Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy (NCT01099449), a randomized phase 3 study. The primary outcome is Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy.

2. Clinical Question

The central statistical question is whether the posted sensory quality-of-life scores distinguish either active schedule from the placebo schedule. The three schedules separate the timing of the infusions: calcium gluconate and magnesium sulfate were given both before and after oxaliplatin, only before oxaliplatin, or replaced by placebo at both times. The primary comparison uses placebo before and after oxaliplatin as the reference for each active schedule.

This is a question about the measured endpoint and its uncertainty, not a direct answer about every aspect of neurotoxicity. The primary measure was a repeated sensory-subscale score summarized as an AUC and prorated by the number of chemotherapy cycles received. Secondary outcomes address other measures, including autonomic and motor subscales, chronic cumulative neurotoxicity, treatment discontinuation, acute neuropathy, and adverse events. The posted record does not establish that a difference on the sensory AUC represents a difference in every other outcome.

3. Trial Design

The registry identifies NCT01099449 as a completed phase III randomized, double-blind, parallel-group, placebo-controlled study. Enrollment was 362. The study concerned patients with colon or rectal cancer receiving oxaliplatin-based combination chemotherapy, and compared three intravenous schedules during FOLFOX chemotherapy.

In one schedule, calcium gluconate and magnesium sulfate were infused over 30 minutes immediately before and after oxaliplatin. In the placebo schedule, placebo was infused over 30 minutes immediately before and after oxaliplatin. In the third schedule, calcium gluconate and magnesium sulfate were given before oxaliplatin and placebo was given after it. The registry describes the chemotherapy regimen as including leucovorin calcium, fluorouracil, and oxaliplatin.

The primary sensory endpoint reports means and standard deviations for the three schedules: 89.2 (SD 8.5) for calcium and magnesium before and after oxaliplatin, 88.3 (SD 9.7) for placebo before and after, and 87.1 (SD 9.9) for calcium and magnesium before and placebo after. The corresponding endpoint analysis counts are 110, 106, and 110. These are outcome-specific counts, not a substitute for the enrollment figure or a complete account of participant flow.

The record lists a start of 2010-06 and primary completion of 2012-12. Further details of randomization implementation, allocation concealment, the original statistical plan, and the rationale for the planned sample size are not reported in the registry record. The analysis-population description for the primary endpoint is limited to enrolled patients with baseline and more than 1 cycle of sensory data.

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: All enrolled patients with Baseline and more than 1 cycle of Sensory data.

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 Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy, measured over Up to 18 months.

The primary endpoint was the sensory-subscale AUC from the EORTC QLQ-CIPN20, a quality-of-life questionnaire for chemotherapy-induced peripheral neuropathy. Sensory symptoms were measured repeatedly during chemotherapy, with the endpoint timeframe listed as up to 18 months. Rather than selecting a score from one fixed chemotherapy cycle, the record describes using a summary measure across repeated assessments. The AUC was prorated by the number of chemotherapy cycles received.

The sensory subscale was calculated using the standard scoring algorithm and converted to a 0-100 scale. The registry states that higher scores represent higher quality of life. Thus the scale direction matters when reading the group means: a larger score is oriented toward higher reported quality of life on this measure, not toward more severe neuropathy. The endpoint is reported as a mean with standard deviation.

A repeated-measure summary can represent experience across treatment assessments rather than at one selected visit. It can also incorporate variation in the number of cycles assessed, which is why the record notes proration by cycles received. This makes the endpoint a summary of the recorded sensory-subscale trajectory, not a direct count of neuropathy events or a single-cycle symptom score. The exact handling of incomplete repeated assessments beyond the stated population criterion is not reported in the registry record.

7. Results Posted in the Registry

• Calcium Gluconate + Magnesium Sulfate (Pre and Post): mean 89.20 versus 88.30 on control; difference 0.90 (95% CI -1.54 to 3.34), standardized effect d = 0.10; z-test p = 0.469.
• Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post): mean 87.10 versus 88.30 on control; difference -1.20 (95% CI -3.81 to 1.41), standardized effect d = -0.12; z-test p = 0.368.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Calcium Gluconate + Magnesium Sulfate (Pre and Post): mean 89.80 versus 86.70 on control; difference 3.10 (95% CI -0.54 to 6.74), standardized effect d = 0.23; z-test p = 0.095.
  • Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post): mean 84.50 versus 86.70 on control; difference -2.20 (95% CI -6.15 to 1.75), standardized effect d = -0.15; z-test p = 0.275.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre and Post) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) and the control. The interval gives the range of effects that remain compatible with the data.

Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Calcium Gluconate + Magnesium Sulfate (Pre and Post): mean 94.10 versus 93.30 on control; difference 0.80 (95% CI -1.32 to 2.92), standardized effect d = 0.10; z-test p = 0.460.
  • Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post): mean 91.60 versus 93.30 on control; difference -1.70 (95% CI -4.18 to 0.78), standardized effect d = -0.18; z-test p = 0.180.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre and Post) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) and the control. The interval gives the range of effects that remain compatible with the data.

Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Calcium Gluconate + Magnesium Sulfate (Pre and Post): mean 8.10 versus 8.40 on control; difference -0.30 (95% CI -1.63 to 1.03), standardized effect d = -0.11; z-test p = 0.658.
  • Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post): mean 8.00 versus 8.40 on control; difference -0.40 (95% CI -1.70 to 0.90), standardized effect d = -0.16; z-test p = 0.545.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre and Post) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the trial's focus beyond the primary sensory AUC. The registry lists autonomic and motor neuropathy AUC scores, chronic cumulative neurotoxicity, timing and duration of chronic neurotoxicity, cumulative oxaliplatin doses without dose-limiting chronic neurotoxicity, chemotherapy discontinuation because of neurotoxicity, acute neuropathy, and adverse events. Nine secondary outcomes are posted.

The pattern of recalculated secondary comparisons is mixed in direction and precision, rather than forming a consistent separation between the active schedules and placebo across all reported measures. The secondary outcomes therefore add context but do not convert the primary result into a definitive conclusion. Differences in outcome definition, available observations, and statistical method also mean that findings across endpoints are not interchangeable.

These results should carry less weight than a prespecified primary analysis when considered as a group. Each additional outcome creates another opportunity to observe a result that appears unusual by chance. Unless multiplicity is addressed through a prespecified strategy, unadjusted secondary p values are exploratory and should not be treated as confirmatory evidence. The registry does not report a multiplicity adjustment plan.

Secondary outcomes can still be informative: they can describe other dimensions of neuropathy and treatment experience and can identify questions for further study. But they do not independently validate a primary-endpoint interpretation, and a result on one secondary measure does not establish the same pattern for the others. Detailed interpretation should remain tied to each outcome's population, measurement, uncertainty, and analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores
• Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores
• Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity.
• Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy
• Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity
• Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity
• Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin
• Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a mean sensory-subscale AUC score. The registry reports the group means and standard deviations, and the recalculated comparisons express the mean in each active-schedule group relative to the placebo-before-and-after group. A positive mean difference means the active-schedule mean was higher on the stated score; a negative mean difference means it was lower. Because higher scores represent higher quality of life on this scale, direction should be interpreted using that scoring convention.

What does the recalculated comparison represent?

The recalculated mean differences are simple, unadjusted comparisons based on the posted summary statistics. They do not represent an adjusted model, a repeated-measures model, or the full sponsor analysis. For the before-and-after active schedule, the estimated mean difference was 0.9. For the before-only active schedule, it was -1.2. The associated confidence intervals and p values describe these recalculations, not necessarily the method used for the registry's reported analyses.

Standard deviation describes how dispersed individual observations are around a group mean. It is not the uncertainty in the mean itself. The standard errors listed with the recalculated results quantify uncertainty in each group mean under the calculation; the uncertainty in a contrast also depends on both groups. A group mean can be estimated with uncertainty even when the underlying observations vary substantially.

What do confidence intervals and p values say?

A confidence interval gives a range of effect values compatible with the data and the method's assumptions at the stated confidence level. If the interval includes zero for a mean difference, the data do not sharply distinguish a positive from a negative difference at that level. That does not prove there is no difference. The primary recalculated intervals extend across zero, so they leave uncertainty about both the direction and magnitude of a mean difference.

A p value describes how unusual data at least as discrepant from a specified null value would be under the test's assumptions. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of a difference. The recalculated p values are unadjusted. They should be read alongside the estimates and intervals, not as stand-alone proof of a conclusion.

Why are different methods reported?

The registry lists Wilcoxon (Mann-Whitney) tests for the primary comparisons, while the recalculations use mean differences from summary statistics. A Wilcoxon test is a rank-based comparison; it does not directly estimate the difference between arithmetic means. It can be useful when the analysis is intended to compare distributions without relying on the same assumptions as a mean-based analysis. The registry does not report the distributional details, test statistic, or additional parameters for these analyses. Therefore, the reported p values and recalculated mean-difference results answer related but not identical statistical questions.

The repeated measurement underlying the endpoint is important. Sensory scores were collected across chemotherapy rather than at one fixed cycle, and the AUC was prorated by the number of cycles received. A model that accounts for repeated observations could use information about the pattern of scores over time, but the registry's detailed model specification is not reported. The posted means and standard deviations do not reproduce such a model.

Why can over-dispersion matter in general?

General explanation: when count data vary more than a model assumes, estimated uncertainty can be too small if that extra variability is ignored. This is called over-dispersion. It is relevant to some count outcomes, but the primary endpoint is a continuous AUC score, not a count. The registry does not describe an over-dispersion model for the primary analysis, so it would be inappropriate to infer that one was used.

The sample-size illustrations are also calculations from observed effects rather than an account of the original trial design. They use the stated two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The registry's own sample-size assumptions and analysis plan are not reported in the registry record.

11. Confidence Intervals and Precision

The recalculated mean difference for calcium and magnesium given before and after oxaliplatin, compared with placebo at both times, was 0.9. Its 95% confidence interval ran from -1.536 to 3.336. For calcium and magnesium given before oxaliplatin and placebo afterward, compared with placebo at both times, the recalculated difference was -1.2, with a 95% confidence interval from -3.814 to 1.414.

These intervals include zero and span possible values in both directions. The data therefore do not pinpoint a single direction of difference. The first interval is compatible with a modest negative difference as well as a positive one; the second is compatible with a negative difference as well as a positive one. This uncertainty is important even though the point estimates are near zero. A point estimate is the center of a calculation, not a guarantee that the true effect equals that value.

Precision is distinct from whether a result passes a significance threshold. A narrow interval would indicate greater precision, while a wide interval indicates that a range of effect sizes remains compatible with the data and method. The intervals should be judged against what differences would matter for this score, but a clinically important threshold or minimal important difference is not reported in the registry record.

The registry's own Wilcoxon analyses provide p values but no effect estimates or confidence intervals. Their p values cannot supply the missing magnitude or precision. The recalculated intervals are unadjusted summaries based on posted means and standard deviations, and should not be confused with intervals from the sponsor's analysis. Neither set of results, as posted, establishes equivalence.

12. 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 sample-size illustrations are planning calculations based on the observed effect, not the trial's original design assumptions. All continuous-outcome figures are participants per arm, not total participants. They assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effects used for planning are the stated fractions of the observed effect. The original trial's sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a future two-arm study to have an 80% chance of detecting the specified effect under the calculation's assumptions, if that effect were the true effect and the assumptions held. The 90% power column gives the corresponding planning count for a 90% chance. These are planning targets, not observed properties of the completed trial. This is not observed power.

Rows planning for 75% or 50% of the observed effect ask what would be needed to detect a smaller effect than the point estimate used in the calculation. Smaller effects are harder to distinguish from random variation, so they require more participants under the same assumptions. The curve should be read as the same planning relationship across effect sizes: greater sensitivity to smaller effects comes at the cost of larger per-arm requirements.

The estimates are not guarantees that a future study will reach a particular conclusion. They depend on the normal approximation, equal allocation, the significance level, and the assumed effect size. They also do not account for details that are not stated in the illustration, such as any adjustment for multiple comparisons or losses of endpoint data. They should be interpreted as planning illustrations tied to the observed estimate, not as evidence about the completed trial's power or design.

13. 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.900; pooled standard deviation σ = 9.109.
2. n = 2 × (1.96 + 0.842)² × 9.109² / 0.900² = 1,607.9, rounded up to 1,608 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
delta <- 0.900000000000006                      # observed difference in means
sigma <- 9.10856123932135                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1099449)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,608 (80% power), 2,153 (90% power)
 75% of observed effect: n per arm = 2,859 (80% power), 3,827 (90% power)
 50% of observed effect: n per arm = 6,432 (80% power), 8,610 (90% power)
power.t.test: 1608.8 
Simulated power at n = 1,608 per arm: 0.805 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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.

14. Analyses Reported by the Sponsor

The registry's own primary comparisons are reported as Wilcoxon (Mann-Whitney) analyses. The listed p values are .73 for calcium and magnesium before and after versus placebo before and after, and .29 for placebo before and after versus calcium and magnesium before followed by placebo after. The registry labels these as legacy non-inferiority-or-equivalence analyses. It does not report a test statistic, estimated contrast, confidence interval, or margin for either comparison.

The recalculated results instead compare arithmetic means using the posted group means and standard deviations. They give an unadjusted mean difference of 0.9 for the before-and-after active schedule and -1.2 for the before-only active schedule, each with a confidence interval spanning zero. These are not substitutes for the sponsor's rank-based analyses, and their p values should not be expected to match the registry's reported p values.

Without the prespecified non-inferiority or equivalence margin, the registry p values cannot establish that either schedule met such a criterion. The record also does not provide enough detail to reproduce the sponsor's analysis. The recalculation is useful as a transparent summary of posted means, but the registry's analysis remains the study's reported analysis; the two should be kept distinct rather than combined into one test.

15. Multiplicity, Missing Data and Analysis Populations

The study has a primary endpoint and multiple secondary outcomes, with comparisons involving two active schedules and placebo. Repeatedly testing several outcomes or comparisons increases the chance that at least one result will appear notable by chance, even when no underlying difference exists. Statistical methods can address this issue by defining a testing hierarchy, adjusting significance thresholds, or clearly treating secondary analyses as exploratory.

The registry record does not report whether a multiplicity strategy was prespecified or applied. The posted recalculated p values are unadjusted. The sponsor's reported Wilcoxon and Kruskal-Wallis results also appear without a description of how the overall family of tests was handled. Consequently, the record does not support treating a collection of nominal p values as if each were the sole planned test.

The registry identifies the primary endpoint population as all enrolled patients with baseline and more than 1 cycle of sensory data. This is an eligibility description for the endpoint analysis, but the record does not explain how missing baseline or follow-up scores were handled, whether incomplete repeated assessments were imputed, or what sensitivity analyses were conducted. Outcome-specific analysis counts are reported, but a fuller account of exclusions and missingness patterns is not reported in the registry record.

The original statistical analysis plan, including model details, prespecified covariates, handling of repeated measurements, and missing-data assumptions, is not reported in the registry record. This limits independent assessment of whether the posted analyses follow the planned approach. It also means that the recalculated summaries should be treated as unadjusted descriptions, not replacements for an unavailable full analysis plan.

16. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diarrhea (7.7%), nausea (2.6%), neutrophil count decreased (2.5%), infusion related reaction (1.7%), atrial flutter (0.9%).

The registry reports serious adverse event counts by schedule among those listed as at risk. For calcium gluconate and magnesium sulfate before and after oxaliplatin, 13 of 117 were affected by serious adverse events. For placebo before and after, 9 of 119 were affected. For calcium and magnesium before oxaliplatin followed by placebo, 8 of 116 were affected. These counts describe the registry's serious-adverse-event summary, not a causal comparison.

The record also gives counts for other, non-serious adverse events: 107 of 117, 108 of 119, and 105 of 116, respectively. The leading serious adverse-event terms listed include diarrhea (7.7%), nausea (2.6%), neutrophil count decreased (2.5%), infusion related reaction (1.7%), atrial flutter (0.9%), and abdominal pain (0.9%). These percentages are reported terms and should not be added or interpreted as mutually exclusive participant categories.

Deaths are not reported in the registry record. The safety summaries do not provide a causal attribution for each event, a comparative statistical analysis, or enough detail to infer that differences in counts were caused by an infusion schedule. These figures describe reported safety experience; they do not by themselves establish a comparative safety conclusion.

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

The primary endpoint results describe average sensory-subscale AUC scores during chemotherapy, with higher scores oriented toward higher quality of life. The posted group means are close in scale, while the recalculated mean-difference confidence intervals include zero and allow values in either direction. The registry's own analyses report p values but do not include effect estimates, confidence intervals, or a non-inferiority or equivalence margin.

Accordingly, the record does not establish that the schedules are identical, nor does it demonstrate a clear difference on the primary AUC measure. A failure to distinguish the group means statistically is not evidence that the true effects are exactly the same. Likewise, a point estimate that is positive or negative does not establish a meaningful benefit or harm. The record does not state a threshold for a clinically important difference on the sensory scale.

The result is also limited to the measured endpoint and its defined population: enrolled patients with baseline and more than 1 cycle of sensory data. It should not be generalized automatically to all patients, other chemotherapy regimens, all forms of neuropathy, or outcomes not captured by the primary endpoint. The secondary outcomes provide additional descriptions, but their unadjusted nature and the missing analysis details constrain the conclusions that can be drawn across the outcome set.

This statistical interpretation is not medical advice and does not recommend a treatment schedule. It describes the posted data and the limits of their precision. The registry record is useful for understanding the endpoint and reported comparisons, but it is not a complete account of the trial's analysis plan or all methods needed to independently reproduce the study analysis.

18. Why This Trial Matters Statistically

This trial raises several important statistical issues for clinical researchers. First, its primary outcome is a repeated-measure summary rather than a score at a single fixed treatment cycle. AUC can summarize information across a treatment period, but the definition, handling of differing numbers of cycles, and treatment of missing assessments matter to interpretation. The registry states that the AUC was prorated by cycles received, but does not report the full computational or modeling details.

Second, the trial compares more than one infusion schedule with a placebo schedule and reports several secondary outcomes. That makes it important to distinguish the primary question from exploratory comparisons and to understand any multiplicity plan. The registry does not report such a plan, so unadjusted secondary findings require caution.

Third, the record presents both rank-based sponsor analyses and summary-statistic recalculations of mean differences. These methods address related but different aspects of the data. Showing their distinction helps prevent readers from treating a mean contrast and a rank-test p value as interchangeable or assuming that one reproduces the other.

Finally, uncertainty is central. Point estimates are not precise answers by themselves, and the primary recalculated intervals include zero while spanning values in both directions. Reporting estimates with intervals, alongside the limitations of the posted analysis details, is more informative than reducing the result to a binary significant-or-not label.

19. 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 does not provide the original sample-size rationale or full statistical analysis plan. It therefore cannot show how the trial's enrollment target was selected, which assumptions informed the design, or whether the posted analyses correspond to every prespecified analysis. The sample-size illustrations based on observed effects are not evidence about the original design.

The primary endpoint uses repeated sensory measurements and an AUC prorated by the number of chemotherapy cycles received. The detailed procedure for constructing the AUC, handling incomplete records, and modeling repeated observations is not reported in the registry record. The stated analysis population requires baseline and more than 1 cycle of sensory data, but further missing-data methods and sensitivity analyses are not reported.

The sponsor's primary analyses are reported as Wilcoxon (Mann-Whitney) tests with p values only. Effect estimates, confidence intervals, test statistics, and the margin needed to interpret a non-inferiority or equivalence claim are not reported. The recalculated mean differences are unadjusted summaries and do not reproduce the sponsor's analysis.

Several secondary outcomes and schedule comparisons are listed, but a multiplicity strategy is not reported. The record also does not report a clinically important difference threshold for the primary score. These gaps limit claims about clinical importance, equivalence, and the consistency of findings across outcomes. The safety summaries provide event counts and selected terms but do not establish causality or report a comparative statistical analysis.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy — NCT01099449.
• Registry record last updated 2022-11-03; status last verified 2022-11.
• Results first posted 2019-05-23.
• 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.

23. Record Summary

NCT01099449 is a completed randomized, double-blind, phase III, parallel-group study with enrollment of 362. It compared intravenous calcium gluconate and magnesium sulfate before and after oxaliplatin, the same agents before oxaliplatin with placebo afterward, and placebo before and after oxaliplatin during FOLFOX chemotherapy.

The primary endpoint was the sensory-subscale AUC of the EORTC QLQ-CIPN20 during chemotherapy, up to 18 months. Higher scores represent higher quality of life. The recalculated unadjusted mean differences versus placebo were 0.9 and -1.2; both confidence intervals included zero. The registry's own reported primary analyses provide Wilcoxon p values but no effect estimates, confidence intervals, or equivalence margin.

Interpretation is limited by unreported details of the original analysis plan, multiplicity approach, and missing-data handling. Secondary and safety findings provide additional context but do not remove those limitations.