SODA-POP: Study of Dietary Additive Phosphorus on Proteinuria and Fibroblast Growth Factor-23

• Sponsor: Geisinger Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02020785
• Collaborator: Johns Hopkins University (Other)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Phosphorus-based food additives are commonly used by food manufacturers for many applications, such as enhancing flavor, in ready-to-eat foods and beverages. While these additives can significantly increase an individual's daily phosphorus intake, little is known about the effect of dietary phosphorus on kidney health. In this study, the investigators will first lower baseline phosphorus intake to about 1000mg/d by educating participants to avoid foods with phosphorus additives. Then, participants will be randomized to a higher phosphorus period (~2gm/d) and a lower phosphorus period (~1gm/d) by providing unaltered, commercially-available food/beverage products with and without phosphorus additives.

The investigators hypothesize that participants will have higher urine albumin excretion and fibroblast growth factor-23 (FGF-23) during the higher phosphorus period compared to the lower phosphorus period.

Condition or Disease	Intervention/Treatment	Phase
Albuminuria	Other: Higher phosphorus period; Other: Lower phosphorus period	N/A

Detailed Description

The Study of Dietary Additive Phosphorus on Proteinuria and FGF-23 (SODA-POP) was a single-center, randomized, double-blind, two-period cross-over study that examined the effect of higher vs. lower phosphorus intake for 3 week periods, achieved by addition of commercially available diet beverages and breakfast bars to diet on albuminuria and fibroblast growth factor 23, in adults with presumed early chronic kidney disease (estimated glomerular filtration rate >= 45 ml/min/1.73m2; and urine albumin/creatinine ratio >=17 mg/g for men or >=25 mg/g for women).

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Cross-over Study Examining the Effects of Phosphorus Additives on Urinary Albumin Excretion and Fibroblast Growth Factor-23
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Higher phosphorus period Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks	Other: Higher phosphorus period; Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks. All participants at the beginning of the study will receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives.
Placebo Comparator: Lower phosphorus period Commercially-available unaltered food/beverage products without phosphorus additives (<10mg/d of phosphorus) will be given for 3 weeks	Other: Lower phosphorus period; Commercially-available unaltered food/beverage products without phosphorus additives (<10mg/d of phosphorus) will be given for 3 weeks. All participants at the beginning of the study will receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives.

Outcome Measures

Primary Outcome Measures

1. 24-hour Urine Albumin Excretion [3 weeks]

   Two 24-hour urine collections will be collected during the 3rd week of each period

2. Fibroblast Growth Factor-23 (FGF-23) [3 weeks]

   Plasma FGF-23 will be measured at the end of each 3 week period in the morning after an overnight fast. As this is a small pilot study, we will not adjust for multiple comparisons. A p value<0.05 will be considered statistically significant for both outcomes

Secondary Outcome Measures

1. Systolic Blood Pressure [2-3 weeks]

   Blood pressure was measured at the end of weeks 1, 2, and 3. At each visit, 3 readings were obtained in the seated position by trained and certified observers after 5 minutes of rest with an Omron HEM-907 device (Omron Healthcare Inc, Bannockburn, Ill) using a standardized protocol. We used the average of all blood pressure measurements at the end of weeks 1, 2, and 3 for each period.

2. Diastolic Blood Pressure [2-3 weeks]

   Blood pressure measured at the end of weeks 1, 2, and 3. At each visit, 3 readings were obtained in the seated position by trained and certified observers after 5 minutes of rest with an Omron HEM-907 device (Omron Healthcare Inc, Bannockburn, Ill) using a standardized protocol. We used the average of all these readings taken during end of weeks 1, 2, and 3 for each period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Adults at least 21 years of age with at least microalbuminuria

Exclusion Criteria:

Estimated glomerular filtration rate <45ml/min/1.73m2, poorly controlled diabetes or hypertension, nephrotic syndrome, hyperparathyroidism, Paget's Disease, multiple myeloma, uncontrolled thyroid disease, chronic antacid use, use of phosphorus binders, phosphorus supplements, or high-dose vitamin D, inability to complete feeding study, investigator discretion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Prohealth Clinical Research Unit	Baltimore	Maryland	United States	21207

Sponsors and Collaborators

• Geisinger Clinic
• Johns Hopkins University

Investigators

• Principal Investigator: Alex R Chang, MD, MS, Geisinger Clinic
• Study Director: Lawrence J Appel, MD, MPH, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Chang A, Batch BC, McGuire HL, Vollmer WM, Svetkey LP, Tyson CC, Sanguankeo A, Anderson C, Houston J, Appel LJ. Association of a reduction in central obesity and phosphorus intake with changes in urinary albumin excretion: the PREMIER study. Am J Kidney Dis. 2013 Nov;62(5):900-7. doi: 10.1053/j.ajkd.2013.04.022. Epub 2013 Jun 28.

• Responsible Party: Alexander Chang, Clinical Investigator, Geisinger Clinic
• ClinicalTrials.gov Identifier: NCT02020785
• Other Study ID Numbers: NA_00082089; 13CRP16970085; Satellite Dialysis
• First Posted: Dec 25, 2013
• Last Update Posted: Jun 5, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Alexander Chang, Clinical Investigator, Geisinger Clinic: proteinuria
• Additional relevant MeSH terms: Proteinuria; Albuminuria

Study Results

Participant Flow

Recruitment Details	Primary recruitment strategies included mass mailing of study brochures to individuals with self-reported type 2 diabetes in neighboring zip codes and to past and current participants of other research studies.

Arm/Group Title	Higher Phosphorus Period First, Then Lower Phosphorus Period	Lower Phosphorus Period First, Then Higher Phosphorus Period
Arm/Group Description	Randomized to higher phosphorus period first, then lower phosphorus period second. Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Randomized to higher phosphorus period first, then lower phosphorus period second. Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks
Period Title: First Intervention (3 Weeks)
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0
Period Title: First Intervention (3 Weeks)
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Higher Phosphorus Period Then Lower Phosphorus Period	Lower Phosphorus Period Then Higher Phosphorus Period	Total
Arm/Group Description	Randomized to higher phosphorus period first, then lower phosphorus period second. Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Randomized to higher phosphorus period first, then lower phosphorus period second. Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks	Total of all reporting groups
Overall Participants	15	16	31
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 46.7%	9 56.3%	16 51.6%
>=65 years	8 53.3%	7 43.8%	15 48.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.0 (7.3)	64.2 (9.9)	66.0 (8.8)
Sex: Female, Male (Count of Participants)
Female	6 40%	12 75%	18 58.1%
Male	9 60%	4 25%	13 41.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	15 100%	16 100%	31 100%
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	14 93.3%	14 87.5%	28 90.3%
White	1 6.7%	2 12.5%	3 9.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%	16 100%	31 100%

Outcome Measures

1. Primary Outcome

Title	24-hour Urine Albumin Excretion
Description	Two 24-hour urine collections will be collected during the 3rd week of each period
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Higher Phosphorus Period	Lower Phosphorus Period
Arm/Group Description	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks
Measure Participants	31	31
Mean (95% Confidence Interval) [mg/day]	86.2	76.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Higher Phosphorus Period, Lower Phosphorus Period
	Comments	Sample size for this study was calculated using the xsampsi module in STATA, based on a previous study with repeat 24-hour urine collections (standard deviation, 1.04). At an α level of 0.05, we anticipated that a sample size of 30 participants with mean albuminuria of 100 mg/d would result in >80% power to detect a 13% difference in log- transformed albuminuria between the higher and lower phosphorus additive periods.
	Type of Statistical Test	Superiority
	Comments	Main analyses were intention-to-treat using mixed effects models allowing intercepts to vary for each individual. Carryover effects were examined by using treatment by assignment-order interaction terms. Pre-specified sensitivity analyses were conducted excluding patients who were non-compliant, prior to data analysis: 1st, noncompliance based on missing product pickups and follow-up visits; 2nd, suspected poor compliance (< 250 mg difference between the higher and lower period).]
Statistical Test of Hypothesis	p-Value	0.05
	Comments	For each outcome, a p value < 0.05 was considered statistically significant without adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.143
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate (14.3%, 95% CI: -2.5%, 34.0%) is the estimated difference between end of higher phosphorus period and end of lower phosphorus period from mixed effects analyses for log-transformed 24-hour urine albumin excretion

2. Primary Outcome

Title	Fibroblast Growth Factor-23 (FGF-23)
Description	Plasma FGF-23 will be measured at the end of each 3 week period in the morning after an overnight fast. As this is a small pilot study, we will not adjust for multiple comparisons. A p value<0.05 will be considered statistically significant for both outcomes
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Higher Phosphorus Period	Lower Phosphorus Period
Arm/Group Description	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks
Measure Participants	31	31
Geometric Mean (95% Confidence Interval) [Relative units/ml]	132.6	128.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Higher Phosphorus Period, Lower Phosphorus Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	For each outcome, a p value < 0.05 was considered statistically significant without adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95%; -0.059 to 0.136
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate (3.4%, 95% CI: -5.9%, 13.6%) is the estimated difference between end of higher phosphorus period and end of lower phosphorus period from mixed effects analyses for log-transformed fibroblast growth factor 23

3. Secondary Outcome

Title	Systolic Blood Pressure
Description	Blood pressure was measured at the end of weeks 1, 2, and 3. At each visit, 3 readings were obtained in the seated position by trained and certified observers after 5 minutes of rest with an Omron HEM-907 device (Omron Healthcare Inc, Bannockburn, Ill) using a standardized protocol. We used the average of all blood pressure measurements at the end of weeks 1, 2, and 3 for each period.
Time Frame	2-3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Higher Phosphorus Period	Lower Phosphorus Period
Arm/Group Description	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks
Measure Participants	31	31
Mean (Standard Deviation) [mmHg]	126.9 (13.5)	128 (15.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Higher Phosphorus Period, Lower Phosphorus Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	For each outcome, a p value < 0.05 was considered statistically significant without adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	mean difference (during each period)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -4.1 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Diastolic Blood Pressure
Description	Blood pressure measured at the end of weeks 1, 2, and 3. At each visit, 3 readings were obtained in the seated position by trained and certified observers after 5 minutes of rest with an Omron HEM-907 device (Omron Healthcare Inc, Bannockburn, Ill) using a standardized protocol. We used the average of all these readings taken during end of weeks 1, 2, and 3 for each period.
Time Frame	2-3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Higher Phosphorus Period	Lower Phosphorus Period
Arm/Group Description	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) will be given for 3 weeks At the beginning of the study participants receive dietary education to reduce their baseline consumption of phosphorus to a goal of ~1gm/d by receiving education on avoiding phosphorus-based additives. Patients then randomized to higher phosphorus period or lower phosphorus period first. Higher phosphorus period: Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks Lower phosphorus period: Commercially-available unaltered food/beverage products without any phosphorus additives given for 3 weeks
Measure Participants	31	31
Mean (Standard Deviation) [mmHg]	69.3 (10.8)	70.2 (11.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Higher Phosphorus Period, Lower Phosphorus Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	For each outcome, a p value < 0.05 was considered statistically significant without adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	mean difference (during each period)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -2.7 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	At the end of each 3 week study period.
Adverse Event Reporting Description	Participants were asked at the end of each study period if they experienced possible side effects.
Arm/Group Title	Higher Phosphorus Period		Lower Phosphorus Period
Arm/Group Description	Commercially-available unaltered food/beverage products containing phosphorus additives (~1gm/d of phosphorus) given for 3 weeks		Commercially-available unaltered food/beverage products without phosphorus additives (<10mg/d of phosphorus) given for 3 weeks
All Cause Mortality
	Higher Phosphorus Period		Lower Phosphorus Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/31 (0%)
Serious Adverse Events
	Higher Phosphorus Period		Lower Phosphorus Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Higher Phosphorus Period		Lower Phosphorus Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/31 (71%)		23/31 (74.2%)
Gastrointestinal disorders
Gastrointestinal symptoms	19/31 (61.3%)	19	21/31 (67.7%)	21
General disorders
Fatigue	7/31 (22.6%)	7	7/31 (22.6%)	7
Infections and infestations
Flu-like symptoms	1/31 (3.2%)	1	3/31 (9.7%)	3
Musculoskeletal and connective tissue disorders
Back pain	8/31 (25.8%)	8	12/31 (38.7%)	12
Skin and subcutaneous tissue disorders
Skin rash	2/31 (6.5%)	2	3/31 (9.7%)	3

Limitations/Caveats

Small sample size, short duration of intervention, changes in background diet during the intervention.

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.