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Vegetarian Nutrition

VN: Therapeutic Vegetarian Diets and Attrition (2009)

Citation:

Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Wong JM, de Souza R, Emam A, Parker TL, Vidgen E, Lapsley KG, Trautwein EA, Josse RG, Leiter LA, Connelly PW. Effects of a dietary portfolio of cholesterol-lowering foods vs. lovastatin on serum lipids and C-reactive protein. JAMA. 2003 Jul 23; 290 (4): 502-510.

PubMed ID: 12876093
 
Study Design:
Randomized control trial.
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To compare the cholesterol-reducing capability of a low-fat vegetarian diet containing plant sterols, viscous fibers, soy protein and almonds with a low-fat diet plus statin medication.

Inclusion Criteria:

Healthy males and post-menopausal females with hyperlipidemia.

Exclusion Criteria:
  • Pre-menopausal females.
  • The authors noted that none of the participants had a history of:
    • Cardiovascular disease
    • Untreated hypertension
    • Diabetes
    • Renal disease
    • Liver disease.
Description of Study Protocol:

Recruitment

  • Recruitment of hyperlipidemic patients at the Clinical Nutrition and Risk Factor Modification Center at St. Michael's Hospital, Toronto, Canada
  • Advertisements in community newspapers.

Design

  • Randomized parallel design (randomization done using a random number generator)
  • Four-week intervention period
  • Three groups
    • Control (C): N=16
    • Statin (S): N=14
    • Dietary Portfolio (DP): N=16.

Blinding Used

Some aspects of the study were blinded and others were not.

  • Blinded
    • Patients and study personnel were blinded to type of medication
      • Participants were randomized into treatment groups by the statistician
      • Statistician held the code for the placebo and statin medication used in the study
      • Statistician was in a separate location from the study site.
    • Laboratory staff received samples labeled with participant codes and dates.
  • Not blinded: Dietitians checked participants' food records.

Intervention

  • Routine therapeutic low-fat diet (similar to current NCEP guidelines) for one month prior to intervention
  • Participants stratified based on sex and pre-treatment LDL-C level
  • Randomized into one of three treatment groups
    • Control diet plus placebo
    • Control diet plus statin
    • Dietary Portfolio diet plus placebo.
  • Four-week intervention. 

Diets

  • Components of the C and DP diets were balanced with respect to fatty acid profile, dietary cholesterol and fiber intake
  • Diets were vegetarian but not vegan (eggs and dairy products were allowed)
  • Each participant's diet was calculated to achieve weight maintenance
  • All foods as well as the okra to be consumed by the participants were provided (participants picked up food at weekly clinic visits)
  • Participants were instructed to purchase specific fruits and non-starchy vegetables and were reimbursed on presentation of receipts
  • Seven-day rotating menu plans were used by all participants with modifications made for personal preferences as long as the overall goals for the diet were met
  • Non-caloric beverages were not restricted
  • Participants were given self-taring electronic scales to measure all foods both prior to and during intervention.
  • Control diet was based on:
    • Skim milk, fat-free cheese and yogurt
    • Egg substitute or egg whites
    • Whole grain breakfast cereals (fiber content 2.5g per 1,000kcal)
    • Whole wheat bread (fiber content 2.0g per 1,000kcal)
    • High monounsaturated sunflower oil and safflower oil incorporated into prepared muffins to balance the fatty acid profile of the DP.
  • Dietary Portfolio diet was based on:
    • Plant sterols (1.0g per 1,000kcal) via a plant sterol-enriched margarine
    • Soy protein (21.4g per 1,000kcal) using soy milk and soy meat analogs
    • Viscous fibers (9.8g per 1,000kcal)
    • Primarily from oats, barley and psyllium
    • Additionally using eggplant (0.2g per 1,000kcal) and okra (0.4g per 1,000kcal)
    • Almonds (14g per 1,000kcal)
    • Eggs (one per week) and butter (nine grams per day) were provided to balance the saturated fat and cholesterol content of C diet.

Statin Therapy

  • 20mg lovastatin
    • Crushed and delivered in Veggiecap capsules
    • One capsule per day in the evening for the 28 days of the study.
  • Placebo
    • Lactose and blue food coloring delivered in veggie cap capsules
    • One capsule per day in the evening for the 28 days of the study.
  • All capsules were dispensed by hospital pharmacy in identical containers
  • Participants returned containers for capsule counts at the end of the month.

Measurements

  • Weight: Measured weekly
  • Blood samples
    • 12-hour overnight fast prior to blood collection
    • Samples taken at two-week intervals.
  • Blood pressure
    • Measured twice in the non-dominant arm at each clinic visit
    • Mercury sphygmomanometer used by the same observer.

Food Records

  • Seven-day diet histories were recorded for the week prior to beginning the intervention
  • Completed menu checklists returned weekly and checked by dietitians
  • Satiety ratings were recorded weekly: Used a nine-point bipolar semantic scale
    • Minus four: Excessively hungry
    • Zero: Neutral
    • Plus four: Discomfort due to excess food intake.

Exercise

Previous week's exercise was reviewed and recorded by dietitians to ensure that it remained constant during the intervention period.

Statistical Analysis

  • Change in values measured between week zero and week four:
    • Body weight
    • Blood lipids
      • Total cholesterol (TC)
      • HDL-C
      • LDL-C
      • Triglycerides.
    • Apolipoproteins A1 and B
    • Ratios
      • TC to HDL-C
      • LDL-C to HDL-C
      • Apo B to Apo A1.
    • C-reactive protein
    • Blood pressure
    • Calculated cardiovascular heart disease CHD risk.
  • Differences between treatments were assessed by Student-Neuman-Keuls multiple range test
  • Analysis of covariance was used to assess treatment interaction by treatment and sex
  • Intention-to-treat analysis done by including the five participants for whom baseline values were available but who dropped out prior to the week two blood sample (two-tailed paired T-test used to assess the significance of the percentage change from baseline for these participants if it was assumed that they would have demonstrated either no change, 50% of the mean change or 100% of the mean change observed)
  • Results reported as mean (SE)
  • Significance: P<0.05.
Data Collection Summary:

Timing of Measurements

  •  Weekly visits to clinic
    • Weight
    • Blood pressure
    • Menu checklists
    • Satiety ratings
    • Exercise level monitored.
  • Blood samples collected at baseline, week two and week four.

Dependent Variables

  • Serum lipids (mmol per L): TC, HDL-CLDL-C and Triglycerides
  • C-reactive protein (mg per L)
  • Blood pressure (mm Hg)
  • Body weight (kg).

Independent Variables

  • Dietary Portfolio diet: Low-fat vegetarian diet containing specific percentages of plant sterols, viscous fibers, soy protein and almonds  
  • Lovastatin.

Control Variables

Most foods provided.

Description of Actual Data Sample:

Initial N

55.

Attrition (Final N)

46; 25 males, 21 females.

  • Four randomized participants did not start the study
  • Three withdrew during first week of study (job relocation, family ill health, time commitment demands)
  • Two withdrawn due to elevation of liver enzymes or muscle discomfort.

Age

59 (one) years; range, 36 years to 85 years of age.

Ethnicity

Race of Study Participants Male Female
European
21
20
East Indian
2
0
Chinese
1
0
Black
0
1
Hispanic
1
0

Location

Toronto, Ontario, Canada.

 

Summary of Results:
  • Reductions in blood lipids and C-reactive protein in the S and DP groups were significantly greater than the respective changes in the C group
  • No difference was observed in changes in blood lipids or C-reactive protein between the S and DP groups.

  Change from Baseline to Week Four

Statistical Significance Between Control and Intervention Groups*

Control Group (C)
(N=16)

Control + Statin Group (S)
(N=14)

Dietary Portfolio Group (DP)
(N=16)

Body Weight (kg)
-0.3 (0.2)
-0.2 (0.1)
-0.4 (0.2)
NS
Total Cholesterol (mmol per L)
-0.40 (0.11)
-1.55 (0.23)
-1.52 (0.22)
P<0.005
LDL-C (mmol per L)

-0.37 (0.09)

 -1.43 (0.18) (  P<0.001)*

-1.36 (0.18) (  P=0.001)

P<0.005

HDL-C (mmol per L)

-0.12 (0.03)

 -0.04 (0.04)

-0.08 (0.03)

NS

TC/HDL ratio
0.25 (0.15)
-1.24 (0.22)
-1.05 (0.24)

P<0.005

LDL/HDL ratio
0.05 (0.09)
-1.17 (0.17) (  P=0.001)
-1.03 (0.19) (  P=0.001)

P<0.005

Triglycerides (mmol per L)
0.19 (0.15)
-0.19 (0.18)
-0.19 (0.18)
NS
C-reactive Protein (mg per L)
-0.28 (0.16)
-1.50 (0.42) (  P=0.002)
-1.25 (0.62) (  P=0.02)
P<0.005
10-year CHD Risk
-0.3 (0.7)
-3.3 (0.9)
-2.9 (0.5 )
P<0.005

* Values with a   P-value indicate a significant within group change from baseline.

Comparisons of S and DP differences are statistically significant from those in C, but differences between S and DP are not significantly different from each other.

 Other Findings

  • High compliance rate for all three groups:
    • C: 93% (3%)
    • S: 95% (3%)
    • DP: 94% (3%)
    • 98% of capsules provided were taken.
  • Participants lost a similar amount of weight in all three groups:
    • C: 0.3 (0.2) kg, P=0.22
    • S: 0.2 (0.1) kg, P=0.15
    • DP: 0.4 (0.2) kg, P=0.06.
  • No differences in response were seen between sexes
  • No differences were noted between week two and week four values for LDL-C, LDL-C : HDL-C or C-reactive protein
  • Calculated CHD risk was reduced similarly in the S [25.8% (4.4%)] and DP [24.9% (5.5%)] groups
  • Blood lipid changes accounted for 70% and 82% of CHD risk reduction in DP and S groups, respectively.
Author Conclusion:

Intake of a combination of cholesterol-lowering plant-based food components increased the effectiveness of diet as a treatment for hypercholesterolemia.

Funding Source:
Government: Federal Government of Canada; Canadian Natural Sciences and Engineering Research Council of Canada
Industry:
Reviewer Comments:
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
  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
  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
  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
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? 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
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? 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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? 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
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? Yes
  2. Was the selection of study subjects/patients free from bias? Yes
  2. Was the selection of study subjects/patients free from bias? 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
  2.1. 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
  2.1. 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
  2.1. 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
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? 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
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  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? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  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
  3.4. 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
  3.5. 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")? Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
  4. Was method of handling withdrawals described? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? 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
  4.2. 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
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? No
  4.4. Were reasons for withdrawals similar across groups? No
  4.4. Were reasons for withdrawals similar across groups? No
  4.4. Were reasons for withdrawals similar across groups? No
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  5. Was blinding used to prevent introduction of bias? Yes
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
  5.1. 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
  5.2. 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
  5.2. 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
  5.2. 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
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  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
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? 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? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
  6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
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
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? 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
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  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
  6.3. 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
  6.4. 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? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? 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? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
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
  7.1. 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
  7.2. 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? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  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
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? 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
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? 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. 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
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? 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
  8.2. 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
  8.3. 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
  8.4. 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
  8.4. 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
  8.4. 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)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? 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
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  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. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? 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. Is bias due to study's funding or sponsorship unlikely? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes