Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients (NCT00383708), a na phase 3 study. The primary outcome is Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period.

2. Clinical Question

The planned treatment question is about the proportion crossing a defined laboratory threshold during combination treatment, rather than the average size of an IGF-1 change. The primary endpoint therefore describes how often participants met the stated normalization criterion at the endpoint assessment. It does not, on its own, describe how far individual values moved, how durable normalization was, or whether symptoms or quality of life changed in parallel.

The record also lists secondary questions about normalization at any time and at individual assessments, IGF-1 Z-score change, symptoms, ACROQoL, weight, and supine blood pressure. These outcomes broaden the scope beyond the primary laboratory measure, but their results are not reported in the registry record. With no control group, the central clinical question is descriptive: what outcome was observed among the participants receiving the combination, rather than whether it outperformed a comparator.

3. Trial Design

This was a Phase III, multicentre, open study with a single-group model. The registry lists allocation as NA and masking as none. Enrollment was 125. The study was marked completed, with a start date of 2006-10 and primary completion of 2008-10. The record names Ipsen as sponsor.

The treatment regimen combined lanreotide Autogel 120 mg, administered by deep subcutaneous injection every 28 days, with pegvisomant at 40 to 120 mg per week, administered subcutaneously once or twice a week. The population described in the title and study summary comprised people with acromegaly failing to respond to lanreotide Autogel 120 mg alone. The stated main aim was to assess the effect of co-administration on IGF-1 over 28 weeks.

The study included a run-in period and a co-administration period in its safety reporting. For primary efficacy, the registry describes a treatment-period endpoint assessed from V3 (Week 12; Baseline) up to V11 (Week 44). IGF-1 assessments were scheduled at V1, V2, V3, V5, V7, V9 and V11, or at an early withdrawal visit for participants who discontinued prematurely. Samples were taken in fasting conditions before study-drug administration.

Because this was a single-group, open study, the record does not describe randomized allocation to different treatments or masking of participants and study personnel. The design can characterize outcomes observed during combination treatment in the defined study population, but it cannot by itself separate treatment-associated changes from changes that might occur over time or for other reasons. The protocol’s rationale for the enrollment target and any detailed statistical design justification 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: A total of 125 patients were screened. Subjects were assigned to treatment if they met all inclusion and none of the exclusion criteria. 92 subjects received treatment during the run-in period and 57 subjects received treatment during the co-administration period.

Enrolment Through Start Treatment

Reasons for not completing this period:

Run-in Period

Reasons for not completing this period:

Co-administration Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint.

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 characteristics are reported for the intention to treat (ITT) population which was defined as all co-administered subjects (i.e. treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period, measured over V3 (Week 12; Baseline) up to V11 (Week 44).

The primary endpoint is the percentage of participants with acromegaly whose serum IGF-1 level was normal at the end of the co-administration period, using age- and sex-adjusted criteria. The registry describes serum IGF-1 as a well-known and validated marker of acromegaly. The endpoint turns that continuous laboratory measurement into a binary outcome: each participant either meets the stated normalization criterion or does not at the relevant assessment.

A percentage is useful for describing the share of the analysis population that reached the specified laboratory status. It is distinct from a mean change in IGF-1: a group average can move without indicating how many individuals crossed a threshold, while a threshold percentage does not show the size of changes among participants who remained outside the normal range. The endpoint also does not by itself capture symptoms, quality of life, weight, blood pressure, or safety.

IGF-1 was assessed using a single fasting serum sample taken before study-drug administration at each scheduled assessment. The registry states that last observation carried forward was used to replace missing IGF-1 values. The endpoint timeframe is given as V3 (Week 12; Baseline) up to V11 (Week 44). The observed percentage, its numerator and denominator, and a measure of uncertainty are not reported in the registry record, so the endpoint’s result and precision cannot be described from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents a binary primary outcome: whether each participant had normal age- and sex-adjusted IGF-1 at the end of co-administration. A binary endpoint records membership in one of two categories rather than preserving the full range of the measured laboratory values. The reported percentage, if available, would describe the fraction of the analysis population meeting the criterion. The actual percentage and the statistical uncertainty around it are not reported in the registry record.

What does a confidence interval convey?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the method used to construct it. For a percentage, it would indicate a range of values compatible with the observed data and method. It is not a guarantee that the underlying value lies within that particular interval. No confidence interval for the primary outcome is reported in the registry record, so the precision of the outcome estimate cannot be assessed from the posted results.

How should the endpoint population be read?

The primary efficacy population is defined as all co-administered participants who received at least one dose of each of the two study drugs within the co-administration period and had at least one baseline and at least one post-baseline primary efficacy assessment. This definition depends on treatment exposure and availability of assessments; it is not described as an analysis of every enrolled participant. The size of this efficacy population is not reported in the registry record. The adverse-event risk sets are reported separately, with 57 participants at risk in each of the two periods, and should not be assumed to be the size of the primary efficacy population.

What does last observation carried forward do?

The record states that last observation carried forward, or LOCF, was used to replace missing IGF-1 values. In general, LOCF substitutes a participant’s last available measurement for a later missing measurement. This creates a value for the analysis but does not recover the unobserved measurement. The method relies on assumptions about how values would have behaved after the last observation; those assumptions may not hold for every participant. The registry does not report how many values were missing, how many were imputed, or whether sensitivity analyses using other missing-data approaches were conducted.

Why does the single-group design matter?

In general, a comparator helps distinguish a change associated with a treatment from changes that could occur over time or under another condition. Here, the registry describes a single group and does not list a randomized control arm. Any reported outcome would therefore describe the participants’ experience in the study, not a randomized estimate of the difference between treatments. Open-label conduct means masking was not used, while allocation is listed as NA. The record does not report further design details that would support a causal comparison.

What can the safety counts establish?

Adverse-event counts describe how many participants in each period had events recorded. They are not, by themselves, estimates of comparative treatment effects. The groups are periods in the study rather than like-for-like randomized arms, and the registry does not provide a causal attribution for the reported events. In general, event interpretation also depends on definitions, observation time, event recurrence, and participants’ exposure; those details are not fully reported in the registry record. No deaths were listed in either period.

What do the planning illustrations mean?

The sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is a total event count; for other outcomes, it is participants per arm for 80% or 90% power where those illustrations are shown. In general, such planning calculations describe hypothetical requirements under their assumptions; they are not observed power and do not indicate the probability that the trial’s result is true. The registry’s trial itself is a single-group study, so the two-arm illustration assumptions are not a description of its design. The specific illustration values and the trial’s own sample-size justification are not reported in the registry record.

The record lists 30 outcome measures and 8 analyses. In general, examining multiple outcomes or analyses can create multiplicity concerns: when many statistical questions are considered, unadjusted significance tests can make chance findings more likely across the full set. The registry record does not report whether multiplicity adjustments were planned or applied, nor does it provide a complete account of the statistical procedures used for each outcome. No interim-analysis plan is reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Lanreotide Autogel + Pegvisomant Co-administration")
n      <- c(57)
events <- c(33)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Lanreotide Autogel + Pegvisomant Co-administration  57  33  57.9  44.1  70.9  45.0  69.8  44.9  69.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 30 outcome measures and 8 analyses, including the primary IGF-1 normalization endpoint and secondary outcomes covering additional IGF-1 assessments, symptoms, ACROQoL, weight and blood pressure. Considering several outcomes can raise multiplicity issues. In general, if many statistical tests are interpreted together without adjustment, the chance of at least one chance finding across the set may increase. Whether that issue was addressed depends on the analysis plan and the interpretation intended for each outcome.

Whether multiplicity was controlled, which outcomes were designated confirmatory, and whether any hierarchy or adjustment procedure was used are not reported in the registry record. The record also does not report interim analyses or the statistical plan in enough detail to determine how the eight analyses were selected or interpreted. The outcome counts alone do not show which findings, if any, were prespecified or how analyses were organized.

For the primary endpoint, the record specifies LOCF for missing IGF-1 values. It does not state the number of missing values, the number replaced by LOCF, or whether alternative missing-data methods were examined. LOCF carries forward an observed value rather than estimating a later measurement from new information. In general, this can affect an estimate if the unobserved values would have changed from the last observed values. The registry-defined efficacy population also requires baseline and post-baseline measurements, in addition to receipt of both study drugs during co-administration. Its size and the disposition of participants who did not meet that definition are not reported in the registry record.

These gaps limit assessment of how robust the primary result would be to missing-data assumptions and how multiple findings should be interpreted. They do not establish that a particular method was or was not used beyond the LOCF statement. The endpoint result itself is not reported in the registry record.

12. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: adrenocortical insufficiency acute (1.8%), wound infection (1.8%), skin cancer (1.8%), impaired healing (1.8%), thrombocytopenia (1.8%).

The registry reports safety by study period, not by randomized treatment arm. In the run-in period, 57 participants were at risk; 2 had serious adverse events, 30 had other adverse events, and no deaths were recorded. In the co-administration period, 57 participants were at risk; 8 had serious adverse events, 41 had other adverse events, and no deaths were recorded. These counts describe participants with events in each period and should not be read as a comparison between independent treatment groups.

The record lists acute adrenocortical insufficiency, wound infection, skin cancer, impaired healing, thrombocytopenia and amnesia among the serious-event terms, each with a reported value of 1.8%. The registry information does not establish that these events were caused by treatment. It also does not provide enough detail to infer event severity beyond the serious-event classification, timing for each event, recurrence, or an individual participant’s exposure. The period counts are descriptive safety information, not proof of a treatment effect or a comparative risk estimate.

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

The registry record describes a Phase III, open, single-group study of lanreotide Autogel with pegvisomant in people with acromegaly failing to respond to lanreotide alone. It specifies a primary endpoint based on age- and sex-adjusted IGF-1 normalization at the end of co-administration and describes how IGF-1 was assessed. The posted results do not report the primary outcome value, so the proportion meeting the criterion and its precision cannot be stated.

Even if a proportion were available, a single-group result would describe the observed outcome among the analyzed participants, not the difference between combination treatment and a control or alternative treatment. Because the study was open and had no randomized comparison group, the design does not isolate the effect of the combination from other possible explanations for an observed change. The record does not report a comparative estimate for the primary endpoint.

The endpoint is a laboratory threshold measure. It does not by itself establish changes in symptoms, quality of life, weight, or blood pressure, even though these outcomes appear among the listed secondary questions. Their results are not reported in the registry record. Likewise, the safety counts record events during study periods but do not establish whether an event was caused by a study drug or how the event pattern would compare with another treatment.

The registry’s description of IGF-1 as a validated marker explains why it was selected as the primary measure. It does not make the missing outcome result available, nor does it allow conclusions about a participant’s individual experience. The listed LOCF approach is relevant to interpretation because it was used to replace missing IGF-1 values, but the amount of missing data and the results of any sensitivity analyses are not reported. Overall, the record supplies design and outcome definitions, but not the primary efficacy result needed to describe the observed response.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a clearly specified outcome and an outcome result that is not reported in the registry record. The endpoint identifies what was to be measured: the percentage of participants whose age- and sex-adjusted IGF-1 level was normal at the end of co-administration. The record also describes the assessment schedule and an approach to missing IGF-1 values. Those details clarify the intended measurement, but they cannot substitute for the observed estimate or its uncertainty.

The single-group design is important when interpreting any reported proportion. A descriptive percentage can characterize the study population, but without a randomized comparator it does not estimate a treatment difference. The open-label design and the defined efficacy population are additional features readers need to keep in mind when considering how outcomes were collected and who contributed to the primary analysis.

The study also lists outcomes extending beyond IGF-1, including symptoms, ACROQoL, weight and blood pressure, while reporting safety separately across run-in and co-administration periods. This range illustrates why results need to be read outcome by outcome: a laboratory endpoint, a patient-reported measure and an adverse-event count answer different questions. The registry lists 30 outcome measures and 8 analyses, but does not report whether multiplicity was addressed.

Finally, the record’s sample-size illustrations are planning exercises based on two-arm assumptions, while the study itself is single-group. Keeping those concepts separate avoids treating a hypothetical planning calculation as an observed finding or as a description of the study’s allocation. The protocol’s own sample-size justification is not reported in the registry record.

15. 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 main limitation for interpreting efficacy is that the primary endpoint result is not reported in the registry record. Without the observed percentage, the number of participants meeting the normalization criterion, the analysis denominator, or an uncertainty interval, the primary result cannot be quantified. The record defines an efficacy population requiring exposure to both study drugs and baseline and post-baseline assessments, but does not report how many participants met that definition.

The design is single-group and open, with allocation listed as NA and masking listed as none. There is no randomized comparator in the registry record. Consequently, the design does not provide a like-for-like treatment comparison, and any observed changes could not be interpreted as a randomized treatment difference. Details about other potential design or analysis safeguards are not reported in the registry record.

The primary endpoint uses LOCF to replace missing IGF-1 values. The extent of missingness, the number of carried-forward values, and the results of any sensitivity analyses are not reported. This leaves uncertainty about how much the endpoint estimate, if available, might depend on the missing-data approach. The record also lists multiple outcomes and analyses but does not report a multiplicity strategy or detailed statistical plan.

Safety data are presented as period-specific participant counts. They are not a randomized comparison, and the registry does not establish causal attribution for the events. The record does not provide all details needed to assess event timing, recurrence, or exposure in relation to specific events. These limitations do not show that outcomes were unfavorable or that particular methods were absent; they identify what cannot be determined from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients — NCT00383708.
• Registry record last updated 2022-09-27; status last verified 2022-09.
• Results first posted 2018-07-23.
• 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.

19. Record Summary

NCT00383708 is a completed Phase III, multicentre, open, single-group study sponsored by Ipsen. It enrolled 125 participants and evaluated lanreotide Autogel 120 mg every 28 days with pegvisomant 40 to 120 mg per week in people with acromegaly described as failing to respond to lanreotide Autogel alone.

The primary endpoint was the percentage with normal age- and sex-adjusted IGF-1 at the end of co-administration. The record describes scheduled fasting IGF-1 assessments and use of LOCF for missing values. The primary endpoint result, its denominator and its statistical precision are not reported in the registry record.

Safety counts are reported for run-in and co-administration periods, with 57 participants at risk in each. No deaths were recorded. The study has no randomized comparator, and the record does not report whether multiplicity was addressed, the rationale for its sample size, or a detailed statistical plan.