A 12-week Extension of the Phase III Study (D3820C00004) to Assess the Effect and Safety of NKTR-118 in Patients With Non-cancer-related Pain and Opioid-induced Constipation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A 12-week Extension of the Phase III Study (D3820C00004) to Assess the Effect and Safety of NKTR-118 in Patients With Non-cancer-related Pain and Opioid-induced Constipation (NCT01395524), a randomized phase 3 study. The primary outcome is Incidence of Patients Experiencing at Least One Adverse Event (AE).

2. Clinical Question

The registry identifies this as a Phase 3 randomized, quadruple-masked, parallel-group extension study. Its stated focus is the effect and safety of NKTR-118 in people with opioid-induced constipation and non-cancer-related pain. The primary endpoint is a safety outcome: whether a participant experienced at least one adverse event. The posted comparisons describe the risk difference for each NKTR-118 dose versus placebo, alongside other effect estimates and unadjusted p-values.

The title describes a 12-week extension, while the primary endpoint timeframe runs from Baseline (Week 0) to the end of follow-up at Week 14. The brief summary describes evaluation over a 6-month period. These are different descriptions in the registry record; how they relate to each other is not reported in the registry record. The primary question should therefore be read in terms of the stated endpoint and its Week 0 to Week 14 timeframe, rather than as a claim about an unreported treatment duration or a broader clinical benefit.

3. Trial Design

This was a Phase 3 randomized, quadruple-masked, parallel-group extension study sponsored by AstraZeneca. The registry gives an enrollment of 302 and lists three arms: NKTR-118 12.5 mg, NKTR-118 25 mg, and placebo. The listed arm sizes for the primary endpoint are 94, 97, and 100 participants, respectively. The registry status is completed. The start is listed as 2011-07, and primary completion as 2012-09.

The study title identifies it as an extension of Study D3820C00004. The safety analysis population was drawn from people who participated in that preceding study and received at least 1 dose of study drug in Study D3820C00007. People found to have been randomized multiple times within the program at different centers were excluded from the safety analysis set. Thus, the population used for the primary endpoint is defined by prior study participation and study-drug exposure, not simply by the enrollment figure.

Randomization and quadruple masking are stated in the registry. The method used to generate the randomization sequence, how allocation was concealed, which roles were masked, and whether masking was maintained are not reported in the registry record. The arm descriptions contain no further details. Route of administration, treatment adherence, and any changes to allocated treatment are not reported in the registry record.

The registry describes the primary outcome as the incidence of participants experiencing at least one adverse event from Baseline (Week 0) to the end of follow-up at Week 14. It also lists change from baseline in the Patient Assessment of Constipation Symptoms Questionnaire and the Patient Assessment of Constipation Quality of Life as secondary outcomes. Results for those secondary measures are not posted in the registry record. The relationship between the title’s 12-week extension, the Week 14 endpoint timeframe, and the brief summary’s 6-month description is 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: Study D380C00007 is an extension study of D3820C00004. Of the patients randomized in D3820C00004, n=302 continued and enrolled into D380C00007. The study duration was up to 14 weeks, consisting of a 12 week treatment period and a follow-up visit 2 weeks after the last dose of study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety analysis set included all patients who participated in Study D3820C00004 and received at least 1 dose of study drug in Study D3820C00007, with the exception of patients who were found to have randomized multiple times within the program at different centers.

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: A total of 6 patients (1 patient in the NKTR-118 25 mg group, 2 patients in the NKTR-118 12.5 mg group, 3 patients in the placebo group) had been previously randomized within the NKTR-118 program at a different study center and were excluded from the ITT and Safety analysis sets. Baseline characteristics are summarized using the ITT analysis set.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Patients Experiencing at Least One Adverse Event (AE), measured over Baseline (Week 0) to end of the follow-up period (Week 14).

The primary endpoint counts participants who experienced at least one adverse event during the randomized treatment and follow-up periods. The registry specifies the timeframe as Baseline (Week 0) to the end of follow-up at Week 14. The outcome is a participant-level event indicator: a participant is counted if at least one adverse event occurred during that period. The endpoint is not a count of all adverse-event episodes, and the posted counts do not describe the number of events each participant experienced.

Safety endpoints of this kind are used to describe the occurrence of adverse events during study participation and to compare their frequency across randomized groups. The resulting arm counts and risk differences summarize how many participants had at least one event, relative to the number assessed in each group. This can provide a broad overview of reported adverse-event incidence, but it does not convey the event’s severity, duration, seriousness, or relationship to treatment for each participant.

The safety analysis set included participants from Study D3820C00004 who received at least 1 dose of study drug in Study D3820C00007, excluding people found to have been randomized multiple times within the program at different centers. This population definition is relevant to interpretation: the endpoint describes the defined safety set, not necessarily every person included in the study’s overall enrollment. The registry lists the incidence of at least one adverse event as the primary outcome; further details on how adverse events were classified, collected, or assessed for relatedness are not reported in the registry record.

7. Results Posted in the Registry

• NKTR-118 12.5 mg: 34.0% (32/94) versus 33.0% (33/100) on control; risk difference 1.0 percentage points (95% CI -12.3 to 14.3), risk ratio 1.03 (0.69–1.53); unadjusted two-proportion z-test p = 0.878.
• NKTR-118 25 mg: 41.2% (40/97) versus 33.0% (33/100) on control; risk difference 8.2 percentage points (95% CI -5.2 to 21.7), risk ratio 1.25 (0.87–1.80); unadjusted two-proportion z-test p = 0.231.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: each participant either experienced at least one adverse event during the specified period or did not. For a binary outcome, the arm-level event count is interpreted relative to the number of participants at risk or assessed. The displayed counts are the observed participant counts for this endpoint: 32 of 94 for NKTR-118 12.5 mg, 40 of 97 for NKTR-118 25 mg, and 33 of 100 for placebo.

What does a risk difference express?

General statistical explanation: a risk difference subtracts the event risk in one group from the event risk in a reference group. It is expressed on the probability scale, so zero represents no difference between groups. Positive and negative values indicate which group has the higher estimated event risk, according to the direction used for the comparison. The registry comparisons use placebo as the reference. The posted risk differences are 0.010 for NKTR-118 12.5 mg versus placebo and 0.082 for NKTR-118 25 mg versus placebo.

These comparisons are based on the arm-level participant counts. The confidence interval around each estimate represents uncertainty about the population difference that could be compatible with the observed data under the statistical method used. A confidence interval is not a range containing a known fixed proportion of individual participant outcomes. It is an interval estimate of the comparison, and its width conveys how precisely that comparison is estimated.

How should the p-values be read?

The registry posts unadjusted p-values of 0.878 and 0.231 for the two risk-difference comparisons. General statistical explanation: a p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, nor is it a measure of the size or importance of an effect. The registry labels these p-values as unadjusted. Whether the sponsor used another analysis or adjustment for the primary endpoint is not reported in the registry record.

The posted relative risk and odds ratio offer alternative scales for comparing event occurrence. General statistical explanation: a relative risk compares risks as a ratio, while an odds ratio compares odds. Their null value is 1, whereas the null value for a risk difference is 0. The posted relative-risk confidence intervals are 0.694 to 1.534 and 0.866 to 1.803; the odds-ratio intervals are 0.577 to 1.903 and 0.797 to 2.546. These intervals span 1. The measures all describe the same primary endpoint and should not be counted as independent findings.

Why does the endpoint definition matter?

The endpoint counts participants with at least one adverse event, rather than the total number of adverse-event episodes. A participant with several events still contributes to the primary endpoint as a participant who experienced at least one. Consequently, this measure does not describe recurrence or event burden. Nor does it distinguish event seriousness, severity, duration, or treatment relatedness. The registry lists serious adverse events separately, which is a different safety summary.

General statistical explanation: binary outcomes can be summarized with counts, risks, risk differences, relative risks, odds ratios, and confidence intervals. Each summary highlights a different aspect of the comparison, and all depend on the outcome definition and analysis population. Here, the stated safety analysis set requires prior participation in Study D3820C00004 and receipt of at least 1 dose in Study D3820C00007, with an exclusion for people randomized multiple times within the program at different centers. The endpoint timeframe is Baseline (Week 0) to the end of follow-up at Week 14.

The posted estimates are simple unadjusted comparisons based on the summary statistics. The registry does not report the statistical test or model used for the sponsor’s analysis, how missing endpoint data were handled, or whether covariates were included. Any discussion of general properties of risk differences, relative measures, p-values, or confidence intervals is statistical context, not a claim that a particular unreported method was used in the trial.

General statistical explanation: over-dispersion is a concern when observed variability exceeds what a statistical model assumes; it can make standard errors too small and confidence intervals too narrow if not addressed. The primary outcome is binary, and the registry does not report a count model or a model-based analysis that would make over-dispersion a stated issue. The analysis plan and model details are not reported in the registry record, so no conclusion about their use can be drawn.

10. Confidence Intervals and Precision

The risk-difference estimates are accompanied by confidence intervals that communicate their precision. For NKTR-118 12.5 mg versus placebo, the estimate is 0.010 and the 95% confidence interval is -0.122 to 0.143. For NKTR-118 25 mg versus placebo, the estimate is 0.082 and the 95% confidence interval is -0.052 to 0.217. Both intervals include zero, the value corresponding to no difference on the risk-difference scale. They also include values on both sides of zero, so the estimates do not pin down the direction of the underlying difference.

General statistical explanation: a confidence interval gives a range of values that are reasonably compatible with the data under the method’s assumptions. A wider interval indicates less precision than a narrower interval. It does not mean that every value inside the interval is equally likely, and it does not describe the range of individual outcomes. The intervals are broad enough to include no difference as well as non-zero differences in either direction.

The relative-risk intervals are 0.694 to 1.534 for NKTR-118 12.5 mg and 0.866 to 1.803 for NKTR-118 25 mg. The odds-ratio intervals are 0.577 to 1.903 and 0.797 to 2.546, respectively. For both relative measures, 1 is the null value, and the posted intervals span it. These summaries do not remove the uncertainty seen in the risk-difference intervals; they represent the comparisons on different scales.

The registry does not report a sponsor confidence-interval method or a detailed analysis plan. The displayed intervals should be interpreted as posted, without assuming unreported adjustments or modeling choices. Their width and inclusion of the null values are important context alongside the point estimates and unadjusted p-values.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations expressed as participants per arm for the binary outcome. They are not total events. The calculations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The sample-size assumptions used for the original trial design are not reported in the registry record.

The entries labelled 100% of the observed effect use the full observed effect as the planning target; the 75% and 50% rows use smaller fractions of that effect. Each row gives the number of participants per arm for 80% power and the number of participants per arm for 90% power. In plain terms, those columns describe planning targets for the chance of detecting the specified effect under the listed assumptions, if that effect were the true difference and the assumptions held. They do not describe what happened in the completed trial.

For NKTR-118 12.5 mg, planning for 100% of the observed effect gives 32,184 participants per arm for 80% power and 43,084 for 90% power. Planning for 75% gives 57,105 and 76,447; planning for 50% gives 128,236 and 171,672. For NKTR-118 25 mg, planning for 100% gives 539 and 721; planning for 75% gives 948 and 1,268; planning for 50% gives 2,106 and 2,819.

Smaller effects require more participants to detect under the same planning assumptions. These values are planning illustrations based on observed effects, not observed power. They should not be read as the trial’s original enrollment target or as evidence about the probability that the trial’s findings are true.

12. 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 = 0.330; treatment proportion p₁ = 0.340; average p̄ = 0.335.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6676 = 1.3085.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6676 = 0.5618.
4. n = (1.3085 + 0.5618)² / (0.0104)² = 32,183.1, rounded up to 32,184 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 <- 0.33                          # control proportion
p1 <- 0.340425531914894                          # 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(1395524)
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 = 32,184 (80% power), 43,084 (90% power)
 75% of observed effect: n per arm = 57,105 (80% power), 76,447 (90% power)
 50% of observed effect: n per arm = 128,236 (80% power), 171,672 (90% power)
power.prop.test: 32183.1 
Simulated power at n = 32,184 per arm: 0.804 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary endpoint of at least one adverse event and two secondary outcomes: change from baseline in the Patient Assessment of Constipation Symptoms Questionnaire and change from baseline in the Patient Assessment of Constipation Quality of Life. Results for those secondary outcomes are not posted in the registry record. The registry reports five outcome measures overall, but does not provide analyses for the secondary measures in the posted results.

There are two posted comparisons for the primary endpoint, one for each NKTR-118 dose versus placebo. Their p-values are labelled unadjusted. Whether the sponsor planned or applied a multiplicity adjustment across doses, outcomes, or other analyses is not reported in the registry record. The statistical analysis plan, any hierarchy among outcomes, and the handling of multiple comparisons are also not reported. Therefore, the p-values should be understood as posted unadjusted results and not as evidence that a particular multiplicity strategy was used.

Missing-data methods are not reported in the registry record. The endpoint results give arm-specific participant counts and numbers experiencing an adverse event, but do not explain how participants with incomplete follow-up or unavailable safety data were handled. The registry does not say whether any imputation or sensitivity analysis was used. No interim analyses or stopping rules are reported in the registry record.

The primary outcome population is described as the Safety analysis set: participants who took part in Study D3820C00004 and received at least 1 dose of study drug in Study D3820C00007, excluding people found to have been randomized multiple times within the program at different centers. The registry does not report a separate intention-to-treat analysis population or other efficacy populations. This matters because the enrollment total and the endpoint denominators are not the same stated quantity; the primary endpoint results should be interpreted using their reported safety-population denominators.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial ischaemia (1.1%), diarrhoea (1.1%), drug withdrawal syndrome (1.1%), non-cardiac chest pain (1.1%), gastroenteritis viral (1.1%).

The registry reports serious adverse events for 6 of 94 participants in the NKTR-118 12.5 mg arm, 6 of 97 in the NKTR-118 25 mg arm, and 5 of 100 in the placebo arm. It also lists other adverse-event counts of 15 of 94, 27 of 97, and 11 of 100, respectively. These are separate safety summaries from the primary endpoint, which counts participants with at least one adverse event of any type during the stated period.

Several serious adverse-event terms are listed, each with a reported frequency of 1.1%: MYOCARDIAL ISCHAEMIA, DIARRHOEA, DRUG WITHDRAWAL SYNDROME, NON-CARDIAC CHEST PAIN, GASTROENTERITIS VIRAL, and URINARY TRACT INFECTION. The registry does not give arm assignments for these terms in the posted list, so they cannot be attributed to a particular study group from that listing.

Death counts are not reported in the registry record. The adverse-event figures do not establish whether events were judged related to study treatment, and the registry does not report further details about event severity, timing, or outcome. They should be read as counts in the reported safety groups, not as a complete characterization of each event or a causal comparison.

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

The posted results describe adverse-event incidence in the defined safety population over the stated Baseline (Week 0) to Week 14 timeframe. The event counts were 32 of 94 for NKTR-118 12.5 mg, 40 of 97 for NKTR-118 25 mg, and 33 of 100 for placebo. The risk-difference estimates were positive for both active-dose comparisons, but the confidence intervals included zero. Thus, the posted data do not precisely establish the direction or size of the difference in incidence for either comparison.

This endpoint does not measure constipation symptoms, quality of life, pain, or treatment benefit. The registry names change from baseline in the Patient Assessment of Constipation Symptoms Questionnaire and the Patient Assessment of Constipation Quality of Life as secondary outcomes, but their results are not posted. The primary endpoint also does not count the total number of adverse-event episodes or communicate each event’s seriousness, severity, duration, or relationship to treatment.

The results are specific to people included in the Safety analysis set, which required participation in Study D3820C00004 and receipt of at least 1 dose of study drug in Study D3820C00007, with the stated exclusion for repeated randomization within the program at different centers. They should not be generalized beyond that population and timeframe without additional evidence.

The registry’s wording identifies a 12-week extension, a primary endpoint through Week 14, and a brief-summary evaluation period of 6 months. How those descriptions align is not reported in the registry record. These results therefore support a limited reading of the posted safety endpoint and its uncertainty; they do not settle broader questions about efficacy, longer-term outcomes, or the cause of individual adverse events.

16. Why This Trial Matters Statistically

Statistically, this trial illustrates why the point estimate and its uncertainty need to be considered together. The two risk differences are positive, but each confidence interval spans zero and values in both directions. A reader who focuses only on the point estimate could overlook the considerable uncertainty around the comparison. The unadjusted p-values and the relative-measure intervals add context, but do not turn an uncertain estimate into a definitive statement about the underlying difference.

The endpoint also makes clear how outcome definitions shape interpretation. Counting participants with at least one adverse event gives a broad participant-level summary. It does not distinguish one event from repeated events, and it does not describe severity or relatedness. The separate serious adverse-event counts answer a narrower question, while the listed serious terms provide limited detail without arm-specific attribution.

The registry’s population definition is another important statistical consideration. The primary endpoint uses a Safety analysis set based on participation in a preceding study and exposure in the extension, with an exclusion for repeated randomization. Readers should use the arm-specific denominators rather than treat the overall enrollment number as the analysis population for this endpoint.

Finally, the planning illustrations show how strongly required sample sizes depend on the assumed effect to detect. The estimates based on smaller fractions of the observed effect require more participants per arm under the stated assumptions. This is useful for understanding planning sensitivity, but it is distinct from the trial’s original design rationale, which is not reported, and from the precision of the completed study’s estimates.

17. Limitations

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

The registry does not report a detailed statistical analysis plan, the method used for the sponsor’s primary comparison, or whether the reported p-values were subject to any adjustment beyond their stated unadjusted status. It also does not describe missing-data handling, sensitivity analyses, interim analyses, or stopping rules. These omissions limit assessment of how the analysis was planned and how robust the estimates are to alternative assumptions.

The primary endpoint is a broad binary indicator of at least one adverse event. The posted summary does not show event-level detail, the number of events per participant, event severity, duration, timing, or the investigator’s assessment of relationship to study treatment. Serious events are reported separately, but the listed serious-event terms are not assigned to study arms in the posted list. Death counts are not reported in the registry record.

The stated endpoint timeframe is Baseline (Week 0) to Week 14, while the title describes a 12-week extension and the brief summary describes a 6-month period. Their relationship is not reported in the registry record. The arm descriptions provide no further intervention details, and the registry does not report information about adherence, treatment changes, or the methods for collecting adverse events.

The registry lists two secondary outcomes, but their results are not posted. Consequently, the available results do not provide the listed symptom or quality-of-life comparisons. The primary endpoint population is a defined safety set from the preceding and extension studies, not an unrestricted description of all enrolled participants. These limitations constrain interpretation to the posted safety results and their specified population and timeframe.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A 12-week Extension of the Phase III Study (D3820C00004) to Assess the Effect and Safety of NKTR-118 in Patients With Non-cancer-related Pain and Opioid-induced Constipation — NCT01395524.
• Registry record last updated 2017-02-23; status last verified 2017-01.
• Results first posted 2015-06-17.
• 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.

21. Record Summary

The registry record describes NCT01395524 as a completed Phase 3 randomized, quadruple-masked, parallel-group extension study sponsored by AstraZeneca, with enrollment of 302. The study compares NKTR-118 12.5 mg and NKTR-118 25 mg with placebo in people with opioid-induced constipation and non-cancer-related pain. The primary endpoint is the incidence of participants experiencing at least one adverse event from Baseline (Week 0) to the end of follow-up at Week 14.

In the safety analysis set, the posted counts were 32 of 94, 40 of 97, and 33 of 100 in the NKTR-118 12.5 mg, NKTR-118 25 mg, and placebo arms, respectively. The risk-difference confidence intervals include zero for both comparisons. The registry also lists serious adverse-event counts and two secondary outcomes, but does not post secondary-outcome results. Details of the analysis plan and missing-data methods are not reported in the registry record.