A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (NCT01327053), a randomized phase 2 study. The primary outcome is Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS).

2. Clinical Question

This was a Phase II randomized, double-blind study with two dose levels and separate efficacy and safety analyses by group. The registry record lists an enrollment of 230. The primary endpoint does not combine laBCC and mBCC into a single percentage: disease status determines the response criteria, and the results are reported for each disease and dose group. That separation matters because the populations and assessment criteria differ.

The central question is descriptive as well as comparative. Arm-level ORR estimates describe the observed proportion meeting the response definition by the stated assessment time. The registry also posts risk-difference contrasts, but these use the 200 mg laBCC arm as the reference. Those estimates should not be read as direct randomized comparisons of the two doses within mBCC, since the reference group has a different disease category. The record does not report an adjusted dose comparison within each disease group.

3. Trial Design

The registry record describes NCT01327053 as a completed Phase II randomized, quadruple-masked, parallel-group study sponsored by Novartis Pharmaceuticals. It lists basal cell carcinoma as the condition and oral LDE225 as the intervention. Enrollment was 230. The recorded study start was 2011-06-29, and primary completion was 2013-06-28.

The official title identifies a randomized, double-blind study of two LDE225 dose levels in patients with locally advanced or metastatic basal cell carcinoma. The registry’s masking classification is quadruple. Both the 200 mg and 800 mg groups are described as receiving daily treatment, and the study assessed efficacy and safety separately in each group. The arm descriptions are truncated in the registry record, so further treatment-duration details are not reported in the registry record.

The posted primary endpoint is objective response rate at 6 months, assessed by central review. The criteria differ by disease: mRECIST is specified for laBCC, and RECIST 1.1 for mBCC. The pEAS is described as a subset of the FAS. For laBCC, it includes patients whose tumors were adequately assessed by MRI or photography, or both; for mBCC, it includes patients in the FAS. The registry record does not fully state the FAS definition in the available description.

Primary efficacy group sizes were 42 and 93 for the laBCC dose groups, and 13 and 23 for the mBCC dose groups. These are the denominators attached to the primary endpoint results, not the overall enrollment. The registry record does not report the allocation ratio, the original sample-size justification, or the full statistical analysis plan. It also does not report interim analyses. The parallel-group label indicates that participants were assigned to study groups rather than followed through a crossover sequence; further details of the randomization procedure are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: All eligible, enrolled patients were randomized in 1:2 ratio to sonidegib treatment with either 200 mg or 800 mg once-daily dose. In total, 230 patients were evaluated as FAS population: 79 and 151 patients randomized to 200mg and 800 mg sonidegib respectively. However, 1 patient randomized to 800 mg sonidegib did not receive study treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The primary efficacy analysis set (pEAS) was a subset of the full analysis set (FAS) including patients with laBCC with tumors that were adequately assessed by MRI or photography or both, \& including all patients with mBCC included in the FAS which comprised all patients who were assigned study treatment irrespective of receiving it.

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: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients). Patients were classified according to the treatment they were assigned in accordance with the intention-to-treat (ITT) principle.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS), measured over 6 months.

The primary endpoint is objective response rate (ORR), expressed as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) by 6 months after starting LDE225. Tumor response was reviewed centrally. The registry specifies mRECIST for locally advanced basal cell carcinoma and RECIST 1.1 for metastatic basal cell carcinoma, so response criteria are matched to the disease group.

Under the posted definition, a partial response requires at least a 30% decrease in the sum of the diameters of target lesions, using the baseline sum as the reference. A complete response requires disappearance of all non-nodal target lesions; pathological lymph nodes assigned as target lesions must also have a short-axis measurement below 10 mm. The endpoint description defines a responder as someone with a confirmed CR or PR at the 6-month assessment.

ORR is used to summarize the proportion meeting a prespecified tumor-response definition at a particular assessment time. Unlike a time-to-event outcome, it does not describe how long a response lasts or when progression occurs. The registry lists duration of response, progression-free survival, and time to tumor response as secondary outcomes, but their numerical results are not reported in the registry record in the results available for interpretation. The primary endpoint description also states that an observed ORR of 30% or higher on any treatment arm at the end of the study was the criterion for considering treatment sufficiently efficacious. That stated criterion is distinct from a statistical test comparing dose groups.

7. Results Posted in the Registry

• LDE225 800mg laBCC: 37.6% (35/93) versus 42.9% (18/42) on control; risk difference -5.2 percentage points (95% CI -23.1 to 12.7), risk ratio 0.88 (0.57–1.36); unadjusted two-proportion z-test p = 0.565.
• LDE225 200mg mBCC: 15.4% (2/13) versus 42.9% (18/42) on control; risk difference -27.5 percentage points (95% CI -52.1 to -2.8), risk ratio 0.36 (0.10–1.35); unadjusted two-proportion z-test p = 0.072.
• LDE225 800mg mBCC: 17.4% (4/23) versus 42.9% (18/42) on control; risk difference -25.5 percentage points (95% CI -47.0 to -3.9), risk ratio 0.41 (0.16–1.06); unadjusted two-proportion z-test p = 0.038.

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.

Complete Response Rate (CRR) Per Central Review (pEAS)

• 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:
  • LDE225 800mg laBCC: 2.2% (2/93) versus 4.8% (2/42) on control; risk difference -2.6 percentage points (95% CI -9.7 to 4.5), risk ratio 0.45 (0.07–3.10); unadjusted two-proportion z-test p = 0.407.
  • LDE225 200mg mBCC: 0.0% (0/13) versus 4.8% (2/42) on control; risk difference -4.8 percentage points (95% CI -11.2 to 1.7); unadjusted two-proportion z-test p = 0.423.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDE225 800mg laBCC 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 LDE225 200mg mBCC and the control. The interval gives the range of effects that remain compatible with the data.

Complete Response Rate (CRR) Per Central Review (FAS)

• 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:
  • LDE225 800mg laBCC: 0.0% (0/128) versus 3.0% (2/66) on control; risk difference -3.0 percentage points (95% CI -7.2 to 1.1); unadjusted two-proportion z-test p = 0.048.
  • LDE225 200mg mBCC: 0.0% (0/13) versus 3.0% (2/66) on control; risk difference -3.0 percentage points (95% CI -7.2 to 1.1); unadjusted two-proportion z-test p = 0.525.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDE225 800mg laBCC 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 LDE225 200mg mBCC and the control. The interval gives the range of effects that remain compatible with the data.

Objective Response Rate (ORR) Based on Site Investigator Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS)

• 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:
  • LDE225 800mg laBCC: 61.3% (57/93) versus 71.4% (30/42) on control; risk difference -10.1 percentage points (95% CI -27.0 to 6.7), risk ratio 0.86 (0.67–1.10); unadjusted two-proportion z-test p = 0.255.
  • LDE225 200mg mBCC: 23.1% (3/13) versus 71.4% (30/42) on control; risk difference -48.4 percentage points (95% CI -75.0 to -21.7), risk ratio 0.32 (0.12–0.89); unadjusted two-proportion z-test p = 0.002.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDE225 800mg laBCC and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for LDE225 200mg mBCC than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary outcomes cover complete response, site-investigator ORR, duration of response, progression-free survival, and time to tumor response, with some outcomes listed for both pEAS and FAS. The available numerical results show that complete responses were uncommon across the reported groups. Site-investigator ORR is also reported at 42 months, whereas the primary central-review endpoint is at 6 months. These measures use different reviewers and assessment timeframes, so they should not be treated as direct replications of the primary endpoint.

The secondary results offer context but do not replace the primary central-review ORR. A secondary outcome can describe a related but distinct feature of response or disease course. Differences between secondary and primary estimates may reflect assessment timing, review method, population, or endpoint definition; the registry record does not provide enough information to isolate the contribution of each. Numerical results for duration of response, progression-free survival, and time to tumor response are not reported in the registry record in the results.

Unadjusted secondary comparisons carry less weight when several outcomes and contrasts are examined. General explanation: each additional statistical test creates another opportunity for a result that appears unusual by chance, even when no true effect exists. A multiplicity procedure can help control that risk, but the registry record does not report whether such a procedure was planned or used. The available p-values should therefore be treated as descriptive, especially when they concern secondary endpoints or cross-disease contrasts.

The secondary outcomes are most useful as a broader map of what the study intended to assess and which results were posted. They do not establish a single overall treatment effect, and they do not resolve the limitations of the primary comparison structure. In particular, the presence of an unadjusted result should not be read as confirmation of the primary finding. The registry record does not report a prespecified hierarchy that would identify which secondary result, if any, was intended to provide confirmatory evidence.

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

• Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)
• Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)
• Complete Response Rate (CRR) Per Central Review (pEAS)
• Complete Response Rate (CRR) Per Central Review (FAS)
• Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)
• Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)
• Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)
• Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each person either met the confirmed complete or partial response definition by the stated assessment time or did not. The reported percentage is the arm-level proportion classified as a responder. General explanation: a proportion is intuitive for describing how common an event was in a group, but its precision depends on both the observed response frequency and the number of people assessed. Smaller groups generally leave more uncertainty around the estimated proportion.

What central review contributes

The registry identifies central review as the source of the primary ORR assessment. Central review applies the stated imaging criteria independently of the treating site’s assessment, which can help make outcome classification more consistent across participants. The primary endpoint uses mRECIST for laBCC and RECIST 1.1 for mBCC. Those are not interchangeable labels: the registry explicitly assigns different criteria to the two disease categories. The record does not describe central-review procedures, reviewer blinding, or how disagreements were resolved.

The endpoint counts confirmed CR or PR by 6 months. That is a fixed-time response measure, not a time-to-event measure. General explanation: a fixed-time proportion answers whether an outcome occurred by a chosen assessment point; it does not encode the exact timing of response or how long it persists. The posted secondary outcomes include duration of response, progression-free survival, and time to tumor response, which address different aspects of the disease course. Their numerical results are not reported in the registry record in the results available for this interpretation.

How to read the comparisons

The posted contrasts use risk difference, which expresses the difference between two response proportions on the probability scale. General explanation: a risk difference near zero indicates similar observed proportions, while a value below zero indicates a lower observed proportion in the group named in the contrast than in its reference group. Its confidence interval describes the range of values reasonably compatible with the estimate under the statistical procedure used. The registry also includes unadjusted p-values. A p-value is a measure of how compatible the data are with a specified null hypothesis under the test assumptions; it is not the probability that the null hypothesis is true, nor does it measure clinical importance.

For the laBCC comparison, both groups are the same disease category, so the contrast compares the 800 mg laBCC group with the 200 mg laBCC reference. The posted mBCC contrasts instead use the 200 mg laBCC group as their reference. A comparison across laBCC and mBCC combines differences in disease category with differences between groups. It therefore cannot be interpreted as a clean estimate of the dose effect among mBCC participants. The registry record does not report a separate formal within-mBCC dose comparison.

The confidence intervals attached to the arm percentages describe uncertainty in each response proportion. The intervals around the risk differences describe uncertainty in a contrast. These are different quantities: the former concern an individual group’s response rate, while the latter concern the difference between groups. General explanation: when an interval for a difference includes zero, values consistent with no difference remain compatible with the data under that interval procedure. Such an interval can also include differences in either direction, so it does not demonstrate equivalence.

Analysis populations and reporting

The primary endpoint uses the pEAS, described as a subset of the FAS. For laBCC, adequate assessment by MRI or photography, or both, is part of the stated pEAS description. For mBCC, the description includes patients in the FAS. The full FAS definition is truncated in the registry record, and further details of the population construction are not reported in the registry record. The FAS and pEAS should not be treated as interchangeable labels when interpreting endpoint results.

Some secondary outcomes are presented for both pEAS and FAS, while the central-review primary ORR is specified for pEAS. Different populations can produce different denominators and estimates. The registry record does not report how missing assessments were handled, whether participants without an evaluable assessment were counted as nonresponders, or how withdrawals and protocol deviations were addressed. Those omissions limit assessment of possible missing-data bias.

The registry posts estimates and confidence intervals, and includes unadjusted comparisons, but does not provide a full statistical analysis plan. The original sample-size assumptions, analysis hierarchy, multiplicity procedure, and interim-analysis plan are not reported in the registry record. The planning illustrations associated with observed effects are separate from the trial’s original design assumptions. General explanation: a planning calculation estimates the sample size needed under specified assumptions; it does not reproduce the conduct or analysis of a completed trial.

The overall study was randomized and parallel-group, but the posted comparison structure warrants care. A reader should distinguish the randomized design from each particular contrast shown in the results. The design does not make a cross-disease contrast a same-disease dose comparison. Nor do unadjusted p-values account for the number of endpoints and contrasts examined. These are reasons to treat the results as estimates with context, rather than as standalone tests that settle the comparative question.

11. Confidence Intervals and Precision

The primary ORR estimates are reported with 95% confidence intervals. For laBCC, the 200 mg estimate was 42.9% with an interval from 27.7% to 59.0%; the 800 mg estimate was 37.6% with an interval from 27.8% to 48.3%. These intervals allow a fairly wide range of underlying response proportions and overlap. The estimates are therefore not precise enough to support a fine distinction between the two laBCC rates.

For mBCC, the 200 mg estimate was 15.4%, with a 95% confidence interval from 1.9% to 45.4%. The 800 mg estimate was 17.4%, with a confidence interval from 5.0% to 38.8%. Both intervals are wide. The mBCC group denominators were 13 and 23, respectively, and the breadth of the intervals indicates that the response-rate estimates remain uncertain. The point estimates are not exact descriptions of the underlying rates.

Confidence intervals are ranges generated by a statistical procedure to express estimation uncertainty. General explanation: a 95% confidence procedure is designed so that, across repeated studies under its assumptions, intervals constructed this way would contain the true parameter at the stated frequency. It does not mean there is a 95% probability that the true value lies in the particular interval after it has been calculated.

The risk-difference interval for the laBCC contrast is -0.231 to 0.127. It includes zero and permits differences in either direction. The posted mBCC contrasts also have intervals, but they compare each mBCC group against the 200 mg laBCC reference rather than comparing the mBCC doses directly. The estimates and their intervals should be read with that population mismatch in view. No interval in the posted results removes the need to consider the small mBCC denominators or the analysis-population definitions.

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 illustrations give participants per arm for binary outcomes such as ORR. They are not total-event counts. They use the observed effect as a reference and show planning for 100%, 75%, and 50% of that observed effect. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For time-to-event outcomes, the registry’s planning description instead specifies total events, but the primary ORR planning figures are participants per arm.

The 80% power column means the number of participants per arm estimated to give an 80% chance of detecting the assumed effect under the stated planning conditions, if that effect and the other assumptions hold. The 90% power column describes the corresponding planning target for a 90% chance. These are design-planning probabilities, not guarantees about the result of a future study. Smaller effects are harder to distinguish from random variation, so planning to detect a smaller fraction of the observed effect requires more participants per arm.

The estimates are illustrative calculations based on the observed effect, not the trial’s original sample-size justification. The trial’s original design assumptions and sample-size justification are not reported in the registry record. These figures are not observed power. Observed power is not a useful substitute for interpreting the estimates and their confidence intervals; the planning values answer a different question about hypothetical future study sizes.

Because the calculations use observed effects, they can be sensitive to how large or small the effect happened to look in the completed groups, especially when group sizes are limited. They should be read as conditional examples, not as a recommendation for a particular study size. The assumed equal allocation may also differ from the actual group sizes in the posted results. The registry does not report enough detail to determine whether the original design used these same assumptions.

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 = 0.429; treatment proportion p₁ = 0.376; average p̄ = 0.402.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6935 = 1.3593.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6925 = 0.5829.
4. n = (1.3593 + 0.5829)² / (-0.0522)² = 1,382.8, rounded up to 1,383 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 <- 0.428571428571429                          # control proportion
p1 <- 0.376344086021505                          # 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(1327053)
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 = 1,383 (80% power), 1,851 (90% power)
 75% of observed effect: n per arm = 2,472 (80% power), 3,309 (90% power)
 50% of observed effect: n per arm = 5,590 (80% power), 7,483 (90% power)
power.prop.test: 1382.8 
Simulated power at n = 1,383 per arm: 0.803 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary ORR endpoint and multiple secondary outcomes, including several outcomes assessed in both pEAS and FAS. It also posts more than one group contrast for some outcomes. Examining multiple endpoints, populations, and contrasts raises a multiplicity issue: the chance of at least one apparently notable result can increase as the number of statistical tests grows. General explanation: multiplicity adjustments or a prespecified testing hierarchy can limit the risk of treating chance findings as confirmatory.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or a complete statistical analysis plan. It does not state how the type I error rate was allocated across outcomes or contrasts. Therefore, posted p-values identified as unadjusted should not be read as if they were protected against the full set of possible comparisons. This is especially important for secondary outcomes and comparisons that are not direct within-disease dose contrasts.

The record also does not report an interim-analysis plan or stopping boundaries. The fact that a trial is listed as completed does not establish whether interim reviews occurred; that information is not reported in the registry record. The original sample-size justification and its assumptions are also not reported. The planning illustrations based on observed effects are separate from evidence about the original design process.

Missing-data handling is not described in the registry record. The pEAS description indicates that adequate tumor assessment is relevant for laBCC, but the record does not explain how missing or unevaluable assessments were treated in the analysis. It also does not state how withdrawals, incomplete follow-up, or missing measurements were handled. These details matter because the response percentage depends on who is included in the denominator and how unobserved outcomes are classified.

The analysis-population descriptions are incomplete. The primary endpoint uses pEAS, and some secondary outcomes are reported for FAS as well, but the full FAS definition is truncated. The registry record does not report enough detail to verify the population construction or assess whether all analyses followed a prespecified plan. These gaps do not invalidate the posted estimates, but they limit independent evaluation of their statistical context.

15. 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: blood creatine phosphokinase increased (4.0%), anaemia (3.3%), rhabdomyolysis (3.3%), vomiting (2.7%), pneumonia (2.5%).

The safety results are listed separately for LDE225 200 mg once daily and 800 mg once daily. The registry reports serious adverse events affecting 16 of 79 participants at risk in the 200 mg group and 58 of 150 at risk in the 800 mg group. Other adverse events affected 76 of 79 and 145 of 150 participants, respectively. The record also reports 1 death in the 200 mg group and 7 deaths in the 800 mg group. These are counts from the posted safety groups and should not be interpreted as evidence about causation.

The most frequently listed serious adverse-event terms include increased blood creatine phosphokinase at 4.0%, anaemia at 3.3%, rhabdomyolysis at 3.3%, vomiting at 2.7%, pneumonia at 2.5%, and nausea at 2.0%. The registry record does not establish from these entries whether an event was caused by study treatment. It also does not provide, in the registry record reported for this summary, timing, duration, severity breakdowns, or participant-level overlap between event categories.

Safety counts describe what was recorded in the study groups; they do not by themselves establish comparative risk. The groups differ in size, and no adjusted safety comparison is reported. The death counts likewise do not state cause or relationship to treatment. These figures should be read as registry-reported safety observations, not as individualized risk predictions or medical advice.

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

The posted primary results describe the proportion of participants with a confirmed complete or partial response by 6 months, using central review. For laBCC, the reported ORR estimates were 42.9% at 200 mg and 37.6% at 800 mg. For mBCC, they were 15.4% and 17.4%, respectively. The 95% confidence intervals are particularly broad for mBCC, so those point estimates should not be mistaken for precise values.

The endpoint description identifies an observed ORR of 30% or higher on any treatment arm at the end of the study as the criterion for considering treatment sufficiently efficacious. That criterion concerns an observed response rate; it is not the same as a formal statistical comparison between doses. Nor does it establish that the underlying response probability is certainly above the threshold. The confidence intervals show meaningful uncertainty around the arm-level estimates.

The results do not establish that one LDE225 dose is superior. The laBCC contrast has a risk-difference confidence interval that includes zero and an unadjusted p-value of 0.565. The mBCC contrasts use a laBCC reference group, so they do not provide direct comparisons between the mBCC doses. The small mBCC groups and wide intervals further limit precision. The registry record does not report an adjusted within-mBCC dose comparison.

ORR by 6 months also does not establish how long a response lasted, whether disease progression was delayed, or how survival differed. Those questions require other outcome data. Although the registry lists duration of response, progression-free survival, and time to tumor response, their numerical results are not reported in the registry record in the results. The available safety counts also do not establish whether events were caused by treatment or how the overall benefit-harm balance should be judged.

These results are statistical descriptions of recorded study groups, not medical advice for an individual. Interpretation depends on the endpoint definition, disease category, analysis population, uncertainty, and comparison being made. The evidence does not justify a broad claim about treatment effectiveness beyond the specific outcomes and groups reported.

17. Why This Trial Matters Statistically

This trial is statistically informative because it reports response estimates separately for locally advanced and metastatic basal cell carcinoma, and separately for two LDE225 dose levels. Keeping those groups distinct avoids obscuring the fact that the primary endpoint uses different response criteria for laBCC and mBCC. The registry also identifies central review and a fixed assessment time, making the endpoint definition explicit.

The results illustrate why an estimated percentage should be read with its confidence interval and denominator. The laBCC estimates have intervals that overlap, while the mBCC estimates have wide intervals in groups of 13 and 23 participants. A point estimate can look different across groups even when the evidence is not precise enough to distinguish the underlying rates confidently. The registered 30% efficacy criterion is also a useful reminder that a threshold-based description and a between-group hypothesis test answer different questions.

The trial highlights the importance of matching a contrast to the scientific question. A randomized study can still have posted comparisons that do not directly answer every possible dose question. Here, the mBCC contrasts use a laBCC reference group, which limits their interpretation as dose comparisons within mBCC. Clear reporting of analysis populations, missing-data methods, and multiplicity procedures would further help readers evaluate the results.

Finally, the registry includes several secondary outcomes, but numerical results are not available for all of them in the results considered. This distinction between outcomes listed and results reported is important. A registry record can indicate the scope of planned assessment while leaving uncertainty about the broader clinical course and the statistical plan. The trial therefore provides useful response-rate estimates while also showing why design context and transparent reporting are essential to interpretation.

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.

The primary efficacy groups are substantially smaller for mBCC than for laBCC: the posted denominators are 13 and 23 for mBCC, compared with 42 and 93 for laBCC. The mBCC confidence intervals are wide, limiting precision. The total enrollment of 230 is not the denominator for every endpoint; the primary analysis uses pEAS group sizes, and some secondary results use different analysis populations.

The posted comparison structure is a specific limitation. The mBCC risk-difference contrasts use the 200 mg laBCC group as the reference, mixing disease categories. They therefore cannot be interpreted as direct dose comparisons within mBCC. The registry record does not report a separate formal within-mBCC comparison. Even for laBCC, the posted contrast is unadjusted and should be interpreted alongside the confidence interval and the lack of reported multiplicity procedures.

The registry record’s analysis-population description is incomplete. It describes the pEAS as a subset of the FAS and gives assessment criteria for laBCC, but the full FAS definition is truncated. Missing-assessment handling, withdrawals, and the treatment of unevaluable tumors are not reported in the registry record. Those details could affect the denominator and interpretation of a response proportion.

The original sample-size justification, statistical analysis plan, multiplicity handling, and interim-analysis plan are not reported in the registry record. The planning illustrations based on observed effects do not fill those gaps. The available secondary results cover only some of the listed outcomes; numerical results for duration of response, progression-free survival, and time to tumor response are not reported in the registry record in the results.

The safety reporting provides counts and selected serious adverse-event terms, but the registry entries reported do not establish causality, event timing, or detailed severity. Death counts are reported without cause or treatment relationship. These limitations constrain conclusions about the comparative safety profile as well as efficacy.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma — NCT01327053.
• Registry record last updated 2019-08-28; status last verified 2019-08.
• Results first posted 2015-11-23.
• 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.

22. Record Summary

NCT01327053 is a completed Phase II randomized, quadruple-masked, parallel-group study sponsored by Novartis Pharmaceuticals. It enrolled 230 patients with locally advanced or metastatic basal cell carcinoma to study oral LDE225 at 200 mg or 800 mg daily. The recorded study start was 2011-06-29, and primary completion was 2013-06-28.

The primary endpoint was centrally reviewed ORR at 6 months, using mRECIST for laBCC and RECIST 1.1 for mBCC, in the pEAS. Arm-level estimates were 42.9% and 37.6% for laBCC, and 15.4% and 17.4% for mBCC, with broad confidence intervals, especially in mBCC. The posted mBCC contrasts use the 200 mg laBCC group as the reference and are not direct within-mBCC dose comparisons.

The registry lists secondary response and time-to-event outcomes, but numerical results are not reported for all listed endpoints. The original statistical plan, sample-size justification, missing-data procedures, and multiplicity handling are not reported in the registry record.