Neurodevelopmental and Growth Outcomes of Early, Aggressive Protein Intake in Very Low Birthweight Infants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Neurodevelopmental and Growth Outcomes of Early, Aggressive Protein Intake in Very Low Birthweight Infants (NCT01860573), a randomized na study. The primary outcome is Number of Participants With Weight<10th Percentile for Age.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, quadruple-masked, parallel-group trial. It lists 168 participants as the enrollment and identifies the status as completed. The recorded study start is 2008-11, and primary completion is recorded as 2013-03. The sponsor is Women and Infants Hospital of Rhode Island. The study title concerns neurodevelopmental and growth outcomes of early, aggressive protein intake in very low birthweight infants.

The two groups differed in their initial amino-acid regimen. The standard group began at 1-2 gm/kg/day at birth and was advanced by 0.5 gm/kg/day toward a 4 gm/kg/day goal. The high group began at 3-4 gm/kg/day at birth and was advanced to a 4 gm/kg/day goal as soon as possible after birth. These descriptions state the intended regimens; the record does not report adherence or exposure received by each participant.

The primary outcome was measured at 36 weeks post-conceptual age and counted participants whose weight was below the 10th percentile for age. The registry notes that data were unavailable for subjects who died or were discharged before that assessment time. The posted primary result has 67 participants in the standard group and 72 in the high group, with 32 and 41 outcome events, respectively. Those outcome denominators differ from the overall enrollment, and the record does not fully explain the disposition of all enrolled participants for this analysis.

The record lists seven outcome measures and three posted secondary outcomes: serum bicarbonate, serum creatinine, and serum blood urea nitrogen. It lists no analysis entries. The record does not report the allocation procedure, the specific masking roles, the original sample-size justification, or the statistical methods planned by the trial team. Those details should not be inferred from the randomized and masking labels.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Data not available for subjects who died or were discharged prior to 36 weeks post-conceptual age

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 Weight<10th Percentile for Age, measured over 36 weeks post-conceptual age.

The primary endpoint counts participants with weight <10th percentile for age at 36 weeks post-conceptual age. It is a binary outcome at the participant level: each assessed participant either met the threshold or did not. The posted result gives the number meeting the threshold and the number in each group with outcome data. The registry record says data were not available for subjects who died or were discharged before 36 weeks post-conceptual age.

A threshold-based growth measure can express whether participants fall below a specified reference percentile at a particular assessment time. It is different from a continuous measure such as mean weight: the count does not show how far each participant's weight was from the threshold, nor the distribution of weights within either group. The endpoint therefore addresses the frequency of crossing the defined percentile threshold, not growth in every dimension or across the full hospital stay.

The outcome was selected in the context of a study whose stated purpose included growth during hospitalization and developmental outcomes by age 2. However, this posted primary endpoint concerns weight at 36 weeks post-conceptual age. The record does not establish that the primary result represents all growth outcomes or developmental outcomes. It also does not explain how participants who died or were discharged before the assessment were handled beyond noting that their data were unavailable. Those details matter when interpreting what population the reported counts describe.

7. Results Posted in the Registry

• High Amino Acids: 56.9% (41/72) versus 47.8% (32/67) on control; risk difference 9.2 percentage points (95% CI -7.4 to 25.7), risk ratio 1.19 (0.86–1.64); unadjusted two-proportion z-test p = 0.279.

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is being compared?

The endpoint is a count of participants who met a defined condition: weight <10th percentile for age at 36 weeks post-conceptual age. In statistical terms, this is a binary outcome. General explanation: a binary outcome has two possible states for each assessed participant, such as meeting or not meeting the specified threshold. A group count can be interpreted alongside its denominator to describe the observed frequency of that outcome. Here, the reported counts are 32 of 67 in the standard group and 41 of 72 in the high group.

Because the outcome is recorded at one assessment time, the comparison does not describe when a participant crossed the threshold or how weight changed over time. It also does not describe the amount by which weight was above or below the threshold. Those would require different outcome information and methods. The registry result concerns the count at the stated time only.

What does a risk difference express?

The posted primary comparison is expressed as a risk difference, with the high-amino-acid group compared with the standard group. General explanation: a risk difference subtracts the event frequency in one group from that in the other. A value of zero represents no difference in event frequencies. A positive value indicates a higher observed event frequency in the group named first in the comparison, while a negative value indicates a lower one. The posted risk-difference interval spans zero, so it includes the no-difference value.

The posted proportions are 0.478 for the standard group and 0.569 for the high group. These values describe the observed event proportions among the respective outcome denominators. They do not adjust for other variables, and they are not a substitute for the uncertainty interval. The record does not report whether the trial's intended primary analysis used this measure or a different model.

How do risk ratios and odds ratios differ?

The record also gives a risk ratio and an odds ratio. General explanation: a risk ratio compares event probabilities as a ratio, for which one represents equal probabilities. An odds ratio compares event odds, also with one as its no-association value. Odds and probabilities are related but are not interchangeable descriptions. Since the reported intervals for both measures include one, neither posted ratio estimate rules out the corresponding no-association value. These measures are alternative ways to summarize the same binary outcome, not separate outcome findings.

The record identifies the comparison as unadjusted. General explanation: an unadjusted comparison uses the group outcome summaries without accounting for other covariates in a model. In a randomized trial, randomization is intended to support a fair comparison, but an unadjusted summary still does not reveal the actual analysis procedures used by the trial team. The registry record does not report a covariate-adjusted analysis or the original statistical plan.

What do the p-value and confidence interval contribute?

The unadjusted p-value is 0.279. General explanation: a p-value measures how unusual data at least as incompatible with a specified null model would be if that model and its assumptions were correct. It is not the probability that the null model is true, and it is not a measure of the size of the effect. The p-value does not resolve uncertainty about whether the groups are equivalent or whether an effect matters clinically.

A confidence interval gives a range of effect values compatible with the observed data under a specified method. General explanation: intervals are useful because an estimate alone can hide uncertainty. An interval that includes the no-effect value indicates that values on both sides of that point remain compatible with the data under the calculation. The posted interval for the risk difference includes zero; the ratio intervals include one. The registry record does not state the confidence level or method used for these intervals, so those details should not be assumed.

What is and is not known about the analysis?

The group comparison and its summary statistics are posted, but the registry record lists no analysis entries. It does not report the analysis population, the method used to handle outcome data unavailable after death or discharge, covariate adjustment, a multiplicity strategy, interim analyses, or the original statistical plan. The record also does not state whether the endpoint was analyzed according to randomized assignment or another population definition. Those omissions limit the ability to reproduce or fully evaluate the sponsor's intended analysis.

The posted comparison is an unadjusted re-calculation from the summary statistics. The discrepancy indicator is false, so the record does not flag a disagreement between that calculation and a sponsor analysis. No sponsor analysis takes precedence in the posted information. This does not fill the gaps in the original analysis plan; it simply describes the status of the comparison available in the registry.

General explanation: when counts are small or outcome frequencies are high, different statistical methods can produce different estimates or uncertainty intervals. The appropriate method depends on the design, assumptions, and analysis plan. No alternative calculation should be treated as the trial's intended analysis unless it is reported as such. The available record supports describing the posted summary and its uncertainty, not reconstructing unreported methods.

10. Confidence Intervals and Precision

The point estimate alone does not convey how precisely the group difference is known. The posted risk-difference confidence interval extends across zero, the value that represents no difference in event frequencies. It also extends to values on either side of zero. Thus the data remain compatible with a lower event frequency in the high-amino-acid group, no difference, or a higher event frequency, within the interval's range. The registry record does not state the confidence level or the method used to construct the interval.

The relative measures tell a similar uncertainty story. The reported risk-ratio interval includes one, as does the odds-ratio interval; one is the no-association value for each ratio. This does not mean the estimated effects are exactly null. It means the uncertainty intervals include the null as well as alternatives. The risk difference and the ratio measures are different scales for describing the same binary endpoint and should not be read as independent confirmations.

The observed outcome counts were 32 of 67 in the standard group and 41 of 72 in the high group. Those denominators are the numbers included in the posted endpoint comparison, not the overall enrollment. The record notes that data were unavailable for subjects who died or were discharged before 36 weeks post-conceptual age, but it does not give the number affected or describe a missing-data method. That uncertainty concerns which participants contribute to the endpoint comparison, in addition to statistical uncertainty in the estimates.

In practical statistical terms, the result is not precise enough to establish a narrow range for the underlying group difference. The interval's breadth permits materially different interpretations, and the registry does not report a prespecified clinical threshold that would define an important difference. Therefore, statistical uncertainty cannot be translated into a conclusion about clinical importance from the posted summary alone.

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 planning figures are participants per arm for a two-group comparison, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each scenario uses a stated fraction of the observed effect as the effect to detect. These are planning illustrations derived from the observed effect, not the original trial's design assumptions, which are not reported in the registry record.

The 80% power column means the illustrative number of participants per arm needed for an 80% chance of detecting the specified effect under the planning assumptions, if that effect and those assumptions were correct. The 90% power column uses a higher target probability of detection and therefore gives a larger required number per arm for the same effect scenario. Power is a design property under assumed conditions; it is not a measure of the probability that the reported finding is true.

The scenarios are labeled as planning for 100%, 75%, and 50% of the observed effect. The posted values are 464 and 620 participants per arm for 100% of the observed effect; 826 and 1,105 for 75% of the observed effect; and 1,861 and 2,490 for 50% of the observed effect, for the 80% and 90% targets respectively. The smaller the effect to be detected, the more participants the illustration requires, because a smaller difference is harder to distinguish from random variation.

This is not observed power. It is a prospective planning illustration, and it does not establish the power of the completed trial. The original sample-size justification and the assumptions used by the trial team are not reported in the registry record. These figures should not be treated as evidence that the trial was adequately or inadequately designed.

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 = 0.478; treatment proportion p₁ = 0.569; average p̄ = 0.524.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7063 = 1.3844.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.7033 = 0.5919.
4. n = (1.3844 + 0.5919)² / (0.0918)² = 463.1, rounded up to 464 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 <- 0.477611940298507                          # control proportion
p1 <- 0.569444444444444                          # 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(1860573)
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 = 464 (80% power), 620 (90% power)
 75% of observed effect: n per arm = 826 (80% power), 1,105 (90% power)
 50% of observed effect: n per arm = 1,861 (80% power), 2,490 (90% power)
power.prop.test: 463.1 
Simulated power at n = 464 per arm: 0.803 (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 seven outcome measures and three posted secondary outcomes: serum bicarbonate, serum creatinine, and serum blood urea nitrogen. It does not report how many outcomes were prespecified as primary in the original protocol, whether outcomes were tested in a hierarchy, or whether any adjustment for multiple comparisons was planned. When several outcomes or comparisons are examined, general statistical practice recognizes that the chance of at least one apparently unusual result can increase. Whether that concern applies to a particular analysis depends on the prespecified plan, which is not reported.

The record lists no analysis entries. It does not identify an analysis population or state whether the primary comparison followed randomized assignment, included only participants with available endpoint data, or used another definition. The posted counts and denominators are 32 of 67 for standard amino acids and 41 of 72 for high amino acids. These endpoint denominators should not be assumed to represent every participant enrolled in the trial.

For the primary endpoint, data were not available for subjects who died or were discharged before 36 weeks post-conceptual age. The record does not report how many participants were excluded for these reasons, whether any other endpoint data were missing, or whether any imputation, sensitivity analysis, or other missing-data method was used. It also does not say whether the unavailable outcome data were treated differently by randomized group. Therefore, the effect of missing outcomes on the comparison cannot be assessed from the posted record.

General explanation: missing data can affect precision because fewer observed outcomes contribute to an estimate. Depending on why data are missing, they can also affect interpretation of the observed comparison. Death before an assessment presents a particular interpretive issue because the endpoint at that later time cannot simply be observed for that participant. The registry's note identifies the limitation but does not describe an analysis that addresses it. No assumptions about the missing outcomes or analysis population should be inferred.

The record also does not report interim analyses or stopping rules. These omissions do not show that such procedures were or were not used; they mean that the registry record does not describe them. The available material supports interpretation of the posted endpoint summary, with these limitations in mind, rather than a complete audit of the trial's analysis conduct.

14. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: sepsis (37.3%), necrotizing enterocolitis (18.1%), death (12.0%), intaventricular hemorrhage grade iii/iv (8.4%), periventricular leukomalacia (6.0%).

The adverse-event record gives separate at-risk and affected counts for serious and other events by group. For serious events, the standard-amino-acid group has 83 at risk and 31 affected; the high-amino-acid group has 85 at risk and 19 affected. For other events, the standard group has 73 at risk and 35 affected, while the high group has 74 at risk and 32 affected. These figures describe the adverse-event record and are not the primary growth endpoint.

The record also lists serious-event terms and percentages: Sepsis, 37.3%; Necrotizing Enterocolitis, 18.1%; Death, 12.0%; Intaventricular Hemorrhage Grade III/IV, 8.4%; and Periventricular Leukomalacia, 6.0%. The denominator and calculation behind these percentages are not reported in the registry record. The death counts by group are also not reported, and a percentage for Death among the serious-event terms should not be interpreted as an arm-specific death risk.

These summaries do not establish that one regimen caused or prevented an adverse event. The record does not provide event-level timing, severity detail beyond the serious/other categories, or an adjusted safety comparison. Counts and percentages describe what was recorded; they require the reporting definitions and denominators for a fuller comparison.

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

The result describes a particular endpoint: weight <10th percentile for age at 36 weeks post-conceptual age. In the posted outcome data, 32 participants in the standard-amino-acid group and 41 in the high-amino-acid group met that threshold. The corresponding endpoint denominators were 67 and 72. The unadjusted comparison has a confidence interval that includes the no-difference value, and the reported p-value is 0.279. These data do not precisely determine the direction or size of the underlying difference.

The result does not demonstrate that the groups are equivalent. A comparison that does not resolve a difference can still be compatible with meaningful differences in either direction, particularly when its interval is broad. The registry record does not report an equivalence margin, a noninferiority objective, or a prespecified threshold for a clinically important difference. Without those, the result cannot be framed as proving that the regimens have the same effect.

Nor does the primary result answer every question named in the study's purpose. The stated purpose includes growth during the hospital stay and developmental outcomes by age 2, whereas this primary endpoint is a weight threshold at 36 weeks post-conceptual age. The record lists seven outcome measures but provides only the listed result details for this primary comparison and names three secondary laboratory outcomes. The available information does not support conclusions about unreported developmental results or other growth measures.

Interpretation is also limited by the missing primary outcome data for subjects who died or were discharged before the assessment. The number of affected participants and the method used to address unavailable outcomes are not reported. Thus the posted counts should not be treated as a complete summary of all randomized participants at the primary endpoint.

Overall, the registry result is an uncertain, unadjusted comparison of observed endpoint counts. It neither establishes benefit nor establishes lack of benefit, and it does not provide a basis for medical advice. Its proper role is to describe what was recorded for this outcome while recognizing the interval uncertainty, missing outcome information, and unreported analysis details.

16. Why This Trial Matters Statistically

This trial illustrates why an event count needs both a denominator and an uncertainty measure. The primary outcome is easy to state as a threshold event, but the group counts alone do not determine whether the observed contrast is stable or whether it generalizes to all randomized participants. The posted comparison includes a confidence interval that crosses the no-difference value, making the uncertainty visible rather than reducing interpretation to which group has the larger raw count.

It also shows the distinction between an outcome's statistical definition and the broader clinical question. A weight percentile threshold at a single assessment is not the same as a trajectory of growth, and neither is interchangeable with neurodevelopment. The study's stated purpose encompasses several domains, but the primary endpoint addresses one defined measure at one time. Keeping those outcomes separate prevents a narrow endpoint from being overinterpreted as a complete account of the study question.

Missing data are central to the interpretation because the registry notes that the primary outcome is unavailable for subjects who died or were discharged before the assessment. Those are not simply unrecorded values with an explained cause and a stated statistical solution: the record does not report counts or methods. That limitation makes it important to distinguish the group denominators in the posted result from overall enrollment.

Finally, the planning illustrations show how the required sample size depends on the effect a study is designed to detect. Smaller target effects require more participants under the stated assumptions. Such planning figures are not a retrospective judgment about the completed trial, and the original design assumptions are not reported. Together, these features make the trial useful for learning how endpoint definition, missingness, precision, and planning assumptions shape statistical interpretation.

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 primary endpoint is available only at 36 weeks post-conceptual age, and the record specifically says data were unavailable for subjects who died or were discharged before that time. It does not report how many participants had unavailable data, reasons for discharge, or the handling of those participants in the analysis. This limits interpretation of the endpoint denominators and the extent to which the comparison represents all randomized participants.

The primary outcome is a binary threshold measure rather than a continuous description of weight or growth over time. It does not show the magnitude of departure from the 10th percentile, nor the pattern of growth during the hospital stay. The posted comparison therefore addresses a limited aspect of the study's broader growth question.

Although the trial is labeled randomized and quadruple-masked, the registry record does not describe the randomization procedure, the masking roles, adherence to the assigned amino-acid regimens, or deviations from the intended regimens. The group labels alone do not establish how these processes were implemented.

The record lists no analysis entries and does not report the original statistical plan, sample-size justification, analysis population, adjustment strategy, multiplicity approach, or interim analyses. The unadjusted summary cannot be assumed to represent the trial team's complete prespecified analysis. The record also does not give the confidence-interval method or confidence level.

Finally, the safety summaries do not state the denominator used for the listed serious-event percentages, and group-specific death counts are not reported. These limitations prevent a detailed assessment of comparative safety from the posted summary alone. They do not establish that any unreported procedure or result was absent; they identify what the registry record does not describe.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Neurodevelopmental and Growth Outcomes of Early, Aggressive Protein Intake in Very Low Birthweight Infants — NCT01860573.
• Registry record last updated 2017-04-10; status last verified 2017-02.
• Results first posted 2017-04-10.
• 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 registry record describes a completed, randomized, quadruple-masked, parallel-group study of amino-acid intake in premature infants with very low birthweight. It lists enrollment of 168 and compares a standard regimen, beginning at 1-2 gm/kg/day, with a high regimen, beginning at 3-4 gm/kg/day. Both regimens aimed for 4 gm/kg/day.

The primary endpoint was the number of participants with weight <10th percentile for age at 36 weeks post-conceptual age. The record reports 32 of 67 in the standard group and 41 of 72 in the high group, alongside an unadjusted comparison with p=0.279. Its confidence interval includes no difference. Data were unavailable for subjects who died or were discharged before the endpoint assessment.

The registry lists three secondary outcomes and adverse-event summaries. It does not report the original statistical plan, the handling of unavailable primary outcome data, or the original sample-size justification. The posted primary result should therefore be read as an uncertain comparison for this specific endpoint, not as a complete account of all growth, developmental, or safety outcomes.