A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS) (NCT04548999), a randomized phase 3 study. The primary outcome is Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12).

2. Clinical Question

The primary outcome brings together confirmed worsening on disability and physical-function measures. An event occurs when at least one of the specified criteria is met: a confirmed increase in Expanded Disability Status Scale (EDSS) score, a confirmed increase of at least 20% from baseline in the Timed 25-foot Walk Test (T25FWT), or a confirmed increase of at least 20% from baseline in the 9-Hole Peg Test (9-HPT). The confirmation period is 12 weeks.

The comparison is randomized, double-blind, controlled, and parallel-group. That design is intended to compare assigned regimens while limiting systematic differences in treatment allocation and expectations. The registry record lists 769 participants enrolled. The posted primary estimate is a hazard ratio for the comparison, alongside medians for each assigned group. These statistics address the time-to-event question; they do not by themselves establish that one regimen is clinically preferable.

3. Trial Design

The registry describes a multicenter, randomized, double-blind, controlled, parallel-group study in adults with PPMS. Its phase is listed as Phase 3, while the official title calls it Phase IIIB. The registry lists 769 participants enrolled and the study status as active, not recruiting. It records a start date of 2020-12-03 and a primary completion date of 2025-06-30.

Participants were assigned to ocrelizumab 600 mg or a higher, weight-based ocrelizumab regimen. The higher-dose assignment was 1200 mg for baseline body weight <75 kg and 1800 mg for baseline body weight ≥75 kg. Both regimens are described as intravenous infusions every 24 weeks. The registry arm descriptions refer to a minimum of 5 treatment doses in the double-blind treatment phase. The approved-dose arm description also says participants may be offered higher-dose ocrelizumab in an optional open-label extension. Actual participation in that extension and subsequent treatment exposure are not reported in the registry record.

The primary analysis population is the full analysis set: all randomized participants, classified according to the treatment they were assigned. The posted arm counts for the primary outcome are 253 for the 600 mg group and 500 for the higher-dose group. Those arm counts describe the analysis and should not be mistaken for a balanced allocation. The registry record does not report the rationale for the allocation ratio or the trial's original sample-size justification.

There are 19 posted outcome measures and 10 posted analyses. The primary outcome is time to 12-week composite confirmed disability progression; several secondary outcomes also assess disability progression, walking, hand function, cognition, or brain-volume change. The registry record does not report a detailed statistical analysis plan, interim analyses, or how the optional extension was incorporated into the primary analysis.

4. Participant Flow and Accounting

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

Before assignment: Participants were randomized in a 2:1 ratio to receive treatment with either ocrelizumab higher dose (1200 milligrams \[mg\] or 1800 mg) based on the participant's body weight (BW) or ocrelizumab 600 mg for a minimum of up to 120 weeks. 16 participants were excluded from all analysis sets used in this study due to serious good clinical practice (GCP) violations. Therefore, results are presented for 753 participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS included all randomized participants, with participants grouped according to the treatment they were assigned.

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: Full analysis set (FAS) included all randomized participants, with participants grouped according to the treatment they were assigned.

6. Primary Endpoint

The registry lists the primary outcome as Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12), measured over Up to approximately 4.5 years.

The primary endpoint is time to onset of 12-week composite confirmed disability progression, or cCDP12. It measures how long it takes until a participant first meets at least one of three worsening criteria, with the relevant change confirmed over 12 weeks. The criteria are an increase in EDSS score, at least a 20% increase from baseline in T25FWT time, or at least a 20% increase from baseline in 9-HPT time.

EDSS is a disability scale, described in the registry as ranging in 0.5-point steps from 0, normal, to 10.0, death. The threshold for a confirmed EDSS increase depends on baseline EDSS: at least 1.0 point for participants with baseline scores ≤5.5, or at least 0.5 point for those with baseline scores >5.5. T25FWT records the time taken to walk a 25-foot course as quickly and safely as possible. The 9-HPT records the time needed to place and remove pegs using each hand. For both timed tests, longer times indicate deterioration.

A time-to-event endpoint uses both whether an event occurred and when it occurred during follow-up. Combining several measures can capture progression through different aspects of function, but it also means the composite result does not identify which component drove an event. Component-specific results for the primary composite are not reported in the registry record. The registry lists the primary endpoint timeframe as up to approximately 4.5 years.

7. Results Posted in the Registry

• Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg: hazard ratio 0.95 (95% CI 0.76–1.18), reported p = 0.638 (as reported in the registry).

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.

Time to Onset of 24-week cCDP (cCDP24)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg: hazard ratio 0.91 (95% CI 0.72–1.15), reported p = 0.415 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg and the control. The interval gives the range of effects that remain compatible with the data.

Time to Onset of cCDP12 Independent of Protocol-defined Relapses (PDR) or Progression Independent of Relapse Activity (PIRA)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg: hazard ratio 0.94 (95% CI 0.75–1.17), reported p = 0.576 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg and the control. The interval gives the range of effects that remain compatible with the data.

Time to Onset of 12-week Confirmed Disability Progression (CDP12)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg: hazard ratio 0.86 (95% CI 0.65–1.15), reported p = 0.322 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Ocrelizumab 600 mg vs Ocrelizumab 1200 mg or 1800 mg and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover related but distinct aspects of progression and function, including 24-week composite progression, progression independent of protocol-defined relapses or relapse activity, 12-week confirmed disability progression, walking, cognition, and brain-volume change. Several outcomes are time-to-event measures, while others use a rate of change. This range can add context to the primary composite, but these endpoints are not interchangeable: they use different definitions, assessment schedules, and measures.

Across the posted secondary time-to-event comparisons, the hazard-ratio confidence intervals include 1, and the reported p-values do not indicate statistically clear differences under the stated log-rank analyses. The secondary results therefore do not provide a clearly different overall message from the primary result. Their estimates remain uncertain, and they do not establish that a treatment effect is absent. Nor should results from one secondary outcome be treated as confirmation of another.

As a general statistical point, examining multiple outcomes creates multiple opportunities for apparently notable results to arise by chance, especially when each is tested separately without an adjustment or a prespecified hierarchy. The registry record lists 19 outcome measures and 10 analyses, but does not report whether multiplicity was controlled or which secondary tests were confirmatory. This makes nominal secondary p-values less persuasive as stand-alone evidence than a prespecified primary result. Secondary outcomes are most useful as supportive context, particularly when their definitions and direction of evidence are consistent, but they do not supersede the primary comparison.

The registry does not provide component-specific analyses for the primary composite, so the secondary results cannot establish which component most contributed to the cCDP12 result. It also does not report the detailed analysis plan or missing-data procedures for each endpoint. The secondary outcome pattern should therefore be interpreted as a set of additional, uncertain comparisons rather than as a definitive explanation of the primary finding.

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

• Time to Onset of 24-week cCDP (cCDP24)
• Time to Onset of cCDP12 Independent of Protocol-defined Relapses (PDR) or Progression Independent of Relapse Activity (PIRA)
• Time to Onset of 12-week Confirmed Disability Progression (CDP12)
• Time to ≥ 20% Increase in 12-week Confirmed T25FWT
• Time to Onset of 12-week Confirmed ≥ 4-point Worsening in Symbol Digit Modalities Test (SDMT)
• Time to Onset of 24-week Confirmed ≥ 8-point Increase in 12-Item Multiple Sclerosis Walking Scale (MSWS-12)
• Annual Rate of Percent Change From Baseline in Total Brain Volume
• Annual Rate of Percent Change From Baseline in Thalamic Volume

9. Statistical Interpretation

10. Statistical Methods Explained

The main reported comparison is a time-to-event analysis. A participant's event is the first qualifying cCDP12 event, and the outcome is the time until that event. This differs from an analysis that simply compares the number of participants with an event at one fixed visit: timing during follow-up contributes to the analysis. The registry reports a log-rank method and a hazard ratio, but does not report the full model specification or the detailed rules used to handle incomplete follow-up.

What does a hazard ratio describe?

As a general statistical explanation, a hazard is the rate at which an event occurs among participants who have not yet experienced it, at a particular point in follow-up. A hazard ratio compares those rates between groups over time, according to the analysis definition. It is not a ratio of median times and is not a direct count of events. The comparison is labelled 600 mg versus 1200 mg or 1800 mg, and the posted hazard ratio is 0.95. The registry record does not report enough detail to determine all aspects of the model's coding or assumptions, so the sponsor's reported estimate and stated comparison are the appropriate reference.

What does the log-rank method contribute?

As a general explanation, the log-rank method compares the timing of events between groups across follow-up, taking account of when participants are still being observed and at risk. In a typical time-to-event analysis, participants whose event has not occurred by their last observation can contribute information up to that point; this is often called censoring. The exact censoring rules and handling of missing follow-up for this trial are not reported in the registry record. The log-rank p-value of 0.638 is evidence about compatibility with the tested no-difference comparison under that method, not a measure of the size or clinical importance of an effect.

How should the confidence interval and p-value be read?

As a general statistical explanation, a confidence interval describes the range of effect estimates that are reasonably compatible with the observed data and the method's assumptions. The 95% confidence interval for the primary hazard ratio is 0.76 to 1.18. Because it includes 1, the posted interval includes the value corresponding to no relative difference in hazard. The p-value, 0.638, summarizes how unusual data at least this inconsistent with the null comparison would be if that null were true, under the test assumptions. It is not the probability that the treatments are the same, nor is it the probability that the observed result occurred by chance.

Confidence intervals and p-values answer related but different questions. The interval emphasizes the range and precision of possible relative effects; the p-value addresses evidence against a specified null value. Neither statistic alone describes clinical importance. The registry does not report a threshold for a clinically important difference or a prespecified equivalence or non-inferiority margin.

Why use a composite time-to-event endpoint?

As a general explanation, a composite endpoint can count an event when any one of several specified components occurs. This can represent a broader concept, such as worsening across disability and functional measures, and can yield an event time based on the earliest qualifying component. In this trial, cCDP12 includes EDSS, T25FWT, and 9-HPT criteria. Because different components can have different meanings and frequencies, an overall composite estimate should not be interpreted as showing a uniform effect across every component. Component-specific primary results are not reported in the registry record.

The endpoint also requires confirmation over a specified period. Confirmation is intended to distinguish a qualifying change that persists through the required confirmation window from a change that does not meet that definition. The registry gives the 12-week confirmation rule but does not report additional operational details, such as how unavailable confirmation assessments were treated.

What does the population definition mean?

The full analysis set includes all randomized participants and groups them by assigned treatment. As a general statistical explanation, analysing by randomized assignment helps retain the benefits of randomization when participants do not follow their assigned treatment exactly. The registry's population definition is explicit, but it does not provide the number of participants with missing primary-outcome data, the amount of follow-up available by group, or the methods used to address missing observations.

The group medians and hazard ratio describe different aspects of the time-to-event distribution. A median is the point by which half of the relevant event-time distribution has experienced the event, under the estimator used. The reported primary median estimates are 158.7 weeks and 169.0 weeks. Their confidence intervals have only lower limits reported; the upper limits are not reported in the registry record. A hazard ratio, by contrast, summarizes the relative event hazard under the reported analysis. It is useful to consider both summaries, but they are not interchangeable.

The registry presents 10 analyses across its posted outcomes and 19 outcome measures. It does not report the full statistical analysis plan, the prespecified testing hierarchy, or any multiplicity adjustment. It is therefore not possible to establish from the registry record which analyses were designated confirmatory beyond the identified primary endpoint, or how the overall chance of false-positive findings was controlled.

11. Confidence Intervals and Precision

The primary hazard ratio is 0.95, with a 95% confidence interval from 0.76 to 1.18. The interval includes 1, the value associated with no relative difference in hazard. It also extends to values on either side of 1, so the posted estimate does not sharply distinguish a lower from a higher relative hazard for the comparison as labelled. The interval is not narrow enough to support a precise claim about the size or direction of the comparative effect.

As a general statistical explanation, a confidence interval reflects sampling uncertainty under the analysis method and its assumptions. A 95% confidence interval does not mean there is a 95% probability that the particular interval contains the true value. Rather, the method is designed so that intervals constructed in the same way would contain the true value in 95% of repeated samples, if the assumptions hold. This interpretation does not account for potential bias from missing data, measurement, or other design limitations.

The reported median estimates are 158.7 weeks in the 600 mg group and 169.0 weeks in the higher-dose group. Their reported lower confidence limits are 120.0 weeks and 144.1 weeks, respectively. The corresponding upper confidence limits are not reported in the registry record. The available median confidence-limit information is therefore incomplete for judging precision around each median.

Precision is distinct from statistical significance and from clinical importance. A result can be imprecise even when its point estimate is near no difference, and the point estimate alone does not show whether a possible difference would matter to patients. A threshold for clinical importance is not reported in the registry record. The primary hazard-ratio interval and p-value should be read together as evidence that the trial's posted comparative estimate remains uncertain, rather than as proof of equivalence or of a particular treatment effect.

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 planning display is an illustration based on the observed effect, not a reconstruction of the trial's original design. For time-to-event outcomes, its entries are total events required across the two groups, not participants per arm. The illustration assumes a two-sided significance level of 0.05, equal allocation between the arms, and a normal approximation. It considers effects equal to 100%, 75%, or 50% of the observed effect. The registry record does not report the original sample-size justification or its design assumptions.

The 80% power column describes the total events the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect under those assumptions, if that effect were truly present. The 90% power column expresses the corresponding event requirement for a 90% chance. These are prospective planning concepts: they describe performance under assumed conditions, not the probability that the trial's conclusion is correct. This is not observed power.

For the primary outcome, the planning row using 100% of the observed effect lists 11,933 total events for 80% power and 15,975 total events for 90% power. The rows using 75% and 50% of the observed effect list larger event requirements. In general, smaller effects are harder to distinguish from random variation, so more information—and, in a time-to-event setting, more events—is needed to detect them at the same target power.

The assumptions used for this illustration differ from the actual posted primary analysis counts: the calculation assumes equal allocation, while the primary analysis includes 253 participants in the 600 mg group and 500 in the higher-dose group. These planning values are not a claim about how many participants or events the original trial was designed to obtain. They should be read as illustrations of how the assumed effect size and desired power affect event requirements.

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

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.950, so ln(HR) = -0.0513.
2. d = 4 × (1.96 + 0.842)² / [ln(0.950)]² = 11,932.9, rounded up to 11,933 events in total 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
hr <- 0.95                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(4548999)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 11,933 (80% power), 15,975 (90% power)
 75% of observed effect: events = 21,215 (80% power), 28,400 (90% power)
 50% of observed effect: events = 47,732 (80% power), 63,900 (90% power)
Simulated power with 11,933 events: 0.805 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Group-Sequential Design Analysis

Many time-to-event trials, especially in oncology, stop or report early when interim data are overwhelming, so a single fixed-sample number understates the real design problem. The calculation below is an illustrative group-sequential design built from this trial's posted control median and hazard ratio. The registry record does not state the planned number of looks or the spending function, so the design is a planning illustration, not a reconstruction of the protocol. Assumed: one-sided α = 0.025, 90% power, three equally spaced looks on information, Lan-DeMets O'Brien-Fleming spending, 24 months of accrual, 60 months in total and a 1% monthly dropout hazard.

Under these assumptions the design needs about 33,693 participants in total, with the boundaries below.

Fixed design versus group-sequential alternatives

Group-sequential designs cost a small increase in maximum sample size and events compared with the fixed design, in exchange for the chance to stop early for overwhelming efficacy. O'Brien-Fleming spending keeps early boundaries very conservative and the final boundary close to the fixed-design value, whereas Pocock spending spends more alpha early.

Sensitivity to a smaller true effect

Planning for exactly the observed effect is optimistic, because observed effects in published trials tend to be somewhat larger than the true effect. The table repeats the main design (three looks, O'Brien-Fleming spending, 90% power) for smaller true hazard ratios.

For context, this trial enrolled 769 participants.

Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993. Agreement between the two packages confirms the boundary calculation.

R code and output

suppressWarnings(suppressMessages({ library(gsDesign); library(rpact) }))
med_control <- 36.6230769230769          # control-arm median, months (converted from the posted unit)
hr          <- 0.95          # hazard ratio used for planning
lambdaC     <- log(2) / med_control
eta         <- 0.01               # dropout hazard per month (assumption)
acc_months  <- 24                 # accrual duration (assumption)
study_months<- 60                 # total study duration (assumption)

design <- function(k, sfu, beta, h = hr) gsSurv(k = k, test.type = 1, alpha = 0.025, beta = beta, sfu = sfu,
  lambdaC = lambdaC, hr = h, hr0 = 1, eta = eta, gamma = 1, R = acc_months, T = study_months, minfup = study_months - acc_months)

# Main design: 3 looks, Lan-DeMets O'Brien-Fleming spending, one-sided alpha 0.025, 90% power
x <- design(3, sfLDOF, 0.10)
cat(sprintf("N_TOTAL|%s\n", format(ceiling(sum(x$gamma * x$R)), big.mark = ",")))
for (i in 1:3) cat(sprintf("GS|%d|%.1f|%.0f|%.3f|%.5f|%.5f\n", i, x$T[i], x$n.I[i], x$upper$bound[i], pnorm(-x$upper$bound[i]), cumsum(x$upper$spend)[i]))
cat("\n"); print(gsBoundSummary(x))

# Comparison of designs
cmp <- list(list("Fixed design, one analysis", 1, sfLDOF), list("Two looks, O'Brien-Fleming", 2, sfLDOF),
            list("Three looks, O'Brien-Fleming", 3, sfLDOF), list("Three looks, Pocock", 3, sfLDPocock))
cat("\n")
for (b in c(0.20, 0.10)) for (d in cmp) {
  y <- design(d[[2]], d[[3]], b)
  cat(sprintf("DES|%s|%d|%.0f|%s|%.1f\n", d[[1]], round(100 * (1 - b)), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ","), tail(y$T, 1)))
}

# Sensitivity: what if the true effect is smaller than the observed one? (3 looks, O'Brien-Fleming, 90% power)
cat("\n")
for (fr in c(1, 0.75, 0.5)) {
  y <- design(3, sfLDOF, 0.10, exp(log(hr) * fr))
  cat(sprintf("SENS|%.2f|%.3f|%.0f|%s\n", fr, exp(log(hr) * fr), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ",")))
}

# Independent cross-check of the boundaries with rpact
r <- getDesignGroupSequential(kMax = 3, alpha = 0.025, beta = 0.10, sided = 1, typeOfDesign = "asOF", informationRates = x$timing)
cat(sprintf("\nCross-check, upper boundaries: gsDesign %s | rpact %s\n", paste(round(x$upper$bound, 3), collapse = ", "), paste(round(r$criticalValues, 3), collapse = ", ")))

Method: LachinFoulkes 
      Analysis               Value Efficacy
     IA 1: 33%                   Z   3.7103
      N: 31692         p (1-sided)   0.0001
  Events: 5388        ~HR at bound   0.9038
     Month: 23    P(Cross) if HR=1   0.0001
               P(Cross) if HR=0.95   0.0338
     IA 2: 67%                   Z   2.5114
      N: 33694         p (1-sided)   0.0060
 Events: 10776        ~HR at bound   0.9528
     Month: 37    P(Cross) if HR=1   0.0060
               P(Cross) if HR=0.95   0.5603
         Final                   Z   1.9930
      N: 33694         p (1-sided)   0.0231
 Events: 16164        ~HR at bound   0.9691
     Month: 60    P(Cross) if HR=1   0.0250
               P(Cross) if HR=0.95   0.9000



Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993

15. Analyses Reported by the Sponsor

The sponsor's posted primary analysis is a log-rank comparison with a hazard ratio of 0.95, a 95% confidence interval of 0.76 to 1.18, and p = 0.638. The registry record does not flag a discrepancy between that analysis and the comparison statistics used in the explanatory calculations. The sponsor's own analysis is therefore the relevant reported result; no alternative recalculation should replace it.

The label “recalculated” refers to simple, unadjusted calculations from posted summary statistics, not a reanalysis of participant-level data. Such calculations cannot reproduce an analysis that depends on individual event times, follow-up, censoring, or covariate information. The registry record does not provide participant-level data or a complete statistical analysis plan. The reported log-rank result should consequently be interpreted as the sponsor's analysis, not as a result independently reconstructed from the group medians.

The sponsor's result does not show a statistically clear difference under the reported test, and the confidence interval includes the no-relative-difference value. That reading is not evidence that the regimens are equivalent: an equivalence conclusion would require a prespecified margin and a suitable analysis, neither of which is reported in the registry record. The posted result should be described with its estimate and uncertainty rather than reduced to a binary statement about success or failure.

16. Multiplicity, Missing Data and Analysis Populations

The registry record identifies cCDP12 as the primary endpoint and lists 18 secondary outcomes, with 19 outcome measures overall. It also lists 10 analyses. Testing multiple outcomes can increase the chance of at least one apparently positive result even when no true effects exist. Statistical methods can address this through a prespecified hierarchy, adjustment procedures, or a distinction between confirmatory and exploratory analyses. The registry record does not report whether any of these approaches were used, or how the primary and secondary tests were ordered.

The absence of reported multiplicity procedures does not alter the numerical primary result, but it limits how confidently secondary findings can be treated as confirmatory. The registry also does not report whether any interim analyses were planned or conducted, or whether interim testing boundaries were used. The statistical analysis plan and sample-size justification are not reported in the registry record.

The primary population is described as the full analysis set, which includes all randomized participants grouped by assigned treatment. This specifies the population principle but does not explain how missing outcome measurements, withdrawal, loss to follow-up, or incomplete confirmation visits were handled. The number of participants with missing primary data and the amount of follow-up by group are not reported in the registry record. Nor are sensitivity analyses for missing data described.

As a general statistical point, missing follow-up can matter in a time-to-event analysis because participants may have different observation periods and event status may be unknown after their last assessment. Analyses commonly require rules for censoring and may examine how conclusions change under alternative assumptions. The registry does not provide enough information to assess those choices for this trial. This uncertainty is separate from the confidence interval's sampling precision: a narrow interval would not, by itself, address possible bias from missing data or unreported analysis decisions.

The available information supports describing the posted primary comparison and its uncertainty. It does not support reconstructing the complete testing strategy, confirming the handling of missing observations, or determining how much weight the investigators intended readers to place on each secondary result.

17. 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: covid-19 pneumonia (1.2%), urinary tract infection (1.0%), covid-19 (0.8%), pneumonia (0.8%), agranulocytosis (0.4%).

The serious adverse-event counts are 29 among 254 participants at risk in the 600 mg group and 61 among 499 at risk in the 1200 mg or 1800 mg group. These figures count participants with a serious adverse event; they are not event rates adjusted for time on treatment or follow-up. Other adverse events affected 176 of 254 participants in the 600 mg group and 381 of 499 in the higher-dose group. The registry also reports 3 deaths in the 600 mg group and 2 in the higher-dose group.

The most frequently listed serious adverse-event terms include COVID-19 pneumonia (1.2%), urinary tract infection (1.0%), COVID-19 (0.8%), pneumonia (0.8%), agranulocytosis (0.4%), and constipation (0.4%). These are the registry's listed terms and percentages; the record does not provide additional information about event timing, duration, severity categories beyond “serious,” or attribution to treatment.

As a general statistical point, safety comparisons depend on exposure and follow-up as well as counts. The posted figures alone do not establish that treatment caused an event, and they do not give a complete account of comparative risk. Differences in time at risk, repeated events, or participant characteristics cannot be assessed from these summaries. Detailed exposure-adjusted analyses and the rules used to classify adverse events are not reported in the registry record.

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

The primary result is a comparison of two assigned ocrelizumab regimens in adults with PPMS, using time to a defined composite disability-progression event. The estimated hazard ratio is 0.95, with a 95% confidence interval of 0.76 to 1.18 and a reported p-value of 0.638. The interval includes the value associated with no relative difference, and the estimate is not precise enough to establish a clear direction or magnitude of effect.

This result does not demonstrate that the regimens are equivalent. Failure to show a statistically clear difference is not the same as showing that any difference is smaller than a clinically acceptable margin. The registry record does not report an equivalence or non-inferiority margin, or identify an analysis designed to answer those questions. The result also does not prove that there is no difference; the interval remains compatible with effects on either side of no relative difference.

The median times offer a descriptive view of the event-time distributions, but the registry reports only lower confidence limits for the primary medians. The upper confidence limits are not reported in the registry record. The median summaries do not replace the hazard-ratio analysis and should not be interpreted as a direct treatment-caused gain in time.

The composite endpoint captures worsening in EDSS, walking, or hand function according to specified thresholds. It does not show which component contributed most to the overall result. Nor does the primary result address every outcome of interest, such as all aspects of daily function, safety, or long-term outcomes beyond the registry's stated timeframe. The posted safety counts provide additional descriptive information but do not establish causal attribution or exposure-adjusted comparative risk.

These findings apply to the trial population, assigned regimens, endpoint definitions, and follow-up represented in the registry record. The study is listed as active, not recruiting, and the record lists a primary completion date of 2025-06-30. The available statistics should be understood as the results posted in the registry, not as a basis for medical advice or a conclusion about treatment choice.

19. Why This Trial Matters Statistically

This trial poses a focused statistical question: whether a higher, weight-based ocrelizumab regimen changes the time to a confirmed disability-progression event compared with the approved 600 mg regimen. The randomized, double-blind, parallel-group design is relevant because random assignment and masking can reduce some sources of systematic difference between groups. The primary outcome also combines disability and functional measures, making the event definition explicit rather than relying on a single measure.

The result illustrates why an estimate, confidence interval, and test result should be read together. The hazard ratio is close to 1, but its confidence interval extends on both sides of 1. The p-value does not show a statistically clear difference under the reported test. These features support a cautious conclusion about uncertainty, not a claim of equivalence or proof that the regimens have identical effects.

The posted results also highlight the distinction between a primary endpoint and a collection of secondary measures. Secondary outcomes can help describe whether related measures point in a similar direction, yet multiple testing and unreported analysis hierarchy limit the strength of separate secondary findings. The registry does not report enough about multiplicity, missing-data handling, or the original design assumptions to fully evaluate those aspects of the evidence.

Finally, the comparison is about dose regimens within one clinical trial, not about whether ocrelizumab should be used or which regimen is appropriate for an individual. Its statistical value lies in documenting the randomized comparison, endpoint, estimate, and uncertainty. That information can inform a broader evidence assessment without being mistaken for a definitive answer to every clinical or methodological question.

20. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary hazard-ratio estimate has a 95% confidence interval of 0.76 to 1.18, which includes 1 and permits a range of possible comparative effects. The reported median confidence intervals are incomplete in the registry record: only lower limits are available, and upper limits are not reported. This restricts assessment of precision for the group medians.

The composite endpoint combines EDSS, walking, and hand-function criteria. The record does not report component-specific results for cCDP12, so it is not possible to determine which criterion most influenced the primary comparison. The registry also does not report the detailed assessment schedule, rules for unavailable confirmation visits, or the censoring and missing-data procedures used in the time-to-event analysis.

The primary analysis population is defined, but group-level numbers with missing outcome data and follow-up completeness are not reported. The complete statistical analysis plan, original sample-size justification, interim-analysis information, and multiplicity strategy are also not reported in the registry record. These omissions limit independent assessment of analysis decisions and the strength of secondary findings.

The higher-dose assignment depends on baseline body weight, while the approved-dose arm description says participants may be offered higher-dose treatment during an optional open-label extension. Actual extension enrollment, treatment uptake, and subsequent exposure are not reported. If treatment exposure changes after the double-blind phase, later follow-up may represent a different treatment contrast than the initial randomized period; the record does not provide the information needed to assess that possibility.

Safety summaries are counts of affected participants and listed serious-event terms. They do not provide exposure-adjusted comparisons, repeated-event analyses, or complete detail on attribution and duration. The registry status and completion information do not establish whether all final results or follow-up are included in the posted record.

21. Related Tutorials

22. Related Statistical Calculators

23. Sources

• ClinicalTrials.gov: A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS) — NCT04548999.
• Registry record last updated 2026-07-24; status last verified 2026-06.
• Results first posted 2026-07-24.
• 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.

24. Record Summary

The registry record describes NCT04548999, a randomized, double-blind, controlled, multicenter, parallel-group Phase 3 study in adults with PPMS. The official title calls it Phase IIIB. The comparison is ocrelizumab 600 mg every 24 weeks versus a higher-dose regimen of 1200 mg or 1800 mg based on baseline body weight. The record lists 769 participants enrolled and a status of active, not recruiting.

The primary outcome is time to onset of 12-week composite confirmed disability progression, assessed using EDSS, T25FWT, and 9-HPT criteria. The posted hazard ratio is 0.95 (95% confidence interval, 0.76 to 1.18; p = 0.638). The reported median estimates are 158.7 weeks for the 600 mg group and 169.0 weeks for the higher-dose group; upper confidence limits for these medians are not reported in the registry record.

Serious adverse events affected 29 of 254 participants in the 600 mg group and 61 of 499 in the higher-dose group. The registry does not report the full statistical analysis plan, original sample-size rationale, multiplicity strategy, or detailed missing-data procedures. The posted estimates therefore warrant interpretation with attention to uncertainty and the limits of registry reporting.