitagliptin prevents the conversion of CF subjects with high-risk prediabetes to frank diabetes. If successful, this would be the first treatment modality available to prevent the development of CFRD, a serious and life shortening complication of CF. Unfortunately, the study sites were unable to achieve enrollment targets and the study was prematurely terminated March 31, 2017 because of low enrollment. For those subjects enrolled in the study, there was no safety concerns. Data are currently being analyzed for the subjects that were enrolled.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-blind, Placebo-controlled Study to Determine Whether Chronic Treatment of Cystic Fibrosis Subjects With Impaired Glucose Tolerance Using Sitagliptin (Januvia) Prevents the Development of Diabetes
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Mar 31, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin 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; 100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.; Other Names: Januvia
Placebo Comparator: Sugar pill 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; 100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.; Other Names: Januvia

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Conversion to Cystic Fibrosis Related Diabetes [Month 15]

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

Secondary Outcome Measures

1. Change in Beta-cell Disposition Index [Baseline through Month 15]

   Preservation of beta-cell function was to be assessed with the disposition index, which is a measurement of beta-cell function adjusted for insensitivity to insulin.

2. Change in Redox Couples Glutathione/Glutathione Disulfide and Cysteine/Cystine [Baseline through Month 12]

   Cysteine (Cys)/cystine (CySS) and glutathione (GSH)/glutathione disulfide (GSSG) redox couples are biomarkers of oxidative stress.

3. Change in Inflammatory Cytokines [Baseline through Month 12]

   Hyperglycemia causes release of pro-inflammatory cytokines which can further compromise beta-cell function by increasing insulin resistance and by inducing beta-cell apoptosis. Inflammatory cytokines that have been shown to contribute to destruction of beta-cells include interleukin 1 beta (IL-1b), tumor necrosis factor alpha (TNFa), and interleukin 6 (IL-6).

4. Change in Percent Predicted FEV1 [Baseline, end of treatment (Month 12 or Month 24)]

   The decline of lung function was assessed with forced expiratory volume (FEV1), which measures how much air is exhaled during one second of a forced exhale. Change is described as the difference in FEV1 at baseline subtracted from FEV1 at the end of treatment study visit. A protocol change during the study reduced the treatment time from 24 months to 12 months. The end of treatment study visit for participants in the early part of the study occurred at 24 months, while the end of treatment visit was a 12 months for participants enrolling later. Negative values indicate a decline in lung function over the course of the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University and Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia	United States	30322
2	Children's Healthcare of Atlanta at Scottish Rite	Atlanta	Georgia	United States	30342
3	Nationwide Children's Hospital	Columbus	Ohio	United States	43205

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: Arlene A Stecenko, MD, Emory University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 1, 2017

More Information

Publications

None provided.

• Responsible Party: Arlene Stecenko, Associate Professor, Emory University
• ClinicalTrials.gov Identifier: NCT00967798
• Other Study ID Numbers: IRB00012724; 1R01FD003527-01
• First Posted: Aug 28, 2009
• Last Update Posted: Jun 25, 2018
• Last Verified: Apr 1, 2018

• 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 Arlene Stecenko, Associate Professor, Emory University: cystic fibrosis; diabetes; inflammation; oxidative stress; redox balance; lung disease
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Sitagliptin Phosphate

Study Results

Participant Flow

Recruitment Details	Participants were recruited between May 2010 and August 2016.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Period Title: Overall Study
STARTED	17	16
COMPLETED	8	13
NOT COMPLETED	9	3

Baseline Characteristics

Arm/Group Title	Sitagliptin	Placebo	Total
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo	Total of all reporting groups
Overall Participants	17	16	33
Age (Count of Participants)
<=18 years	7 41.2%	5 31.3%	12 36.4%
Between 18 and 65 years	10 58.8%	11 68.8%	21 63.6%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 41.2%	6 37.5%	13 39.4%
Male	10 58.8%	10 62.5%	20 60.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 6.3%	1 3%
Not Hispanic or Latino	17 100%	15 93.8%	32 97%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 5.9%	0 0%	1 3%
White	16 94.1%	15 93.8%	31 93.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 6.3%	1 3%
Region of Enrollment (Count of Participants)
United States	17 100%	16 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Conversion to Cystic Fibrosis Related Diabetes
Description	The number of participants with conversion to cystic fibrosis related diabetes was determined.
Time Frame	Month 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Measure Participants	17	16
Count of Participants [Participants]	2 11.8%	1 6.3%

2. Secondary Outcome

Title	Change in Beta-cell Disposition Index
Description	Preservation of beta-cell function was to be assessed with the disposition index, which is a measurement of beta-cell function adjusted for insensitivity to insulin.
Time Frame	Baseline through Month 15

Outcome Measure Data

Analysis Population Description

Samples for the serum assays were destroyed when a freezer broke over a weekend and the samples thawed.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Measure Participants	0	0

3. Secondary Outcome

Title	Change in Redox Couples Glutathione/Glutathione Disulfide and Cysteine/Cystine
Description	Cysteine (Cys)/cystine (CySS) and glutathione (GSH)/glutathione disulfide (GSSG) redox couples are biomarkers of oxidative stress.
Time Frame	Baseline through Month 12

Outcome Measure Data

Analysis Population Description

Samples for the serum assays were destroyed when a freezer broke over a weekend and the samples thawed.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Measure Participants	0	0

4. Secondary Outcome

Title	Change in Inflammatory Cytokines
Description	Hyperglycemia causes release of pro-inflammatory cytokines which can further compromise beta-cell function by increasing insulin resistance and by inducing beta-cell apoptosis. Inflammatory cytokines that have been shown to contribute to destruction of beta-cells include interleukin 1 beta (IL-1b), tumor necrosis factor alpha (TNFa), and interleukin 6 (IL-6).
Time Frame	Baseline through Month 12

Outcome Measure Data

Analysis Population Description

Samples for the serum assays were destroyed when a freezer broke over a weekend and the samples thawed.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Measure Participants	0	0

5. Secondary Outcome

Title	Change in Percent Predicted FEV1
Description	The decline of lung function was assessed with forced expiratory volume (FEV1), which measures how much air is exhaled during one second of a forced exhale. Change is described as the difference in FEV1 at baseline subtracted from FEV1 at the end of treatment study visit. A protocol change during the study reduced the treatment time from 24 months to 12 months. The end of treatment study visit for participants in the early part of the study occurred at 24 months, while the end of treatment visit was a 12 months for participants enrolling later. Negative values indicate a decline in lung function over the course of the study.
Time Frame	Baseline, end of treatment (Month 12 or Month 24)

Outcome Measure Data

Analysis Population Description

The participants included in this analysis are limited to those who have a FEV value for the baseline and end of treatment visits.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin	Participants randomized to receive a placebo
Measure Participants	8	13
Mean (Standard Deviation) [percent predicted]	-9.7 (29.4)	-8.5 (14.3)

Adverse Events

Time Frame	For this study, the reporting period for adverse events is from the time the subject signs the informed consent form to 90 days after taking the last dose of the study medication, up to 15 months.
Adverse Event Reporting Description	Over 90% of the morbidity in cystic fibrosis (CF) is due to respiratory dysfunction and to readily identify an increase in the frequency of respiratory exacerbations, adverse events will be classified as respiratory or non-respiratory events. Respiratory events are defined as any increase in respiratory symptoms and/or signs (increase sputum production, increase in cough, runny or stuffy nose, a cold, decrease in lung function, and/or change in physical findings of the respiratory system).
Arm/Group Title	Sitagliptin		Placebo
Arm/Group Description	Participants randomized to receive Sitagliptin		Participants randomized to receive a placebo
All Cause Mortality
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/16 (0%)
Serious Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/17 (64.7%)		9/16 (56.3%)
General disorders
Hospitalization due to fever and body aches	0/17 (0%)	0	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Hospitalization due to osteochondroplasty of femoral neck due to previous motor vehical accident	0/17 (0%)	0	1/16 (6.3%)	1
Renal and urinary disorders
Lithotripsy with stent placement	1/17 (5.9%)	1	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalization due to Respiratory Event	11/17 (64.7%)	30	9/16 (56.3%)	27
Skin and subcutaneous tissue disorders
Hospitalization due to erythematous maculopapualr rash	1/17 (5.9%)	1	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)		16/16 (100%)
Gastrointestinal disorders
Constipation	1/17 (5.9%)	2	0/16 (0%)	0
Diarrhea	1/17 (5.9%)	1	3/16 (18.8%)	3
Gastritis	0/17 (0%)	0	1/16 (6.3%)	1
Heartburn	0/17 (0%)	0	1/16 (6.3%)	1
Intestinal blockage	0/17 (0%)	0	1/16 (6.3%)	1
Stomach blockage with abdominal pain	1/17 (5.9%)	1	0/16 (0%)	0
Nausea/vomiting	2/17 (11.8%)	2	0/16 (0%)	0
Vomiting and diarrhea	2/17 (11.8%)	2	0/16 (0%)	0
General disorders
Abdominal pain	2/17 (11.8%)	2	2/16 (12.5%)	3
Abnormal lab results	0/17 (0%)	0	1/16 (6.3%)	1
Decreased appetite	1/17 (5.9%)	1	0/16 (0%)	0
Difficulty sleeping	1/17 (5.9%)	2	0/16 (0%)	0
Elevated bilirubin	1/17 (5.9%)	1	0/16 (0%)	0
Elevated CO2	0/17 (0%)	0	1/16 (6.3%)	1
Elevated eosinophils	1/17 (5.9%)	1	0/16 (0%)	0
Elevated lipid panel/triglycerides	0/17 (0%)	0	1/16 (6.3%)	2
Elevated prothrombin induced by vitamin K absence-II (PIVKA-II)	1/17 (5.9%)	1	0/16 (0%)	0
Fatigue	0/17 (0%)	0	2/16 (12.5%)	2
Fever	2/17 (11.8%)	2	1/16 (6.3%)	1
Head tingling	1/17 (5.9%)	1	0/16 (0%)	0
Increased thirst and urination	0/17 (0%)	0	1/16 (6.3%)	1
Migraine headache	1/17 (5.9%)	1	0/16 (0%)	0
sleeplessness, restlessness, bruising, and muscle tightness	0/17 (0%)	0	1/16 (6.3%)	1
Tongue numbness due to colistin	1/17 (5.9%)	2	0/16 (0%)	0
Weight loss	1/17 (5.9%)	1	3/16 (18.8%)	3
Infections and infestations
Athletes foot	1/17 (5.9%)	1	0/16 (0%)	0
Ehrlichiosis	1/17 (5.9%)	1	0/16 (0%)	0
Tooth abcess	0/17 (0%)	0	1/16 (6.3%)	1
Urinary tract infection	1/17 (5.9%)	1	1/16 (6.3%)	1
Yeast infection	1/17 (5.9%)	1	2/16 (12.5%)	2
Musculoskeletal and connective tissue disorders
Ankle injury	0/17 (0%)	0	1/16 (6.3%)	1
Back pain	1/17 (5.9%)	1	0/16 (0%)	0
Broken/fractured hand bones	0/17 (0%)	0	1/16 (6.3%)	2
Spinal compression fracture	1/17 (5.9%)	1	0/16 (0%)	0
Foot pain	1/17 (5.9%)	1	2/16 (12.5%)	2
Joint pain	1/17 (5.9%)	1	0/16 (0%)	0
Joint stiffness in hands	1/17 (5.9%)	1	0/16 (0%)	0
Knee pain	1/17 (5.9%)	1	1/16 (6.3%)	1
Myositis	1/17 (5.9%)	1	0/16 (0%)	0
Neck pain from pulled muscle	1/17 (5.9%)	1	0/16 (0%)	0
Open wound to left forearm	0/17 (0%)	0	1/16 (6.3%)	1
Right knee contusion with edema	1/17 (5.9%)	1	0/16 (0%)	0
Shoulder pain	1/17 (5.9%)	1	1/16 (6.3%)	1
Tendinitis due to levaquin	1/17 (5.9%)	1	0/16 (0%)	0
Psychiatric disorders
Anxiety	2/17 (11.8%)	3	0/16 (0%)	0
Depression	2/17 (11.8%)	2	1/16 (6.3%)	1
Renal and urinary disorders
Acute kidney injury	0/17 (0%)	0	1/16 (6.3%)	1
Elevated creatinine	1/17 (5.9%)	1	2/16 (12.5%)	3
Elevated potassium	1/17 (5.9%)	1	0/16 (0%)	0
Hematuria	1/17 (5.9%)	1	0/16 (0%)	0
Kidney stones with colic	0/17 (0%)	0	1/16 (6.3%)	1
Reproductive system and breast disorders
Bacterial vaginosis	1/17 (5.9%)	1	0/16 (0%)	0
hydroceles with scrotal pain	0/17 (0%)	0	1/16 (6.3%)	1
Prostratitis with hematuria	0/17 (0%)	0	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory event	16/17 (94.1%)	63	16/16 (100%)	109
Skin and subcutaneous tissue disorders
Psoriasis	0/17 (0%)	0	1/16 (6.3%)	1
Rash	1/17 (5.9%)	3	1/16 (6.3%)	1
Sebaceous cyst, carbuncle on back	1/17 (5.9%)	1	0/16 (0%)	0
Skin irritation from colistin	0/17 (0%)	0	1/16 (6.3%)	1
Surgical and medical procedures
Complications with PICC line	3/17 (17.6%)	3	0/16 (0%)	0
Complications with port	1/17 (5.9%)	2	0/16 (0%)	0
Wisdom teeth extraction	0/17 (0%)	0	2/16 (12.5%)	2

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE 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.