Trial Outcomes & Findings for Diet and Systemic Inflammation (NCT NCT01424306)

Results Overview

The concentration of C-reactive protein in fasting plasma will be measured by high-sensitivity assay at the beginning (day 1) and end (day 9) of each 8-day dietary period.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

25 participants

Primary outcome timeframe

Beginning (day 1) and end (day 9) of each diet period.

Results posted on

2017-08-14

Participant Flow

63 volunteers who responded to newspaper advertisements and fliers posted in the Seattle area were screened for eligibility between December 2011 and December 2013.

Of those 63 volunteers screened, 38 did not meet inclusion criteria and 0 declined to participate. 25 subjects randomized

Participant milestones

Participant milestones
Measure	Fructose - Glucose - HFCS Subjects treated in the order fructose-sweetened beverage - wash out - glucose-sweetened beverage- wash out - HFCS-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Fructose - HFCS - Glucose Subjects treated in the order fructose-sweetened beverage - wash out - HFCS-sweetened beverage- wash out - glucose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	HFCS - Fructose - Glucose Subjects treated in the order HFCS-sweetened beverage - wash out - fructose-sweetened beverage- wash out - glucose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	HFCS - Glucose - Fructose Subjects treated in the order HFCS-sweetened beverage - wash out - glucose-sweetened beverage- wash out - fructose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Glucose - Fructose - HFCS Subjects treated in the order glucose-sweetened beverage - wash out - fructose-sweetened beverage- wash out - HFCS-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Glucose - HFCS - Fructose Subjects treated in the order glucose-sweetened beverage - wash out - HFCS-sweetened beverage- wash out - fructose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.
Overall Study STARTED	4	4	3	3	5	6
Overall Study COMPLETED	4	4	3	3	4	6
Overall Study NOT COMPLETED	0	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Fructose - Glucose - HFCS Subjects treated in the order fructose-sweetened beverage - wash out - glucose-sweetened beverage- wash out - HFCS-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Fructose - HFCS - Glucose Subjects treated in the order fructose-sweetened beverage - wash out - HFCS-sweetened beverage- wash out - glucose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	HFCS - Fructose - Glucose Subjects treated in the order HFCS-sweetened beverage - wash out - fructose-sweetened beverage- wash out - glucose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	HFCS - Glucose - Fructose Subjects treated in the order HFCS-sweetened beverage - wash out - glucose-sweetened beverage- wash out - fructose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Glucose - Fructose - HFCS Subjects treated in the order glucose-sweetened beverage - wash out - fructose-sweetened beverage- wash out - HFCS-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.	Glucose - HFCS - Fructose Subjects treated in the order glucose-sweetened beverage - wash out - HFCS-sweetened beverage- wash out - fructose-sweetened beverage Treatments each lasted 8 days and were separated by a 20-day washout.
Overall Study Protocol Violation	0	0	0	0	1	0

Baseline Characteristics

Diet and Systemic Inflammation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Study Subjects n=24 Participants All six treatment orders combined
Age, Continuous	36 years STANDARD_DEVIATION 12 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants
Region of Enrollment United States	24 Participants n=5 Participants
BMI	27.4 kg/m^2 STANDARD_DEVIATION 4.8 • n=5 Participants
Fasting glucose	92 mg/dL STANDARD_DEVIATION 10 • n=5 Participants
Physical activity	68.7 MET-hr/wk STANDARD_DEVIATION 45.9 • n=5 Participants
Estimated total calorie requirement	2560 kcal/d STANDARD_DEVIATION 370 • n=5 Participants

PRIMARY outcome

Timeframe: Beginning (day 1) and end (day 9) of each diet period.

Population: All completed participants combined in per protocol analysis

The concentration of C-reactive protein in fasting plasma will be measured by high-sensitivity assay at the beginning (day 1) and end (day 9) of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 n=24 Participants CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 n=24 Participants CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 n=24 Participants CRP measured on day 9 of HFCS-sweetened beverage intervention period
Fasting Plasma C-reactive Protein	0.91 mg/L Interval 0.45 to 2.35	1.07 mg/L Interval 0.48 to 2.1	1.67 mg/L Interval 0.36 to 2.91	1.09 mg/L Interval 0.38 to 3.04	1.18 mg/L Interval 0.38 to 2.49	0.84 mg/L Interval 0.49 to 2.48

PRIMARY outcome

Timeframe: End (day 9) of each diet period

Population: All completed participants combined in per protocol analysis

The concentration of interleukin-6 in fasting plasma will be measured by high-sensitivity enzyme-linked immunosorbent assay at the end (day 9) of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Fasting Plasma Interleukin-6 on Day 9 of Each Diet Period	0.97 pg/mL Interval 0.62 to 1.9	1.14 pg/mL Interval 0.61 to 1.95	0.96 pg/mL Interval 0.61 to 1.79	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: All completed participants combined in per protocol analysis

The concentration of adiponectin in fasting plasma will be measured by enzyme-linked immunosorbent assay at the end (day 9) of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Fasting Plasma Adiponectin	4635 ng/mL Standard Deviation 2545	4353 ng/mL Standard Deviation 2198	4514 ng/mL Standard Deviation 2195	—	—	—

SECONDARY outcome

Timeframe: The mean daily calorie intake during each of the 8-day diet periods will be calculated.

Population: All completed participants combined in per protocol analysis

Mean daily calorie intake will be assessed during each of the three 8-day diet periods. All foods will be provided to the subjects in excess of what they are estimated to require, and calorie intake will be assessed by subtracting returned foods from foods administered.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Mean Daily Calorie Intake	2970 kcal/d Standard Deviation 482	2940 kcal/d Standard Deviation 460	2950 kcal/d Standard Deviation 535	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: All completed participants combined in per protocol analysis

Intestinal permeability will be assessed on day 9 of each diet period by administering a beverage containing 2 g of mannitol and 5 g of lactulose followed by collecting urine for 5 hours afterwards. Recovery of mannitol and lactulose in urine will be measured by gas chromatography, and will be indicative of the degree of intestinal permeability.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Intestinal Permeability, as Assessed by the 5-hour Urinary Lactulose/Mannitol Test	0.047 ratio Interval 0.031 to 0.054	0.043 ratio Interval 0.031 to 0.048	0.031 ratio Interval 0.026 to 0.035	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: All completed participants combined in per protocol analysis

Zonulin concentrations will be measured by enzyme-linked immunosorbent assay in fasting plasma collected on day 9 of each diet period. Plasma zonulin is a marker of intestinal permeability.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Fasting Plasma Zonulin Concentrations	12.78 ng/mL Standard Deviation 1.54	12.69 ng/mL Standard Deviation 1.70	12.92 ng/mL Standard Deviation 1.49	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: All completed participants combined for protocol analysis

Lipopolysaccharide-binding protein (LBP) will be measured by enzyme-linked immunosorbent assay in fasting plasma collected on day 9 of each diet period. LBP is an acute phase protein secreted by the liver in response to endotoxin (lipopolysaccharide) exposure.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=24 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=24 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=24 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Fasting Plasma Lipopolysaccharide-binding Protein (LBP)	27.7 ug/mL Interval 19.8 to 34.2	26.1 ug/mL Interval 21.7 to 40.0	29.8 ug/mL Interval 21.5 to 36.0	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of TNF-alpha mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of TNF-alpha mRNA	1.40 copy number/ng total RNA Standard Deviation 0.58	1.44 copy number/ng total RNA Standard Deviation 0.89	1.24 copy number/ng total RNA Standard Deviation 0.67	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of IL-1beta mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of IL-1beta mRNA	0.41 copy number/ng total RNA Interval 0.26 to 0.54	0.33 copy number/ng total RNA Interval 0.25 to 0.41	0.32 copy number/ng total RNA Interval 0.27 to 0.84	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of IL-6 mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of IL-6 mRNA	0.53 copy number/ng total RNA Interval 0.35 to 0.74	0.49 copy number/ng total RNA Interval 0.37 to 0.58	0.51 copy number/ng total RNA Interval 0.38 to 0.75	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of IL-10 mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of IL-10 mRNA	0.66 copy number/ng total RNA Interval 0.34 to 1.14	0.90 copy number/ng total RNA Interval 0.65 to 1.19	0.95 copy number/ng total RNA Interval 0.34 to 1.44	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of CCL2 mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of CCL2 mRNA	31.5 copy number/ng total RNA Interval 22.9 to 47.6	27.2 copy number/ng total RNA Interval 22.6 to 33.6	25.3 copy number/ng total RNA Interval 19.3 to 34.4	—	—	—

SECONDARY outcome

Timeframe: End (day 9) of each diet period.

Population: A subset of the study population opted to undergo voluntary adipose tissue biopsy

A subgroup of the study population will be enrolled into an ancillary study that will aim to assess the effects of consuming fructose- vs. high-fructose corn syrup- vs. glucose-sweetened beverages on adipose tissue inflammation. Adipose tissue inflammation will be assessed by whole adipose tissue gene expression analysis of IFN-gamma mRNA. Abdominal subcutaneous adipose tissue samples will be obtained from subjects enrolled into the ancillary study by needle aspiration biopsy on day 9 of each 8-day dietary period.

Outcome measures

Outcome measures
Measure	Fructose Arm - Day 1 n=14 Participants CRP measured on day 1 of fructose-sweetened beverage intervention period	Fructose Arm - Day 9 n=14 Participants CRP measured on day 9 of fructose-sweetened beverage intervention period	Glucose Arm - Day 1 n=14 Participants CRP measured on day 1 of glucose-sweetened beverage intervention period	Glucose Arm - Day 9 CRP measured on day 9 of glucose-sweetened beverage intervention period	HFCS Arm - Day 1 CRP measured on day 1 of HFCS-sweetened beverage intervention period	HFCS Arm - Day 9 CRP measured on day 9 of HFCS-sweetened beverage intervention period
Adipose Tissue Inflammation - Tissue Expression of IFN-gamma mRNA	0.23 copy number/ng total RNA Interval 0.15 to 0.44	0.20 copy number/ng total RNA Interval 0.15 to 0.27	0.23 copy number/ng total RNA Interval 0.17 to 0.38	—	—	—

Adverse Events

Fructose Arm

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Glucose Arm

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

HFCS Arm

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Fructose Arm n=24 participants at risk Powdered fructose mixed with powdered drink flavoring (Lemon)	Glucose Arm n=25 participants at risk Powdered dextrose mixed with powdered drink flavoring (Lemon) and aspartame to match sweetness	HFCS Arm n=24 participants at risk HFCS liquid mixed with powdered drink flavoring (Lemon) and aspartame to match sweetness
Skin and subcutaneous tissue disorders Bruise from abdominal needle aspiration biospy	7.1% 1/14 • Number of events 1 • Through study completion, an average of 2 years.	7.1% 1/14 • Number of events 1 • Through study completion, an average of 2 years.	0.00% 0/13 • Through study completion, an average of 2 years.
Gastrointestinal disorders Gastrointestinal discomfort	4.2% 1/24 • Number of events 1 • Through study completion, an average of 2 years.	0.00% 0/25 • Through study completion, an average of 2 years.	0.00% 0/24 • Through study completion, an average of 2 years.

Additional Information

Mario Kratz

Fred Hutchinson Cancer Research Center

Phone: 206-667-7362

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place