A Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving High-Dose Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving High-Dose Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma (NCT02919670), a randomized na study. The primary outcome is Number of Participants With Grade 3 or Higher Diarrhea GI Toxicity.

2. Clinical Question

The clinical question is whether the posted event counts differ between the Enterade and placebo arms when both are used alongside supportive care. The endpoint is a binary participant-level outcome: each participant is counted according to whether the specified toxicity occurred. The registry record describes Fisher’s exact test for the evaluation.

The outcome counts are 18 participants among 49 in the Enterade arm and 21 among 50 in the placebo arm. Those totals describe the posted primary result, but the record also says that only 17 participants met the protocol definition of compliance. It does not explain how that compliance subgroup relates to the participant set used for the primary comparison. That ambiguity matters when deciding which population the result represents.

The question is about this outcome in this trial, not every possible effect of Enterade. Other outcomes listed include stool frequency, hospitalization duration, weight change, antidiarrheal medication, calorie consumption, tolerability, and fever or neutropenia. Their numerical results are not reported in the registry record.

3. Trial Design

This was a randomized, triple-masked, parallel-group study comparing Enterade with placebo. Both arms also received standard supportive care, which the record says was administered according to institutional practice. The official title describes the study as Phase 2, while the registry phase field is recorded as NA; the record does not explain this difference.

The trial concerned patients with multiple myeloma or Non-Hodgkin’s lymphoma receiving high-dose melphalan conditioning followed by autologous stem cell transplantation. The registry record lists enrollment as 114. The primary outcome report refers to 99 participants who received some intervention, with the arm-level outcome counts covering 49 in the Enterade group and 50 in the placebo group.

Participants assigned to Enterade were scheduled to receive two 8 oz. bottles daily. The placebo arm was assigned two 8 oz. bottles daily as well. Both products were to be taken orally from admission until day +14 or discharge. The placebo is described as a mixture of water, electrolytes, and sweetener. The standard supportive care was not described as a uniform study-specific regimen; it followed institutional practice.

The record lists the study status as completed, with a start date of 2016-10 and primary completion of 2019-05. It does not report how the random sequence was generated, how allocation was concealed, or exactly which people were masked. It also does not report detailed eligibility criteria or a fuller account of the trial procedures. The words randomized and triple-masked describe the recorded design, but the registry record does not provide enough detail to assess how those procedures were implemented.

The planned parallel comparison is straightforward to describe, but interpretation depends on the population included in the outcome analysis. The registry outcome description says the result concerns participants who received some intervention and separately notes that only 17 met the protocol definition of compliance. It does not fully specify how the compliance information affected the analysis.

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.

Before assignment: Of 114, 6 patients did not receive transplant and 1 patient had a delayed transplant..5 patients withdrew consent , 1 patient did not take any amount due to the finding mold, 1 patient did not take due to subjects inability to swallow liquids and 1 patient had an insurance issue. Thus a total of 15 patients are excluded. (114-15=99).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only 17 participants met the protocol definition of compliance

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Grade 3 or Higher Diarrhea GI Toxicity, measured over 14 days.

The primary endpoint is the number of participants with Grade 3 or higher diarrhea GI toxicity during the 14-day timeframe. It is a binary outcome at the participant level: the count records whether each participant experienced an event meeting the stated grade threshold. It does not describe how often an individual had diarrhea, how long symptoms lasted, or the total severity burden across all episodes.

A thresholded toxicity endpoint can give a clear count for comparing randomized groups. It focuses attention on events at or above the specified severity grade rather than treating every symptom occurrence as equivalent. The registry record says the evaluation was to use Fisher’s exact test, a method suited to comparing categorical event counts across groups, especially when event counts are limited.

This endpoint is only one part of the study’s assessment. Other listed measures include maximum daily stool frequency, diarrhea on the day of maximum stool frequency, hospitalization duration, weight change, antidiarrheal medication use, tolerability, calorie consumption, and fever or neutropenia. Those measures can capture different aspects of the clinical course, but their numerical results are not reported in the registry record.

The record reports 18 participants with the primary event among 49 assigned to Enterade and 21 among 50 assigned to placebo. It also states that the outcome description concerns 99 participants who received some intervention and that only 17 met the protocol definition of compliance. Because the registry record does not clarify the role of compliance in the endpoint analysis, the exact analysis population cannot be fully reconstructed from these details alone.

7. Results Posted in the Registry

• Enterade: 36.7% (18/49) versus 42.0% (21/50) on control; risk difference -5.3 percentage points (95% CI -24.5 to 14.0), risk ratio 0.87 (0.54–1.43); unadjusted two-proportion z-test p = 0.592.

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is being compared?

The primary outcome is a count of participants with Grade 3 or higher diarrhea GI toxicity. For each participant, the relevant status is whether the specified event occurred during the 14-day timeframe. This makes the endpoint binary, even though the reported result is presented as a count. The two arm counts are 18 among 49 for Enterade and 21 among 50 for placebo.

Binary outcomes can be summarized in several ways. Counts show how many participants experienced an event. A risk difference expresses the difference between the event proportions in the two arms. A risk ratio compares those proportions by division, while an odds ratio compares the odds of an event. These are general statistical descriptions of measures, not additional analyses of the trial. Each measure answers a slightly different descriptive question, and their numerical scales are not interchangeable.

Why does the record name Fisher’s exact test?

The registry outcome description says the evaluation will use Fisher’s exact test. In general, Fisher’s exact test assesses whether an association between treatment group and a binary outcome is compatible with the observed table of counts, without relying on a large-sample approximation to that table. It is commonly useful when the number of events is limited. The registry record does not report further details about the test, such as whether the test was one-sided or two-sided, or provide a sponsor-reported test statistic and p-value in the information.

The unadjusted recalculation shown alongside the posted counts is a separate descriptive calculation. It gives a risk difference of -0.053 and an unadjusted p-value of 0.592. The fact that the registry names Fisher’s exact test does not by itself establish that every displayed recalculated measure was generated by that test. The posted counts remain the most direct description of the observed primary outcome.

How should the effect estimates be read?

The recalculated risk difference is -0.053 for Enterade relative to placebo. In general, a negative risk difference means the event proportion in the first group is lower than the event proportion in the reference group for the specified subtraction order. The associated interval, -0.245 to 0.140, indicates that the estimate is not precise enough to rule out differences in either direction. The interval is a range of effect values compatible with the data under the interval’s statistical procedure; it is not a range of individual participant outcomes.

The risk ratio of 0.875 and odds ratio of 0.802 summarize the same comparison using ratio scales. Their intervals are 0.535 to 1.429 and 0.357 to 1.799, respectively. For ratio measures, a value of 1 represents no relative difference. Both reported intervals include that value. This is consistent with uncertainty about whether the arms differ, rather than proof that they are the same.

In general, an unadjusted analysis compares the groups without accounting for additional covariates or other adjustments. The record does not describe a covariate-adjusted primary analysis. Nor does it report enough detail to determine whether any planned adjusted or sensitivity analyses were conducted. The displayed recalculated measures should therefore be understood as simple comparisons of the reported arm summaries.

What is over-dispersion, and does it apply?

Over-dispersion is a general concern when variation in count data is greater than a statistical model expects. It can make standard errors too small if a model assumes less variation than is actually present. This primary endpoint is reported as a binary participant count rather than a repeated count per person, so the registry summaries do not offer the information needed to assess over-dispersion in a count model. The record does not report a model-based analysis of repeated daily stool counts; maximum daily stool frequency is listed as a secondary outcome, but its results and analysis details are not reported.

What analysis details are unavailable?

The registry record does not report the original sample-size justification, the statistical analysis plan, missing-data methods, a detailed definition of the analysis population, or the handling of protocol noncompliance. It gives a compliance note: 17 participants met the protocol definition, while the primary outcome description refers to 99 participants who received some intervention. The record does not clarify how those statements connect to the primary analysis.

The record also does not report interim analyses, stopping rules, the method of random-sequence generation, or allocation concealment. Those omissions do not change the arithmetic of the posted counts, but they limit assessment of the trial’s intended analysis and conduct. The sample-size illustration on this page is a planning exercise based on the observed effect and its stated assumptions, not a reconstruction of the study’s original design.

10. Confidence Intervals and Precision

The risk-difference estimate is -0.053, with an interval from -0.245 to 0.140. The interval spans zero, so the data are compatible with an estimate favoring either arm as well as with little or no difference. Its breadth means that the observed point estimate alone should not be treated as a precise measure of the underlying difference.

In general, a confidence interval summarizes uncertainty in an estimated effect under a statistical procedure. It is not a guarantee that the true effect lies within the displayed limits, and it does not describe the range of outcomes for individual participants. The confidence level associated with the displayed intervals is not reported in the registry record, so no level should be inferred from the interval alone.

The relative measures also have broad intervals: the risk ratio is 0.875 with an interval from 0.535 to 1.429, and the odds ratio is 0.802 with an interval from 0.357 to 1.799. For these ratios, 1 represents no relative difference. Their intervals include that value and extend to values on both sides, reinforcing that the posted result is not precise enough to pin down the direction or magnitude of the comparison.

The arm counts are limited to 49 participants in the Enterade group and 50 in the placebo group. The outcome description additionally notes 17 participants meeting the protocol definition of compliance, without explaining how that subgroup was used. This creates a further interpretive limitation beyond interval width: the exact population represented by the primary comparison is not fully clear from the registry record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The table and curve are planning illustrations based on the observed effect, not a report of the trial’s original design calculations. For this binary endpoint, the table reports participants per arm. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The registry record’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the planned participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect were the true effect. The 90% power column gives the corresponding number for a design with a 90% chance under those same assumptions. These are prospective planning quantities, not probabilities that the observed result is correct and not a measure of the trial’s observed power.

The rows show planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The listed requirements rise as the assumed effect becomes smaller: for planning for 100% of the observed effect, the figures are 1,351 participants per arm for 80% power and 1,808 for 90% power. For planning for 75% of the observed effect, they are 2,416 and 3,233. For planning for 50% of the observed effect, they are 5,465 and 7,315.

The curve visualizes the same general relationship: under the stated planning assumptions, smaller effects require more participants to achieve a chosen power. The displayed values depend on those assumptions and on using the observed effect as the reference. They should not be read as the actual enrollment target or as evidence that the completed trial had a particular probability of finding a result.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.420; treatment proportion p₁ = 0.367; average p̄ = 0.394.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6909 = 1.3542.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6899 = 0.5807.
4. n = (1.3542 + 0.5807)² / (-0.0527)² = 1,350.4, rounded up to 1,351 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.42                          # control proportion
p1 <- 0.36734693877551                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2919670)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 1,351 (80% power), 1,808 (90% power)
 75% of observed effect: n per arm = 2,416 (80% power), 3,233 (90% power)
 50% of observed effect: n per arm = 5,465 (80% power), 7,315 (90% power)
power.prop.test: 1350.4 
Simulated power at n = 1,351 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and multiple secondary outcomes. These include maximum daily stool frequency, diarrhea on the day of maximum daily stool frequency, duration of hospitalization, percent change in weight, antidiarrheal medication use, tolerability, calorie consumption, and fever or neutropenia. The numerical results for these secondary outcomes are not reported in the registry record.

When a study evaluates several outcomes, the chance of finding at least one apparently notable result can increase if each outcome is tested separately without an appropriate strategy for multiplicity. In general, multiplicity methods may define a hierarchy of outcomes, adjust significance thresholds, or describe analyses as exploratory. The registry record does not report a multiplicity strategy, a hierarchy among the secondary outcomes, or whether any adjustment was used.

The registry outcome description identifies Fisher’s exact test for the primary endpoint. It does not report a complete statistical analysis plan, the prespecified significance threshold for the primary outcome, interim analyses, or any adjustment for interim monitoring. These details are not reported in the registry record and should not be inferred from the planning illustration, whose significance-level assumption is for that illustration rather than evidence of the trial’s original analysis plan.

Information about missing data is also absent. The record does not describe how participants with missing endpoint information were handled, whether all randomized participants were included, or whether any sensitivity analyses assessed missing outcomes. It lists 114 as enrollment and reports primary outcome counts for 99 participants who received some intervention, but the details needed to reconcile those figures are not reported in the registry record.

The record says that only 17 participants met the protocol definition of compliance. It does not clarify whether the primary endpoint analysis was based on all participants who received some intervention, a compliance-defined subset, or another population. This limits the ability to judge how closely the posted comparison follows an intention-to-treat analysis or a per-protocol analysis. Neither analysis population should be assumed from the record’s brief description alone.

14. 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: clostridium septicum septic shock (2.0%).

The serious adverse event figures are counts of participants with a serious adverse event in each group: 0 of 49 in the Enterade and standard supportive care group, and 1 of 50 in the placebo and standard supportive care group. The record also lists 0 deaths in the Enterade group and 1 in the placebo group. These are descriptive counts; the record does not state whether the reported death was related to treatment or provide circumstances for the event.

The listed serious term is Clostridium septicum septic shock, shown as 2.0%. The registry summary does not establish which arm this term belongs to, so it should not be attributed to either group based on these details alone. The separate counts for participants affected by other adverse events are 18 of 49 and 21 of 50, respectively. Those figures should not be conflated with serious adverse events.

In general, adverse-event counts describe what was recorded during the specified safety reporting, but interpretation also depends on definitions, observation time, event severity, and attribution. Detailed information about these items is not reported in the registry record. The figures should be read as descriptive safety reporting, not as a definitive comparison of risk.

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

The posted results show 18 participants with Grade 3 or higher diarrhea GI toxicity among 49 in the Enterade arm and 21 among 50 in the placebo arm. The unadjusted recalculated risk difference is -0.053, and its interval ranges from -0.245 to 0.140. The corresponding unadjusted p-value is 0.592. Together, these summaries describe an uncertain comparison: the point estimate favors fewer events in the Enterade arm, while the interval allows values in either direction.

This result does not establish that the two arms are equivalent. A non-significant or unadjusted p-value is not proof of no difference, and an interval that includes no difference does not show that every clinically meaningful difference has been excluded. Conversely, the negative point estimate does not establish that Enterade reduced the endpoint. The uncertainty is substantial relative to the estimate, and the arm counts are limited.

The finding is specific to the primary endpoint and the participants represented in the posted counts. It does not answer whether the groups differed in stool frequency, hospitalization, weight, medication use, tolerability, calorie consumption, fever, or neutropenia. Those outcomes are listed, but their numerical results are not reported in the registry record.

The record’s compliance note also matters. It says that only 17 participants met the protocol definition of compliance, while the primary outcome description refers to 99 participants who received some intervention. Because the record does not explain how compliance was used in the analysis, the target population represented by the result remains uncertain. The posted counts can be described accurately, but their interpretation should not assume an analysis population that the record does not specify.

Overall, the registry results support a careful description of observed counts and an imprecise unadjusted comparison. They do not justify a broad conclusion about all effects of the supplement or about other clinical settings. Interpretation should remain tied to the particular endpoint, trial population, reported follow-up window, and limitations of the registry information.

16. Why This Trial Matters Statistically

This trial is statistically instructive because its primary endpoint is a simple participant-level event count, while the clinical interpretation still depends on more than the direction of the point estimate. The observed counts are easy to read, but the risk-difference interval extends from -0.245 to 0.140. The width and direction of that interval communicate uncertainty that a comparison of the two counts alone can conceal.

It also illustrates why a p-value should not be used as a yes-or-no verdict. The unadjusted recalculation gives 0.592, but that value does not quantify the probability that the treatment is effective or that the arms are identical. The effect estimate and its interval provide complementary information, and neither eliminates the need to understand the analysis population and methods.

The registry record names Fisher’s exact test for the primary endpoint, which is a recognizable approach for comparing binary counts. Yet the record does not provide a full statistical analysis plan, missing-data strategy, or multiplicity approach. The gap between a named test and a fully specified analysis is important: statistical interpretation relies on knowing not just which test is mentioned, but how outcomes and participants were selected for analysis.

Finally, the compliance note highlights a population question that can materially shape what a result means. The record reports 17 compliant participants and a primary outcome description referring to 99 participants who received some intervention, without explaining how the two relate. This makes the case useful for distinguishing what the posted numbers directly show from what the registry record leaves unresolved.

17. 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 registry record provides only a brief account of the study methods. It does not report how the random sequence was generated, how allocation was concealed, or which trial personnel and participants were masked. Although the design is recorded as randomized and triple-masked, these implementation details cannot be evaluated from the information.

The relationship between listed enrollment, intervention receipt, and primary outcome analysis is not fully explained. The record lists enrollment as 114, while the primary description refers to 99 participants who received some intervention and the posted arm counts comprise 49 and 50. It also says that only 17 participants met the protocol definition of compliance. The reason for these differences and the way compliance affected the endpoint analysis are not reported in the registry record.

The original sample-size justification and the trial’s own analysis plan are not reported in the registry record. The planning table is an illustration based on the observed effect and stated assumptions; it cannot establish what the investigators planned before the trial. Missing-data handling, sensitivity analyses, multiplicity procedures, and any interim monitoring are also not reported.

The registry record lists secondary outcomes, but their numerical results are not reported in the information. Detailed adverse-event descriptions, exposure timing, and attribution are also limited. These omissions constrain assessment of the broader pattern of results and safety reporting. The primary endpoint comparison should therefore be interpreted narrowly as a summary of the posted counts, with the uncertainty and analysis-population questions kept in view.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving High-Dose Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma — NCT02919670.
• Registry record last updated 2023-03-16; status last verified 2022-06.
• Results first posted 2023-03-16.
• 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.

21. Record Summary

The record describes a completed randomized, triple-masked, parallel-group study of Enterade plus standard supportive care versus placebo plus standard supportive care in patients receiving high-dose melphalan conditioning followed by autologous stem cell transplantation for multiple myeloma or Non-Hodgkin’s lymphoma. The official title calls the study Phase 2; the registry phase field is recorded as NA.

The primary endpoint was the number of participants with Grade 3 or higher diarrhea GI toxicity over 14 days. The posted counts are 18 among 49 participants in the Enterade arm and 21 among 50 in the placebo arm. An unadjusted recalculation gives a risk difference of -0.053, with an interval from -0.245 to 0.140, and an unadjusted p-value of 0.592.

The record identifies Fisher’s exact test for evaluation, but does not report the full analysis plan, missing-data methods, or the role of the 17 participants who met the compliance definition. Those details limit interpretation of the analysis population. Secondary outcomes are listed, but their numerical findings are not reported in the registry record.