CPI-006 Plus Standard of Care Versus Placebo Plus Standard of Care in Mild to Moderately Symptomatic Hospitalized Covid-19 Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CPI-006 Plus Standard of Care Versus Placebo Plus Standard of Care in Mild to Moderately Symptomatic Hospitalized Covid-19 Patients (NCT04734873), a randomized phase 3 study. The primary outcome is Proportion of Participants Alive and Respiratory Failure Free of CPI-006 Plus SOC Versus Placebo Plus SOC.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, placebo-controlled, double-blind, multicenter, stratified study with a parallel-group model. The registry lists quadruple masking. The study compared two single-dose CPI-006 regimens, each given with standard of care, with placebo plus standard of care. The registered enrollment was 46, and the study status is terminated.

The registry lists the study start as 2021-02-25 and primary completion as 2021-08-18. These dates describe the registered study timeline; they do not establish why the trial was terminated or whether the posted results include every participant enrolled. The reason for termination is not reported in the registry record.

The intervention descriptions specify a single intravenous dose on Day 1. The 2 mg/kg dose had a maximum of 200 mg, and the 1 mg/kg dose had a maximum of 100 mg. The placebo arm also received a single intravenous dose on Day 1. All arms were described as receiving standard of care.

The registry reports outcome counts of 14 of 15 for the 2 mg/kg arm, 12 of 14 for the 1 mg/kg arm, and 9 of 11 for the placebo arm. These outcome denominators reflect the primary-outcome results and should not be assumed to describe every participant enrolled or every analysis population. The record’s primary-outcome population required receipt of any study drug and a post-baseline efficacy assessment. How the randomized groups were defined for the posted analysis, and how participants without the required assessment were handled, 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received any amount of study drug (CPI-006 or placebo) and have post-baseline efficacy assessment based on the 8-point ordinal scale.

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: 42 participants were randomized however only 40 received study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Proportion of Participants Alive and Respiratory Failure Free of CPI-006 Plus SOC Versus Placebo Plus SOC, measured over During the 28 days after dosing.

The primary endpoint was the count and proportion of participants alive and free from respiratory deterioration during the 28 days after dosing. It was assessed with a modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale ranges from not hospitalized to death and distinguishes levels of respiratory support and ongoing medical care while hospitalized. The endpoint therefore combines survival with a clinical status measure: a participant had to be alive and not have reached a respiratory-deterioration state to meet the endpoint.

A composite outcome of this kind can summarize more than one clinically important aspect of a disease course. In general, combining components can make an endpoint more informative when the components represent related states of clinical worsening, but the result does not reveal the separate contribution of each component. In this trial, the registry’s primary description focuses on being alive and free from respiratory deterioration; it does not give a separate component-level breakdown for the posted primary result.

The stated analysis population consisted of participants who received any amount of study drug and had a post-baseline efficacy assessment based on the scale. The posted counts were 14 of 15 in the 2 mg/kg arm, 12 of 14 in the 1 mg/kg arm, and 9 of 11 in the placebo arm. The endpoint timeframe and assessment population matter when interpreting these counts: they are not automatically equivalent to outcomes for every randomized participant.

7. Results Posted in the Registry

• Treatment B: CPI-006 1 mg/kg + SOC: 85.7% (12/14) versus 93.3% (14/15) on control; risk difference -7.6 percentage points (95% CI -29.9 to 14.6), risk ratio 0.92 (0.71–1.18); unadjusted two-proportion z-test p = 0.501.
• Treatment C: Placebo + SOC: 81.8% (9/11) versus 93.3% (14/15) on control; risk difference -11.5 percentage points (95% CI -37.6 to 14.5), risk ratio 0.88 (0.64–1.19); unadjusted two-proportion z-test p = 0.364.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the endpoint definition during the stated timeframe or did not. The posted arm-level results are counts of participants meeting the endpoint among those included in the primary-outcome population. The registry reports these counts as 14 of 15, 12 of 14, and 9 of 11 for the 2 mg/kg, 1 mg/kg, and placebo arms, respectively.

What does a risk difference represent?

A risk difference compares the proportion meeting the endpoint in one group with the proportion in a reference group. It is expressed on the proportion scale, so zero corresponds to equal proportions. A negative difference means the proportion in the comparison group is lower than the proportion in the reference group, given the contrast direction used. The registry reports -0.076 for Treatment B compared with Treatment A, and -0.115 for Treatment C compared with Treatment A. Treatment A is the 2 mg/kg arm, Treatment B is the 1 mg/kg arm, and Treatment C is placebo. These posted contrasts therefore answer comparisons against the higher-dose arm, not placebo-referenced comparisons for both active doses.

How should the confidence intervals be read?

A confidence interval expresses the uncertainty around an estimate under the statistical method used. General explanation: a 95% confidence interval is produced by a procedure that, over repeated studies under its assumptions, would include the underlying value at the stated frequency. It does not mean there is a 95% probability that this particular interval contains the true value. For the 1 mg/kg versus 2 mg/kg contrast, the reported interval is -0.299 to 0.146; for placebo versus 2 mg/kg, it is -0.376 to 0.145. Both cover zero and span differences in either direction, indicating substantial uncertainty around each point estimate.

What do the p-values tell us?

The reported p-values are unadjusted: 0.501 for the 1 mg/kg arm compared with the 2 mg/kg arm, and 0.364 for placebo compared with the 2 mg/kg arm. General explanation: a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the analysis assumptions were true. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of a difference. The registry record does not report whether a different inferential procedure, covariate adjustment, or prespecified testing sequence was used by the sponsor.

Why do the groups and analysis population matter?

Random allocation is intended, in general, to support comparable groups at the start of a trial. The registry lists randomization, but the posted primary population is defined by receipt of any study drug and availability of a post-baseline efficacy assessment. This definition is not identical to an explicit statement that all randomized participants were included. The handling of missing assessments, withdrawals, and participants excluded from this population is not reported in the registry record. That limits assessment of potential bias from missing outcome data or exclusions.

The record lists a parallel design, quadruple masking, and stratification in the official study description. General explanation: masking can reduce the chance that knowledge of assigned treatment influences care or outcome assessment, while stratification can be used to organize randomization by specified characteristics. The stratification factors and the practical details of masking are not reported in the registry record, so their implementation cannot be assessed from the posted information.

What can be inferred from the posted analysis information?

The registry lists four outcome measures and three secondary outcomes, but no analyses are posted in the analysis count. This does not establish that no statistical analyses were performed; it means the registry record does not include posted analysis records. The primary results include unadjusted p-values and confidence intervals, but the original statistical analysis plan, planned estimand, model specification, and any adjustment for multiple comparisons are not reported in the registry record.

General explanation: when several outcomes or contrasts are tested, the chance of at least one apparently unusual result can increase if testing is not accounted for. A prespecified multiplicity approach can address that issue, but whether one was planned or applied for this trial is not reported. No adjustment should be assumed from the posted unadjusted p-values.

10. Confidence Intervals and Precision

The risk-difference estimates are accompanied by broad confidence intervals. For the comparison of the 1 mg/kg arm with the 2 mg/kg reference arm, the estimate is -0.076 and the interval is -0.299 to 0.146. For placebo compared with the 2 mg/kg reference arm, the estimate is -0.115 and the interval is -0.376 to 0.145. Each interval includes zero, and each includes values on both sides of zero.

General explanation: a confidence interval gives a range of values compatible with the observed data under the method’s assumptions. A narrow interval would indicate greater precision, while a wide interval indicates that the data do not pin down the contrast closely. These intervals cover a wide range of possible risk differences, so the point estimates alone should not be read as precise estimates of the underlying group differences.

The outcome denominators were 15 for the 2 mg/kg arm, 14 for the 1 mg/kg arm, and 11 for the placebo arm. With groups of this size, general statistical reasoning suggests that estimates can vary considerably with a small change in the observed participant counts. The registry record does not report a precision target or a justification for the achieved sample size.

The posted comparisons also have a reference-group limitation: both use the 2 mg/kg arm, rather than presenting the stated placebo-referenced treatment contrasts. Their confidence intervals therefore describe uncertainty in the comparisons actually reported and should not be substituted for intervals for a different contrast. The record does not report adjusted estimates or additional uncertainty measures that would resolve this limitation.

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, not total events. They are illustrative calculations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

For the 1 mg/kg versus 2 mg/kg comparison, planning for 100% of the observed effect gives 253 participants per arm for 80% power and 338 participants per arm for 90% power. Planning for 75% of the observed effect gives 414 participants per arm for 80% power and 553 participants per arm for 90% power. Planning for 50% of the observed effect gives 847 participants per arm for 80% power and 1,133 participants per arm for 90% power.

For the placebo versus 2 mg/kg comparison, planning for 100% of the observed effect gives 128 participants per arm for 80% power and 171 participants per arm for 90% power. Planning for 75% of the observed effect gives 205 participants per arm for 80% power and 274 participants per arm for 90% power. Planning for 50% of the observed effect gives 408 participants per arm for 80% power and 546 participants per arm for 90% power.

In plain terms, the 80% and 90% columns describe the planned chance of detecting the specified effect if that effect were real and the planning assumptions held; the higher power target requires more participants. Smaller effects require more participants to detect under the same assumptions. These are planning illustrations, not observed power.

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 = 0.933; treatment proportion p₁ = 0.857; average p̄ = 0.895.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4331 = 0.8489.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4297 = 0.3617.
4. n = (0.8489 + 0.3617)² / (-0.0762)² = 252.4, rounded up to 253 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 <- 0.933333333333333                          # control proportion
p1 <- 0.857142857142857                          # 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(4734873)
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 = 253 (80% power), 338 (90% power)
 75% of observed effect: n per arm = 414 (80% power), 553 (90% power)
 50% of observed effect: n per arm = 847 (80% power), 1,133 (90% power)
power.prop.test: 252.4 
Simulated power at n = 253 per arm: 0.808 (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 lists the primary outcome and three secondary outcomes: time to recovery, time to clinical improvement, and mortality due to any cause. It reports four outcome measures in total. The posted primary results contain comparisons between the 2 mg/kg arm and each of the other arms, with unadjusted p-values. The registry record does not report a multiplicity strategy, such as a testing order or adjustment for the number of outcomes or comparisons.

General explanation: testing multiple outcomes or contrasts without an adjustment can make it more likely that at least one result appears statistically unusual by chance alone. This is a consideration when interpreting the unadjusted p-values, not evidence that any particular result is false. Whether the sponsor used a prespecified multiplicity procedure outside the posted registry information is not reported in the registry record.

The record lists no posted analysis records. The absence of posted analysis records does not show that no analyses were conducted; it means that details such as the analysis model, covariate adjustment, and any sensitivity analyses are not available in the registry record. The reason for termination and whether analyses were changed after termination are also not reported.

The primary-outcome population included participants who received any amount of study drug and had a post-baseline efficacy assessment. The registry record does not report how missing post-baseline assessments were handled, whether any imputation was used, or whether participants were excluded for other reasons. It also does not report a detailed accounting of participants randomized, treated, and analyzed by arm beyond the posted outcome denominators.

These gaps make it difficult to assess the robustness of the primary results to missing data, exclusions, or analysis choices. The stated analysis population should therefore be kept distinct from the full randomized population, and the posted unadjusted comparisons should be read as the results available in the registry rather than as a complete account of the statistical analysis plan.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: substance-induced psychotic disorder (9.1%), acute respiratory distress syndrome (9.1%).

The registry reports serious adverse events for each arm as counts among the listed participants at risk. There were 0 serious adverse events among 15 participants at risk in the CPI-006 2 mg/kg plus standard-of-care arm, and 0 among 14 at risk in the 1 mg/kg arm. In the placebo plus standard-of-care arm, 2 serious adverse events were reported among 11 participants at risk. The registry lists no deaths in any of the three arms.

Other adverse events were reported for 5 of 15 participants in the 2 mg/kg arm, 2 of 14 in the 1 mg/kg arm, and 2 of 11 in the placebo arm. The registry’s top serious adverse event terms are Substance-induced psychotic disorder and Acute respiratory distress syndrome, each listed as 9.1%. The record does not identify the arm attribution for these terms in the information, so they should not be assigned to an arm.

General explanation: adverse-event counts describe events observed and recorded under the trial’s safety reporting approach; they do not by themselves establish that a study drug caused an event. The registry record does not report event timing, exposure-adjusted rates, severity beyond the serious-event classification, or a comparative safety analysis. The small arm denominators also mean that these counts alone provide limited precision for comparing safety outcomes.

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

The registry’s posted primary results describe how many participants in each arm were alive and free from respiratory deterioration during the 28 days after dosing, among those in the stated primary-outcome population. The counts are 14 of 15 for CPI-006 2 mg/kg plus standard of care, 12 of 14 for CPI-006 1 mg/kg plus standard of care, and 9 of 11 for placebo plus standard of care.

The reported risk differences compare each of the other arms with the 2 mg/kg arm. Both estimates are negative, and both confidence intervals include zero while extending across values in either direction. This means the results do not precisely establish the size or direction of a difference. The posted p-values are unadjusted and should not be treated as proof of equivalence or as a measure of clinical importance.

The title and study objective describe comparisons of CPI-006 plus standard of care with placebo plus standard of care. However, the posted numerical contrasts use the 2 mg/kg CPI-006 arm as the reference for both the 1 mg/kg and placebo arms. Interpretation should follow the contrast actually reported, rather than assume that the displayed estimates directly answer a placebo-referenced question for each CPI-006 dose.

The record does not report the reason for termination, the sponsor’s original sample-size justification, or the detailed statistical analysis plan. It also does not describe the handling of missing primary assessments. These omissions, together with the limited group sizes and broad confidence intervals, constrain what can be concluded from the registry results.

Accordingly, the posted data are best read as a small, imprecise set of arm-level outcome counts and comparisons. They do not provide a definitive answer about the underlying treatment differences, and they do not by themselves establish whether a regimen does or does not have a clinical effect.

16. Why This Trial Matters Statistically

This trial illustrates why the reference group used in a statistical contrast matters. The study objective describes comparison of CPI-006 plus standard of care with placebo plus standard of care, but the posted numerical estimates compare the 1 mg/kg arm and the placebo arm separately with the 2 mg/kg arm. Those are different questions. Clear identification of the reference group is essential for interpreting both the direction and meaning of a risk difference.

The endpoint also combines survival and respiratory status. That offers a single summary of two important aspects of clinical progression, but it does not show which component accounts for an observed outcome. The scale’s ordered states provide clinical context, while the posted binary result reduces those states to whether a participant met the alive-and-respiratory-failure-free definition.

Small arm denominators and broad confidence intervals highlight the distinction between a point estimate and its precision. The observed counts can be stated exactly, but the uncertainty around between-arm differences remains substantial. The planning illustrations further show how assumed effect size and desired power influence sample-size requirements; they are not evidence of the trial’s original design rationale.

Finally, the record demonstrates the importance of transparent reporting about analysis populations, missing data, multiplicity, and termination. The posted information identifies an efficacy-assessment population and unadjusted comparisons, but does not describe several details needed to evaluate the full analysis. Such context is necessary to judge how closely a registry result answers the clinical question the study set out to address.

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.

Several limitations are specific to the registry information for this trial. First, the posted risk-difference comparisons use the 2 mg/kg CPI-006 arm as the reference for both the 1 mg/kg and placebo arms. The intended comparison described in the study objective is CPI-006 plus standard of care versus placebo plus standard of care, but the registry’s displayed contrasts do not provide a placebo-referenced estimate for each active dose.

Second, the primary-outcome population is defined as participants who received any amount of study drug and had a post-baseline efficacy assessment. The record does not report how many randomized participants lacked an assessment, how missing outcomes were handled, or whether the analysis included all randomized participants. This limits evaluation of possible selection or missing-data effects.

Third, no statistical analysis records are posted. The original analysis plan, model details, adjustment for stratification factors, multiplicity approach, and sensitivity analyses are not reported in the registry record. The original sample-size justification and the reason for termination are also not reported.

Finally, the outcome groups are small and the risk-difference confidence intervals are broad. The registry’s safety figures are counts with limited accompanying detail; the arm attribution of the listed serious-event terms is not reported in the information available for this analysis. These limitations mean the posted results support description of the observed data, but leave important questions about analysis choices, safety context, and precision unresolved.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: CPI-006 Plus Standard of Care Versus Placebo Plus Standard of Care in Mild to Moderately Symptomatic Hospitalized Covid-19 Patients — NCT04734873.
• Registry record last updated 2022-09-21; status last verified 2022-09.
• Results first posted 2022-08-23.
• 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 NCT04734873, a phase 3 randomized, placebo-controlled, double-blind, multicenter, stratified, parallel study of CPI-006 plus standard of care versus placebo plus standard of care in hospitalized patients with mild to moderately symptomatic Covid-19. It lists quadruple masking, registered enrollment of 46, and a terminated status.

The primary outcome was the proportion alive and free from respiratory deterioration during the 28 days after dosing, assessed using a modified WHO 8-point ordinal scale. The posted outcome counts were 14 of 15 for CPI-006 2 mg/kg, 12 of 14 for CPI-006 1 mg/kg, and 9 of 11 for placebo. The posted risk differences compare each of the latter arms with the 2 mg/kg arm, with confidence intervals that include zero.

The record also lists three secondary outcomes and adverse-event counts. Detailed analysis methods, missing-data handling, the reason for termination, and the original sample-size justification are not reported in the registry record.