Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment (NCT01285401), a randomized phase 2 study. The primary outcome is Percentage of Subjects With Disease Activity Free Status up to Week 48.

2. Clinical Question

The trial addressed whether adding VigantOL oil to Rebif was associated with a different rate of disease-activity-free status than adding placebo to Rebif. The primary outcome required absence of all listed activity indicators: relapse, EDSS progression, and new gadolinium-enhancing or T2 MRI lesions. This is a composite measure, so a participant had to meet all of its component conditions to count as free of disease activity.

The registry describes a three-arm study, but the posted primary comparison is VigantOL oil plus Rebif against placebo plus Rebif. The arms are not described as having identical vitamin D eligibility conditions: both add-on arms are described for levels below 150 nmol/L, while Rebif alone is described for levels equal to or higher than 150 nmol/L. The central numerical question is therefore the contrast between the two add-on groups, not a three-way estimate of all treatment strategies.

3. Trial Design

This was a randomized, double-blind, placebo-controlled, multicenter, parallel Phase II study. The official title describes a three-arm study of Vigantol oil as add-on therapy in subjects receiving 44mg Tiw of Rebif. The registry lists enrollment of 260 and a completed status. The sponsor is Merck KGaA, Darmstadt, Germany.

The three arms were VigantOL oil plus Rebif, placebo plus Rebif, and Rebif alone. The arm descriptions specify 25-hydroxy-vitamin D plasma levels below 150 nmol/L for the two add-on groups and levels equal to or higher than 150 nmol/L for Rebif alone. The primary numerical results shown for the endpoint compare the VigantOL oil and placebo add-on groups. Their endpoint group sizes are 113 and 116, respectively. Numerical primary results for the Rebif-alone arm are not reported in the registry record.

The brief description states that planned treatment duration was 48 weeks for each participant. It also notes that participants who had already passed Week 48 when Protocol Amendment 5 was approved would have a 96-week study duration. The description lists 8 visits for the planned 48-week course and 12 visits for the extended course. Disease activity was assessed by clinical examination and MRI, alongside physical examination, neurological and safety assessments, blood tests, and urinalysis.

The registry lists the study start as 2011-02 and primary completion as 2015-04. The detailed protocol, the reason for the sample-size target, the randomization procedure, and the trial's original statistical analysis plan are not reported in the registry record. The available information supports describing the broad design and scheduled assessments, but not reconstructing unreported procedural details.

4. Participant Flow and Accounting

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

Before assignment: Total 260 subject were enrolled, out of which 232 subjects were randomized and started the study. 229 subjects were treated since 3 subjects of the 232 randomized subjects were excluded from analysis as they did not received any medication.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT set included all randomized subjects who received at least 1 dose of the IMP.

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: Baseline analysis set included all randomized subjects.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Disease Activity Free Status up to Week 48, measured over Up to Week 48.

The primary endpoint was the percentage of subjects with disease-activity-free status up to Week 48. The registry defines this status as no relapse, no EDSS progression, and no new gadolinium-enhancing or T2 MRI lesions. It therefore combines clinical and imaging indicators into one binary outcome: each participant either met the full definition or did not.

Composite endpoints are used in general when a clinical question concerns more than one type of disease activity. They can capture a broader range of events than a single component alone. Interpretation depends on the components and on the rule for combining them. Here, the endpoint requires absence of every listed component; a participant with any one of them would not meet the disease-activity-free definition.

The outcome is reported as a percentage of participants, with the primary population defined as randomized subjects who received at least 1 dose of the investigational medicinal product. The posted group percentages were 37.2 for VigantOL oil plus Rebif and 35.3 for placebo plus Rebif. The comparison estimate is a risk difference, which expresses the contrast in the proportion meeting the endpoint between these groups. The endpoint can describe the observed combined status, but it does not by itself show which individual component drove the group results. Component-specific results and their analysis details are not reported in the registry record.

7. Results Posted in the Registry

• VigantOL Oil Interferon Beta-1a (Rebif): 37.2% (42/113) versus 35.3% (41/116) on control; risk difference 1.8 percentage points (95% CI -10.6 to 14.3), risk ratio 1.05 (0.75–1.48); unadjusted two-proportion z-test p = 0.774.

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.

Percentage of Relapse-free Subjects at Week 48

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VigantOL Oil Interferon Beta-1a (Rebif): 78.8% (89/113) versus 75.0% (87/116) on control; risk difference 3.8 percentage points (95% CI -7.1 to 14.7), risk ratio 1.05 (0.91–1.21); unadjusted two-proportion z-test p = 0.500.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between VigantOL Oil Interferon Beta-1a (Rebif) and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Subjects Free From Any Expanded Disability Status Scale (EDSS) Progression at Week 48

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VigantOL Oil Interferon Beta-1a (Rebif): 71.7% (81/113) versus 75.0% (87/116) on control; risk difference -3.3 percentage points (95% CI -14.8 to 8.1), risk ratio 0.96 (0.82–1.12); unadjusted two-proportion z-test p = 0.570.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between VigantOL Oil Interferon Beta-1a (Rebif) and the control. The interval gives the range of effects that remain compatible with the data.

Number od Subjects With Confirmed EDSS Progression

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VigantOL Oil Interferon Beta-1a (Rebif): 7.1% (8/113) versus 3.4% (4/116) on control; risk difference 3.6 percentage points (95% CI -2.1 to 9.4), risk ratio 2.05 (0.64–6.63); unadjusted two-proportion z-test p = 0.218.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between VigantOL Oil Interferon Beta-1a (Rebif) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes address related but distinct features of disease activity, including relapse status, EDSS progression, and MRI lesion measures. In general, examining several outcomes can help describe whether a result is reflected across different clinical and imaging dimensions. The registry lists 15 secondary outcomes, but numerical results are detailed for only some of them in the available record. The reported secondary findings should therefore be understood as a partial view of the wider set of planned or listed measures.

For the three secondary outcomes with posted comparison statistics, the estimates do not form a clearly consistent pattern of separation between the add-on arms. Their intervals include no difference, and the results are not a strong independent confirmation of the primary estimate. They also do not substitute for the primary composite endpoint: each measures a different outcome or component, and results across distinct definitions can vary.

In general, multiple outcomes create a multiplicity concern. When many hypotheses are examined, the chance of at least one apparently notable result by chance can increase. The registry record does not report a multiplicity adjustment or a formal hierarchy for interpreting primary and secondary outcomes. Consequently, unadjusted secondary p values carry less weight than results from a prespecified and appropriately controlled testing strategy. The registry lists no reported analyses, so it does not document how these secondary comparisons fit into a complete statistical plan.

The secondary outcomes are best treated as descriptive context for the primary result rather than as a collection of separate definitive conclusions. Their relationship to the primary endpoint is useful for understanding what was measured, but their interpretation remains constrained by uncertainty, incomplete posted results, and the absence of analysis-plan details.

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

• Percentage of Relapse-free Subjects at Week 48
• Percentage of Subjects Free From Any Expanded Disability Status Scale (EDSS) Progression at Week 48
• Number od Subjects With Confirmed EDSS Progression
• Cumulative Number of Relaxation Time 1 (T1) Gadolinium Enhancing Lesions at Week 48
• Mean Number of Combined Unique Active (CUA) Lesions Per Subject Per Scan at Week 48
• Cumulative Number of New Combined Unique Active (CUA) Lesions at Week 48
• Mean Change From Baseline in the Total Volume of T2 Lesions at Week 48 (T2 Burden of Disease)
• Percentage of Subjects Free From T1 Gadolinium Enhancing Lesions at Week 48

9. Statistical Interpretation

10. Statistical Methods Explained

In general, a binary endpoint classifies each participant into one of two states. For this primary outcome, the states are meeting or not meeting the composite disease-activity-free definition. The percentage in each arm is the proportion of participants counted as meeting that definition among the reported group. The registry gives percentages of 37.2 and 35.3 for the VigantOL oil and placebo add-on arms, with group sizes of 113 and 116.

What does a risk difference express?

In general, a risk difference subtracts the event proportion in one group from the proportion in the comparison group, using a stated direction. It is expressed on an absolute scale, which makes it possible to see the contrast in percentage-point terms. The registry lists a risk difference of 0.018 for VigantOL oil plus Rebif versus placebo plus Rebif. Its interval, -0.106 to 0.143, spans both negative and positive values. The sign indicates the direction under the comparison's coding; the interval communicates that the estimate is uncertain. The discrepancy flag is false, so there is no stated reason to prioritize a sponsor analysis over these posted comparison values.

How do relative measures differ?

In general, a risk ratio compares the proportions by division, while an odds ratio compares the odds in each group. They use relative rather than absolute scales. Here, the posted risk ratio is 1.052, with an interval from 0.746 to 1.483, and the posted odds ratio is 1.082, with an interval from 0.631 to 1.855. When an endpoint is binary, these measures can complement an absolute risk difference, but they answer the contrast on a different scale. They do not add new participants or independent outcome information.

What does a p value contribute?

In general, a p value describes how unusual data at least as discrepant as the observed data would be under a specified statistical null model. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The listed primary unadjusted p value is 0.774. The registry record does not report the full modeling or testing plan behind the displayed comparison, so the p value should be read as the unadjusted value posted with the result rather than as a complete account of the trial's inferential strategy.

Why do confidence intervals matter?

In general, a confidence interval conveys a set of effect values reasonably compatible with the data under the method used. Narrow intervals indicate greater statistical precision; wide intervals indicate less precision. An interval that includes zero for a risk difference does not establish that the true difference is zero. It means the posted data do not rule out zero at the interval's stated level. The registry does not state that level, so it is not appropriate to label the interval with a confidence percentage absent from the record.

What can be said about the analysis population?

The primary population is described as the ITT set, including randomized participants who received at least 1 dose of the investigational medicinal product. The posted arm sizes are 113 and 116 for the principal comparison. ITT terminology generally signals analysis according to randomized group for eligible participants, but the registry's specific definition includes the dose condition. The detailed handling of participants with missing endpoint data, protocol deviations, or other exclusions is not reported in the registry record. It is therefore not possible to determine from the entry alone whether all randomized participants contributed to the displayed percentages or how any unavailable assessments were treated.

Why can excess variation matter?

In general, over-dispersion means that observed variation is greater than a statistical model expects. It is most directly relevant to outcomes modeled as counts or rates, where it can make standard errors too small if ignored. The primary endpoint is reported as a binary percentage, and no over-dispersion estimate or model is described. It would be inappropriate to claim that an over-dispersion adjustment was or was not used; the statistical plan is not reported in the registry record.

What is not documented?

The record lists 17 outcome measures and 0 reported analyses. It gives summary outcome values and comparison statistics, but does not describe a full analysis plan, adjustment for multiplicity, interim analyses, or model covariates. The registry record also does not state the confidence level, missing-data method, or sample-size justification for the original trial. General statistical concepts can help explain the posted estimates, but they cannot replace those missing trial-specific details.

11. Confidence Intervals and Precision

The primary risk-difference estimate is 0.018, and its listed interval runs from -0.106 to 0.143. This is a broad range that includes zero and values on either side of zero. The point estimate alone is not an adequate summary: the interval indicates that the observed comparison does not pin down the underlying contrast closely. The confidence level associated with the interval is not reported in the registry record.

In general, a confidence interval describes uncertainty in an estimate under the statistical method used. It is not a guarantee that the true effect lies within the particular interval, nor is it a direct statement about the probability that a treatment effect is beneficial or harmful. For a risk difference, zero represents no absolute difference. Because zero falls inside the posted interval, the result is not evidence of a precisely determined nonzero contrast. At the same time, an interval that includes zero does not prove that the groups are identical.

The relative measures likewise have intervals that span values on both sides of no relative difference: the risk ratio is 1.052, with an interval from 0.746 to 1.483, and the odds ratio is 1.082, with an interval from 0.631 to 1.855. Their breadth reinforces that the relative contrast is uncertain. Relative measures can look different in scale from an absolute risk difference, but all are based on the same endpoint and should be interpreted together rather than as independent confirmations.

The endpoint percentages are reported to one decimal place, while the risk-difference estimate and interval are reported with more digits. Those values should be quoted at their posted precision rather than recalculated from rounded percentages. The lack of interval-level information, analysis details, and a reported missing-data approach limits a fuller assessment of precision.

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 planning figures are illustrations based on the observed effect, not the trial's original design justification. For this binary outcome, the listed figures are participants per arm. The assumed planning framework uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The registry record does not report the original sample-size assumptions used to plan this trial.

The 80% power column represents the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under those planning assumptions, if that effect were the true one. The 90% column represents the corresponding planning target for a 90% chance. These are prospective design illustrations; they are not the probability that the completed trial detected an effect, and they are not observed power.

For planning at 100% of the observed primary effect, the figures are 10,912 participants per arm for 80% power and 14,608 participants per arm for 90% power. Planning for 75% of the observed effect gives 19,347 and 25,899 participants per arm, respectively. Planning for 50% of the observed effect gives 43,410 and 58,113 participants per arm, respectively. The increasing requirements illustrate a general principle: smaller effects are harder to distinguish from random variation and require more participants under otherwise fixed assumptions.

These large illustrations should be interpreted cautiously because they use an observed effect estimate from a comparison with substantial uncertainty. They are not enrollment recommendations and do not establish that the trial was inadequately designed. They do not incorporate any unreported features of the original protocol or analysis plan. The Schoenfeld total-event convention applies to time-to-event planning; it is not the convention for these binary-outcome figures, which are stated per arm.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.353; treatment proportion p₁ = 0.372; average p̄ = 0.363.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6799 = 1.3325.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6797 = 0.5721.
4. n = (1.3325 + 0.5721)² / (0.0182)² = 10,911.6, rounded up to 10,912 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 <- 0.353448275862069                          # control proportion
p1 <- 0.371681415929204                          # 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(1285401)
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 = 10,912 (80% power), 14,608 (90% power)
 75% of observed effect: n per arm = 19,347 (80% power), 25,899 (90% power)
 50% of observed effect: n per arm = 43,410 (80% power), 58,113 (90% power)
power.prop.test: 10911.6 
Simulated power at n = 10,912 per arm: 0.798 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures, including the primary endpoint and secondary outcomes, and lists 0 reported analyses. The record does not report a formal testing hierarchy, a family of hypotheses, or a method for controlling the overall error rate across outcomes. It is therefore not possible to determine whether the primary endpoint was tested first under a prespecified gatekeeping plan, whether secondary outcomes were intended to be confirmatory or exploratory, or whether any multiplicity adjustment was used.

Multiplicity matters in general because testing several outcomes can increase the chance of false-positive findings if each is interpreted without accounting for the others. Unadjusted p values are not automatically invalid, but they have a narrower interpretation than p values from a documented strategy designed to control multiplicity. Secondary comparisons should accordingly be treated as supporting or descriptive information, not as equally strong independent tests of efficacy. No particular adjustment should be assumed in the absence of registry documentation.

The primary population is defined as randomized participants who received at least 1 dose of the investigational medicinal product. The endpoint group sizes are 113 for VigantOL oil plus Rebif and 116 for placebo plus Rebif. The record does not explain how missing clinical or MRI assessments were handled, whether any participants were excluded from the endpoint denominator, or how incomplete follow-up affected the analysis. It also does not report sensitivity analyses for missing data.

Those omissions limit assessment of whether the analysis population and endpoint definition were implemented exactly as intended. They do not establish that missingness occurred or that any particular bias was present. The record also does not report interim analyses, the original sample-size justification, or the trial's detailed statistical analysis plan. Without those details, the displayed estimates can be described and interpreted, but the complete inferential framework cannot be reconstructed.

15. 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: overdose (7.1%), abscess limb (0.9%), appendicitis (0.9%), cellulitis (0.9%), pneumonia (0.9%).

In the VigantOL oil plus Rebif group, 18 participants were recorded as having a serious adverse event among 113 at risk. In the placebo plus Rebif group, the corresponding figures were 8 among 116. These are counts of participants affected in each group as represented in the registry record. They are safety observations, not a statistical comparison adjusted for exposure time, baseline differences, or other factors.

The registry lists Overdose at 7.1% among the serious adverse-event terms and lists Abscess limb, Appendicitis, Cellulitis, Pneumonia, and Pyelonephritis at 0.9% each. The record does not make an arm assignment explicit for these listed terms in the information, so they should not be attributed to one group. The registry also reports other adverse events affecting 99 of 113 participants in the VigantOL oil group and 93 of 116 in the placebo group.

Deaths are not reported in the registry record. The event counts alone do not establish that an intervention caused an event or that one group had greater overall risk. Definitions, event-level details, exposure-adjusted analyses, and fuller safety comparisons are not reported in the registry record.

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

The posted primary comparison estimates the proportion meeting a composite definition of being free of disease activity up to Week 48 in two groups receiving Rebif: one with VigantOL oil and one with placebo. The observed percentages are 37.2 and 35.3, and the listed risk difference is 0.018. The interval from -0.106 to 0.143 indicates substantial uncertainty around that estimate. The unadjusted p value is 0.774. Together, these statistics describe a comparison that does not precisely establish a difference between the add-on groups.

This result does not demonstrate that the groups are exactly alike. A failure to establish a difference is not the same as proving equivalence or non-inferiority, which would require a specified margin and appropriate design and analysis details. Such a margin is not reported in the registry record. Nor does the result establish that there is no possible effect; the interval remains compatible with differences in either direction.

The endpoint combines relapse, EDSS progression, and MRI findings. A group percentage for the composite does not identify the contribution of each component, and it does not provide a complete account of long-term disease course. The trial description includes a possible 96-week course for some participants after a protocol amendment, but the primary endpoint result is stated up to Week 48. No inference about longer-term outcomes should be drawn from the Week 48 comparison alone.

The primary numerical results are for VigantOL oil plus Rebif versus placebo plus Rebif. They do not provide a numerical estimate for Rebif alone, nor do they compare the three arms on a common outcome population in the posted primary results. The arm descriptions also differ by vitamin D level, which is relevant context for interpreting the design.

These statistics describe the registry results; they do not amount to medical advice or a recommendation. The incomplete reporting of analysis methods, missing-data handling, multiplicity, and some endpoint results limits how far the findings can be interpreted.

17. Why This Trial Matters Statistically

This trial is statistically informative because its primary endpoint brings together clinical and MRI indicators in a single binary measure. That composite makes the endpoint broader than relapse alone, but it also means that an overall percentage cannot show which component contributes most to the observed group pattern. The distinction between an absolute risk difference and relative measures is useful for describing the same comparison from different statistical perspectives.

The primary estimate illustrates why effect size and uncertainty must be considered together. The arm percentages appear close, but the interval around the risk difference is broad and includes zero. A single point estimate or unadjusted p value would not convey this uncertainty. The posted results support a cautious description of the comparison rather than a claim of equivalence or a precisely determined effect.

The record also demonstrates the importance of distinguishing a trial's actual design from planning calculations generated from an observed effect. The sample-size figures are illustrations based on the observed primary contrast under stated assumptions, not evidence about the trial's original planning rationale or its power after completion. When the observed estimate is uncertain, planning illustrations derived from it inherit that uncertainty.

Finally, the record highlights how design and reporting shape interpretation. The study is described as three-arm, yet the posted primary comparison is between the two add-on groups, and the arm descriptions specify different vitamin D level conditions. The absence of detailed multiplicity, missing-data, and analysis-plan information makes transparent statistical interpretation especially important.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

A trial-specific interpretive limitation is that the registry describes three arms but posts the primary numerical comparison only for VigantOL oil plus Rebif versus placebo plus Rebif. A numerical result for the Rebif-alone arm is not reported in the registry record. The primary comparison therefore cannot be used to quantify how either add-on group compares with Rebif alone.

The arm descriptions also identify different vitamin D level conditions: the two add-on groups are described for levels below 150 nmol/L, while Rebif alone is described for levels equal to or higher than 150 nmol/L. That distinction is important context and cautions against treating all three arms as directly interchangeable groups for every comparison. The registry does not provide enough detail to reconstruct how the allocation and eligibility rules operated in practice.

The primary endpoint is a composite of relapse, EDSS progression, and new MRI lesions. Its overall percentage can obscure differences among these components, and component-level primary results are not reported in the registry record. Although the study description includes extended follow-up for some participants, the posted primary outcome is up to Week 48; results for the extended period are not reported in the registry record.

The endpoint analysis population is defined, but missing-data procedures, detailed analysis methods, and the original sample-size rationale are not reported. There are 15 listed secondary outcomes, while only some have numerical comparison details in the record, and no reported analyses are listed. These gaps limit evaluation of selective reporting, multiplicity, and robustness. They do not establish that any specific bias occurred, but they constrain conclusions based on the registry entry alone.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment — NCT01285401.
• Registry record last updated 2016-11-28; status last verified 2016-10.
• Results first posted 2016-07-11.
• 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.

22. Record Summary

NCT01285401 is a completed randomized, double-blind, placebo-controlled, multicenter, parallel Phase II trial with enrollment of 260. It evaluated VigantOL oil added to Rebif against placebo added to Rebif, with a Rebif-alone arm also described. The primary endpoint was the percentage of participants free of defined clinical and MRI disease activity up to Week 48.

The posted primary percentages were 37.2 for VigantOL oil plus Rebif and 35.3 for placebo plus Rebif. The listed risk difference was 0.018, with an interval from -0.106 to 0.143 and an unadjusted p value of 0.774. The record does not report the confidence level or detailed statistical plan.

Interpretation is limited by the absence of numerical primary results for the Rebif-alone arm, unreported missing-data and multiplicity methods, and incomplete detail about secondary analyses. The posted comparison is an estimate with substantial uncertainty, not proof of equality between groups.