EAL

CKD: Fish Oil Therapy (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

This study was designed to evaluate whether a two-year course of alternate-day prednisone or of daily omega-3 fatty acids (O3FA) on a background of angiotensin-converting enzyme (ACE) inhibitor therapy in hypertension patients provides an effective means of preventing deterioration of GFR in young patients with IgA nephropathy.

Inclusion Criteria:

Age less than or equal to 40 years at the time of entry
A renal biopsy showing IgAN
Estimated GFR (eGFR) more than or equal to 50ml per minute per 1.73m² using an age-appropriate formula (Schwartz equation) or (Cockcroft-Gault equation)
Proteinuria or biopsy findings of persistent severe proteinuria or moderate proteinuria.

Exclusion Criteria:

Systemic Lupus Erythematosus (SLE)
Henoch-Schonlein purpura
Abnormal liver function
Diabetes, cataracts, aseptic necrosis of any bone, or other conditions that potentially are exacerbated by prednisone
Use of prednisone or other immunosuppression and/or fish oils for more than three months.

Description of Study Protocol:

Recruitment: A network of 37 adult and pediatric nephrology centers recruited patients for the trial
Design: Placebo-controlled, double-blind, prospective clinical trial
Blinding used: Double-blinding was used.

Intervention

Participants were randomized into three treatment arms: Prednisone group, O3FA group and placebo group.

The prednisone group received two years of treatment with a tapering regimen of alternate day prednisone
- First three months: Subjects received 60mg per m²(maximum of 80mg per m²) every other day
- Next nine months: Subjects received 40mg per m²(maximum of 60mg per m²) every other day
- Next 12 months: Subjects received 30mg per m²(maximum of 40mg per m²) every other day.
The O3FA group received two years of treatment with Omacor, a purified preparation of O3FA, which provides 1.88g per day of EPA and 1.48g per day DHA with the administration of four grams of this product
The patients in the placebo group received two years of treatment with placebo. Half of them received prednisone placebo tablets and half of them received O3FA placebo capsules containing corn oil.

*All patients with hypertension were given enalapril in addition to the study medications. Patients were stratified on the basis of the presence or absence of hypertension.

Statistical Analysis

The product limit method was used to describe the distribution of time to failure and to estimate the cumulative proportion of failures at three years in the three treatment arms
The log-rank test was used to compare the O3FA and prednisone arms with the placebo group with respect to time to failure
The proportional hazards model was used to determine the relationship between time to failure and demographics, hypertensive status and protein excretion at baseline
Chi-squared analyses were used to compare the three treatment arms with respect to categorical variables. When significance was detected, a Fisher exact test was used to compare the placebo arm with the other treatment arms.
Two-way ANOVAs were used to evaluate the effects of treatment arm, time and hypertensive status on UP/C ratio and GFR and on changes from baseline in these measures
An intention-to-treat analysis was performed with all randomly assigned patients.

Data Collection Summary:

Timing of Measurements

Patients received treatments for two years but measurements were taken until three years. It is difficult to find how often measurements (BP, eGFR, etc.) were measured.

Dependent Variables

Time to failure: The interval until the eGFR fell to less than 60% of baseline value
Urinary protein/creatinine ratio: UP/C (first morning urine protein to creatinine ratio)
Phospholipid fatty acid profiles: Phospholipid fatty acid profiles for the O3FA group and the placebo group receiving corn oil supplements
Laboratory values: For example, blood urea nitrogen (BUN), creatinine (Cr), alkaline phosphatase (Alk Phos), albumin (Alb), cholesterol (Chol), hemoglobin (Hgb), white blood cells (WBC), etc.

Independent Variables

A tapering regimen of alternate-day prednisone tablets
Omega-3 fatty acid supplements
Placebo.

Description of Actual Data Sample:

Initial N: 96 patients randomly assigned (33 to prednisone group, 32 to O3FA group and 31 to placebo group)
Attrition (final N): 72 patients (18 exited prematurely and six people opted out after randomization but before the start of the study drugs)
Age: Average age was 21.7±10 years. Differences between groups was 24±10 years for prednisone group, 20±10 years for O3FA group, and 21±10 years for placebo group.
Ethnicity: Only stated as percentage being Caucasian. Overall percentage was 71.7% white. Differences between groups:
- 59% for prednisone group
- 72% for O3FA group
- 84% for placebo group.
Other relevant demographics: Patients were stratified on the basis of the presence or absence of hypertension. Other features of patients for each group included: Percentage of hypertensive, systolic BP, diastolic BP, eGFR and UP/C ratio. There were significant differences between the three groups in regards to ethnicity (percentage who were Caucasian) and UP/C ratio at the beginning of the study.
Location: This was a multi-center study that included nephrology centers in the United States and Canada.

Summary of Results:

Variables	Prednisone Group	O3FA Group	Placebo Group	Statistical Significance of Group Difference
Time to failure (GFR <60%)	Two patients (9.2%) (P=0.496)	Eight patients (18.8%) (P=0.232)	Four patients (8.7%)	No statistical significance between treatment groups and placebo group
*Subgroup: Time to failure (GFR <60%)	One patients (5.6%) (P=0.303)	Six patients (23.7%) (P=0.683)	Two patients (16.4%)	No statistical significance between treatment groups and placebo group
**UP/C ratio >1				No significant difference between treatment arms with respect to percentage of visits at which the UP/C ratio was less than one
UP/C ratio >1 at >50% of visits	Four patients (15%)	14 patients (50%)	Eight patients (29%)	No significant difference between treatment arms with respect to percentage of visits at which the UP/C ratio was more than 50% or the proportion of patients whose UP/C ratio was 50% of baseline at more than half of their visits
Albumin (g per dL)	Start (3.9) Finish (4.1)	Start (3.6) Finish (3.9)	Start (4.0) Finish (4.2)	Significant difference between treatment arms with respect to albumin levels at baseline (P=0.018)
ALT (IU per L)	Start (20) Finish (20)	Start (15) Finish (16)	Start (12) Finish (18)	Significant difference between treatment arms with respect to changes from baseline for ALT levels (P=0.041)
Triglycerides (mg per dL)	Start (141) Finish (200)	Start (151) Finish (124)	Start(144) Finish (168)	Significant difference between treatment arms with respect to changes from baseline for triglycerides (P=0.041)
WBC count	Start (6,300) Finish (9,500)	Start (6,600) Finish (6,000)	Start (6,100) Finish (5,800)	Significant difference between treatment arms with respect to changes from baseline for WBC levels (P=0.005)

*Baseline proteinuria was significantly associated with time to failure (P=0.009). Because of this, a subset analysis of failure was performed on 52 patients that had baseline UP/C ratios between one and three. In this subgroup, there were 16 (48%) patients in the prednisone group, 23 (72%) in the O3FA group and 13 (39%) in the placebo group. In this subgroup, there were nine events (see second row of table).
** Data was not provided in article except for the statement about significance.

Other Findings

Phospholipid fatty acid profiles were compared among 23 patients who received O3FA and 13 who received placebo capsules. Figure One in the study shows that there is a clear difference/improvement in the fatty acid profiles among the treatment group vs. the placebo group; however, no values are listed and no report of statistical significance was available.

Adverse Events

There was a significant difference between the prednisone group and the placebo group in respect to the incidence of heartburn (48% vs. 16%; P=0.018) and increased appetite (73% vs. 32%; P<0.001).

Author Conclusion:

The results from this study did not support the hypothesis that patients with IgAN derive significant benefit from the use of prednisone or O3FA. Pitfalls of the study listed by the author include:

The placebo group had fewer patients with higher proteinuria at baseline than the treatment groups
Small sample size, and therefore a poorly powered study
Five of the 14 (36%) treatment failures occurred after 36 months of follow-up, which indicates that the rate of progression is not constant over time.

The authors propose that further studies should be conducted to evaluate the response to corticoseroids and O3FA in a larger number of patients over a longer period of time. The design of a future study should also include a reflection of the variability of the rate of progression over time.

Funding Source:

Reviewer Comments:

The study was well designed; however, the limitations as pointed out by the authors did hinder the study. There seemed to be some missing data that made it difficult to interpret the results.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	No
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes