Efficacy of a Spirulina Supplement for Amelioration of Benign ThYroid Nodules: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of a Spirulina Supplement for Amelioration of Benign ThYroid Nodules (NCT03535974), a non-randomized na study. The primary outcome is Percent Change in Area of Thyroid Nodules.

2. Clinical Question

3. Trial Design

The registry describes a completed, double-blind, non-randomized crossover trial. Participants were to receive the Spirulina-based preparation and placebo in different sequences. The brief summary describes a 6-week period for each treatment, with ultrasound and blood testing performed at three visits for each patient. The arm descriptions specify twice-daily administration. The registry gives enrollment as 38; its brief summary describes enrollment of approximately 30 patients.

The primary comparison is described as occurring after the first 6 weeks, between the treatment sequences receiving the supplement and placebo. The record also describes assessment after 12 weeks, when participants in each sequence had received both treatments, and says that no difference was expected for that comparison. The details of the sequence-assignment process, any washout period, and how period or carryover effects were handled are not reported in the registry record.

Non-randomized allocation matters when interpreting the treatment comparison: the registry’s own caution says the arms are not a like-for-like control comparison. Blinding may reduce some influences on measurement or reporting, but it does not establish that the sequences were comparable at the start. The registry does not describe how blinding was maintained or assessed.

The trial status is completed. Its start date is 2018-05-15 and its primary completion date is 2018-12-20. Those dates describe the registry record, not the timing of any individual participant’s treatment or follow-up. The phase is listed as NA. Details of recruitment, participant flow and the number contributing data to each outcome are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

First Intervention Weeks 0-6 (V1-V2)

Reasons for not completing this period:

Second Intervention Weeks 6-12 (V2-V3)

Analysis population for the primary outcome, as defined in the registry: Effects of AI vs P between the two arms is calculated after the first 6 weeks (V1-V2, AI vs P). After 12 weeks (V1-V3) patients in each arm/sequence receive the same treatment in a different sequence (AI+P; vs P+AI) and no difference is expected. A second outcome compares results of all administrations of 6 weeks each of AI (39) and P (29)

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: For the primary outcome we compared the effect of the AI vs P after the initial 6 weeks of the study (V1-V2). For this we combined the AI-AI sequence and AI-P sequence in one arm, and compared with the P-AI sequence arm.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change in Area of Thyroid Nodules, measured over after 6 weeks of administration of the supplement and placebo.

The primary endpoint is percent change in the area of thyroid nodules after 6 weeks of administration of the supplement and placebo. The record says that ultrasound measurements use two perpendicular diameters and that area is calculated as the product of those diameters. It specifies measurement at V1 and V2, using the same incidence and operator.

Area is a continuous measure: it can represent degrees of change rather than only whether a nodule crossed a threshold. Expressing the endpoint as percent change is intended to describe change relative to a measurement baseline, but the registry does not fully explain the calculation, the baseline used for each treatment period, or how measurements from multiple nodules were combined. Those details are not reported in the registry record.

Ultrasound is the stated method for assessing nodule size. Repeated measurements can be sensitive to acquisition and measurement procedures, which is why the record’s reference to the same incidence and operator is relevant. It does not, however, establish the reliability of the measurements or quantify their precision.

The endpoint is reported as a mean with standard deviation. A mean describes the average observed change, while the standard deviation describes variability among observations. Neither numerical endpoint estimates nor their uncertainty are reported in the registry record, so the size and precision of the observed change cannot be assessed from that record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous and is described as a mean percent change in nodule area with standard deviation. The registry does not provide numerical results or a detailed statistical analysis plan. The concepts below are general explanations of how these methods are usually interpreted, not claims about analyses performed in this trial.

What does a mean describe?

A mean is an average that combines observations into a single summary. For a change outcome, its interpretation depends on the direction and definition of the change. The registry names percent change in area, but does not provide its numerical mean or fully specify the calculation. Without the estimate, it is not possible to say whether the average change favored one treatment or to assess its magnitude.

The standard deviation describes how spread out individual observations are around their mean. It is not the same as the uncertainty around the mean. A confidence interval is a range of values compatible with the data and statistical assumptions; it communicates uncertainty in an estimate. The registry does not report a confidence interval for the primary comparison, nor the information needed to derive one without making assumptions.

Why does crossover structure matter?

In a crossover design, participants receive treatments in different sequences, allowing comparisons that may use measurements from the same participant under different treatments. This can help account for characteristics that remain stable within a participant. However, interpretation depends on the order of treatment and on whether the outcome in a later period could be influenced by earlier treatment. Changes over time that affect participants regardless of treatment can also complicate the contrast.

Here, allocation is listed as non-randomized. Consequently, sequence groups may differ in ways that could affect outcomes. The registry does not report the sequence-assignment method, any washout period, or the statistical handling of treatment period, sequence or carryover. These omissions prevent assessment of how well the analysis separates treatment differences from other differences.

What does blinding contribute?

The registry lists double masking. In general, blinding can reduce the influence of treatment knowledge on participant experience, clinical decisions or outcome assessment. For an ultrasound endpoint, consistent measurement procedures are also relevant; the record specifies the same incidence and operator for the described measurements. The registry does not say who was masked, how masking was maintained, or whether it was successful. Blinding cannot establish sequence comparability in a non-randomized study.

How should planning illustrations be read?

General sample-size planning uses assumptions about the effect to detect, variability, significance level, allocation and statistical model. The registry’s planning note describes an illustration using a two-sided significance level of 0.05, equal allocation, a normal approximation and fractions of the observed effect. Such planning quantities are not observed power and are not trial outcome estimates. Sample sizes calculated for planning do not show whether the trial achieved an effect, nor do they replace uncertainty intervals for observed results. Because the numerical primary results are not reported in the registry record, the basis and interpretation of any effect-dependent illustration cannot be evaluated from that record.

What can be inferred from the posted results?

No numerical primary endpoint estimate or inferential result is reported in the registry record. A p-value, if reported, would address compatibility with a specified null hypothesis under an analysis model; it would not by itself show the magnitude or practical importance of an effect. A confidence interval would help describe precision, but none is reported for the primary outcome. The registry also does not report the analysis model, handling of repeated observations, covariate adjustment, or the primary analysis population. Therefore, the methods and results needed to judge the treatment contrast are not available in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Preparation With Spirulina", "Placebo")
n   <- c(17, 17)
m   <- c(-19.98, -9.31)
sp  <- c(15.55, 14.29)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Preparation With Spirulina  17  -19.980  15.550  -27.975  -11.985
CARM  Placebo  17  -9.310  14.290  -16.657  -1.963

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and one analysis, but it does not report a multiplicity procedure or explain how outcomes were ordered for inference. When a study evaluates multiple outcomes or comparisons, the chance of at least one apparently notable result can increase if each is tested separately. General approaches include prespecifying a primary outcome, adjusting inference, or treating additional outcomes as exploratory. The registry record does not say which approach was used.

Missing-data handling is not reported in the registry record. The record does not state how incomplete ultrasound measurements, missed visits, withdrawals or unavailable blood tests were handled. It also does not report the number of participants contributing to the primary analysis or whether analysis followed an intention-to-treat, per-protocol or other population definition. In a crossover study, missing observations in either treatment period can affect the within-participant comparison, so the handling approach is important.

The registry does not describe imputation, sensitivity analyses, exclusions, or reasons for missing data. It also does not report whether the analysis accounted for sequence, treatment period or possible carryover. These omissions limit assessment of the robustness of any treatment contrast. No additional assumptions about the analysis can be made from the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: allergic reaction while on placebo (3.4%).

The registry lists serious adverse event information by treatment group. For Preparation With Spirulina, 34 were at risk for serious adverse events and none were affected; deaths were also listed as none. For Placebo, 29 were at risk and one was affected by a serious adverse event; deaths were listed as none. The registry identifies “allergic reaction while on placebo” as a serious adverse event term and reports 3.4% for that term.

These figures are descriptive. The registry does not provide a statistical comparison of serious adverse events between treatments or explain whether events were attributed to treatment. In a crossover study, participants may contribute exposure to both treatments, and the listed at-risk group sizes differ. The record does not clarify how exposure periods or repeated participation were handled in the safety summaries.

The registry also lists one other adverse event for Placebo among 29 at risk, and none for Preparation With Spirulina among 34 at risk. It does not report the event term for this other-event listing in the available record. Serious and other adverse-event listings should not be treated as separate participants or added together; the record does not state whether categories overlap. The reported counts alone do not establish comparative safety.

13. What the Result Does, and Does Not, Mean

The registry record documents a completed trial designed to compare a Spirulina-based preparation with placebo using a crossover approach. Its stated primary endpoint is percent change in thyroid nodule area measured by ultrasound. The record also describes repeated ultrasound and blood testing and gives a stated expectation of change during supplement administration.

That expectation is not an outcome result. The registry does not report the numerical primary endpoint estimates, their variability, confidence intervals or a test result. It therefore does not establish the direction, size or precision of the primary treatment contrast. The lack of numerical results should not be interpreted as evidence that there was no effect, nor as evidence that an effect occurred.

The record describes non-randomized allocation and cautions that the arms are not a like-for-like control comparison. The crossover structure may allow within-participant comparisons, but valid interpretation depends on sequence, period and carryover considerations. Details of these features and their statistical handling are not reported in the registry record. Double masking is listed, but does not resolve those design questions.

The serious adverse event listings report one affected participant in the placebo group and none in the Spirulina group, with no deaths listed. These descriptive entries do not provide a comparative safety analysis and do not establish whether an event was caused by a treatment. The event count is limited information, not a complete characterization of safety.

Overall, the registry record permits a description of the study question, planned measurement and design, but does not support a conclusion about efficacy or comparative safety. Further interpretation would require numerical outcome results and details of the analysis and participant flow, which are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises a useful statistical question: how should a continuous ultrasound measure be compared when participants receive treatments in different sequences? A crossover design can use repeated measurements within participants, but its interpretation depends on whether sequences are comparable and whether treatment effects persist into later periods. The registry identifies these design features without reporting how the associated analytic issues were handled.

The endpoint also illustrates why measurement definitions matter. The primary outcome is percent change in area, calculated from two perpendicular ultrasound diameters. The brief summary, meanwhile, describes an expected decrease in volume or largest diameter. These are not the same measure. A clear link between the stated expectation, the primary endpoint and the analysis would help readers understand which outcome drives the main inference; that link is not reported in the registry record.

The record’s non-randomized allocation caution is important for statistical interpretation. Blinding can reduce some measurement or reporting influences, but it does not guarantee that treatment sequences are comparable. This distinction helps readers avoid treating a crossover label as sufficient evidence of a controlled causal comparison.

Finally, the absence of numerical primary results demonstrates the difference between a registered study description and an interpretable result. Enrollment, endpoint definitions and adverse-event counts provide context, but without an effect estimate and its uncertainty, readers cannot judge the magnitude or precision of the primary comparison. The registry’s planning note also illustrates that sample-size calculations are planning tools, not observed evidence about treatment effects.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting the primary outcome is that numerical results are not reported in the registry record. The record gives no mean percent change, standard deviation, confidence interval or inferential test. Participant flow and the number included in the primary analysis are also not reported.

The trial is described as non-randomized, and the registry cautions that its arms are not a like-for-like control comparison. The sequence-assignment process is not reported. Although the study is listed as double-blind, the record does not explain who was masked or how masking was maintained. It also does not report how the analysis addressed sequence, treatment period or carryover in the crossover design.

The endpoint description leaves some details unclear. It specifies area calculated as the product of two perpendicular diameters, but does not fully describe the percent-change calculation or how results across nodules were combined. The stated expectation refers to volume or largest diameter, whereas the listed primary endpoint is area. The relationship between these outcomes is not reported in the registry record.

Missing-data procedures, analysis populations, multiplicity handling and protocol deviations are not reported in the registry record. Safety information is limited to the posted event summaries and does not include a comparative analysis. These limitations constrain interpretation of both the primary endpoint and safety findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy of a Spirulina Supplement for Amelioration of Benign ThYroid Nodules — NCT03535974.
• Registry record last updated 2020-05-19; status last verified 2020-05.
• Results first posted 2020-05-19.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes NCT03535974, a completed, double-blind, non-randomized crossover trial of a Spirulina-based preparation and placebo for benign thyroid nodules. Enrollment is listed as 38; the brief summary describes approximately 30 euthyroid patients. Each treatment period is described as 6 weeks, with assessment after 6 weeks and again after 12 weeks.

The primary outcome is percent change in nodule area measured by ultrasound, reported as a mean with standard deviation. Numerical primary outcome results and details of the statistical analysis are not reported in the registry record. The record lists one serious adverse event for Placebo and none for Preparation With Spirulina; no deaths are listed. It cautions that the non-randomized arms are not a like-for-like control comparison.