A Long Term Safety Study to Test the Combination of Aliskiren/ Amlodipine / Hydrochlorothiazide in Participants With Essential Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Long Term Safety Study to Test the Combination of Aliskiren/ Amlodipine / Hydrochlorothiazide in Participants With Essential Hypertension (NCT00667719), a na phase 3 study. The primary outcome is Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs) and Death.

2. Clinical Question

3. Trial Design

This was a completed Phase 3, open-label, multicenter study of the long-term safety and tolerability of aliskiren, amlodipine and hydrochlorothiazide in participants with essential hypertension. The official title describes a 28 to 54-week study. The primary safety outcome has a timeframe of 54 weeks. Enrollment was 564, and the registry record lists the study as completed.

The design is identified as single group, with allocation listed as NA and masking listed as none. Participants were not assigned through a randomized comparison. Instead, the arm description presents a sequence of medication exposure: aliskiren 300 mg plus hydrochlorothiazide 12.5 mg for one week, followed by aliskiren 300 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg for one week. The text then reports force titration, but ends before fully specifying that dose. The safety records list three dose-group labels: aliskiren/hydrochlorothiazide 300/12.5 mg, aliskiren/amlodipine/hydrochlorothiazide 300/5/12.5 mg, and aliskiren/amlodipine/hydrochlorothiazide 300/10/25 mg.

The registry record gives a start date of 2008-06-05 and a primary completion date of 2009-10-05. It does not report a randomized control group, a masking procedure, or a parallel-group treatment comparison. The different dose-group safety counts should therefore be interpreted as records associated with the study’s medication exposures, not as outcomes from independent, comparable randomized arms. The reasons the numbers at risk vary across these records 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 635 participants entered the washout period, of which 564 participants met the study entry criteria and entered the study treatment phase.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated Population consisted of all participants who received at least one dose of trial medication.

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: Treated Population consisted of all participants who received at least one dose of trial medication.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs) and Death, measured over 54 weeks.

The primary endpoint counts participants with any adverse events, serious adverse events and death over 54 weeks. It is a safety endpoint: its purpose is to describe the occurrence of unwanted events during study medication exposure, rather than to estimate a blood-pressure treatment effect. The registry record defines an adverse event as the appearance or worsening of an undesirable sign, symptom or medical condition after starting study drug, whether or not considered related to the drug.

A serious adverse event is defined by consequences or clinical significance. The listed criteria include fatal or life-threatening events; persistent or significant disability or incapacity; congenital anomaly or birth defect; inpatient hospitalization or prolongation of existing hospitalization; and events judged medically significant because they jeopardize the participant or may require medical or surgical intervention to prevent one of those outcomes. These criteria make seriousness distinct from whether an event is thought to have been caused by the study medication.

The endpoint is reported as counts of participants, and the defined treated population consists of everyone who received at least one dose of trial medication. This approach makes the safety summary relevant to those exposed to treatment. Counts alone do not describe event timing, duration, recurrence or causal attribution. The registry record lists the primary outcome category but does not report a detailed analysis plan, participant-level event histories or an inferential comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a count endpoint describe?

The primary endpoint records the number of participants with adverse events, serious adverse events and death. A count is a direct summary of how many participants met the outcome definition. It is not, by itself, a measure of the severity or duration of an event, the number of repeated events, or the likelihood that the study medication caused it. The registry record defines who was included in the treated population, but it does not describe detailed event-level analysis methods.

As a general statistical point, counts are often easier to interpret alongside the number of participants at risk. The registry provides those denominators for the three safety group entries: 564, 561 and 556. Because the study is single group and the group entries are not randomized comparisons, the denominators should be read in the context of the medication sequence rather than as separate controlled groups. The registry record does not explain the changes in numbers at risk.

What can the serious-event definition tell a reader?

The registry definition classifies an event as serious according to consequences or medical significance, such as being life-threatening, requiring inpatient hospitalization, or involving persistent or significant disability. It also includes specified circumstances such as congenital anomaly or birth defect. An event can meet this definition regardless of whether it is considered related to the study drug. Seriousness and causal attribution are separate questions; the definition does not establish that treatment caused an event.

The record lists both serious adverse events and other adverse events, along with deaths. These categories should be kept distinct when interpreting the reported counts. The available summary does not give a full breakdown of onset, duration, recurrence, relatedness or severity for each event. Those details are not reported in the registry record.

Why does the study design matter for comparisons?

General statistical interpretation depends on how treatment groups are formed. Random allocation can help make groups comparable at the start of a trial, while masking can reduce some forms of measurement or reporting bias. This study is listed as single group, with allocation NA and masking none. The arm descriptions indicate a sequence of treatment exposure and the safety records use different dose-group labels. These features do not provide a randomized control comparison.

As a general principle, a difference between descriptive counts in nonrandomized groups can reflect factors other than the treatment dose, including who contributed data to each group and when exposure occurred. The registry record does not report an adjusted comparison, an analysis accounting for the sequence, or an inferential estimate for differences across the entries. For that reason, the group counts are best read descriptively.

What does uncertainty mean for these results?

In general, a confidence interval gives a range of values compatible with an estimated effect under the assumptions of a statistical model. It helps show how precise an estimate is; a point estimate alone does not communicate that precision. The registry record does not report confidence intervals or p-values for the safety counts. It also does not report inferential comparisons between the dose-group entries. Consequently, statistical uncertainty around those counts cannot be evaluated from the posted summaries alone.

Over-dispersion is a general concern for some count models when observed variation exceeds what a simpler model assumes. It can lead to uncertainty estimates that are too narrow if not addressed. The registry record does not identify a count model, describe a dispersion assessment, or report model-based estimates. There is therefore no basis to say whether over-dispersion was assessed or how it would affect an analysis of these data.

What can be said about sample-size planning?

The registry record includes general assumptions for a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a fraction of the observed effect. Those assumptions describe a planning illustration, not the design basis of this single-group safety study. The record does not report an actual sample-size justification or planning target tied to the primary safety endpoint. No sample-size illustration values are reported in the registry record, so no number of participants needed for a target power can be interpreted.

General sample-size illustrations describe hypothetical future planning under stated assumptions. They are not observed power and do not show the probability that this completed study detected a true effect. Moreover, the registry record’s illustration assumptions refer to a two-arm comparison, whereas the trial itself is recorded as single group. The illustration should not be mistaken for an analysis of the observed safety counts.

More broadly, the registry record does not report a complete statistical analysis plan, interim analyses, or methods for missing data. The number of listed outcome measures is six, while the number of analyses is recorded as zero. That distinction matters: an outcome being listed does not mean an analysis result is available. The posted information therefore supports explanation of the outcome definitions and descriptive counts, but not reconstruction of unreported inferential methods.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures overall and names five secondary outcomes: change from baseline in mean sitting diastolic blood pressure, change from baseline in mean sitting systolic blood pressure, achievement of the blood-pressure control target, diastolic blood-pressure response, and systolic blood-pressure response. The primary outcome concerns adverse events, serious adverse events and death. Although these outcomes are listed, the record reports zero analyses. Results for the named secondary outcomes are not reported in the registry record.

When a study evaluates multiple outcomes, multiplicity can matter because repeated statistical testing may increase the chance of a misleading positive finding. General approaches include prespecifying a primary outcome and controlling how multiple tests are interpreted. The registry record does not report a multiplicity procedure, hierarchy among secondary outcomes, or a complete statistical analysis plan. It is not possible to determine from the posted record how multiplicity was handled.

The primary endpoint specifies a treated population consisting of all participants who received at least one dose of trial medication. That definition identifies the population for the safety endpoint. The record does not describe how missing observations were handled, whether any imputation was used, or how participants with incomplete follow-up contributed to each outcome. Reasons for the differences in the numbers at risk across dose-group entries are also not reported in the registry record. These omissions limit assessment of the completeness and precision of the safety summaries.

11. 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: palpitations (0.4%), thrombocytopenia (0.2%), atrial fibrillation (0.2%), inguinal hernia, obstructive (0.2%), non-cardiac chest pain (0.2%).

The serious adverse event counts are 0 among 564 participants at risk in the aliskiren/hydrochlorothiazide 300/12.5 mg entry, 1 among 561 in the aliskiren/amlodipine/hydrochlorothiazide 300/5/12.5 mg entry, and 14 among 556 in the aliskiren/amlodipine/hydrochlorothiazide 300/10/25 mg entry. The corresponding death counts are 0, 0 and 0. Other adverse event counts are 21, 14 and 141, respectively.

The registry also lists serious-event terms and percentages: palpitations, 0.4%; thrombocytopenia, 0.2%; atrial fibrillation, 0.2%; inguinal hernia, obstructive, 0.2%; non-cardiac chest pain, 0.2%; and bronchitis, 0.2%. The summary does not provide individual event histories or explain the basis for each term’s percentage.

These figures are descriptive, not a randomized comparison. The study is single group, and the dose-group entries should not be treated as like-for-like controls. The record does not report event-relatedness analyses or adjusted statistical estimates. Counts alone cannot establish that a medication caused an event or that the entries differ because of dose.

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

The posted results describe safety events recorded during a single-group study of a combination of aliskiren, amlodipine and hydrochlorothiazide. The primary outcome is a participant count over 54 weeks. The registry provides at-risk counts and counts of serious adverse events, other adverse events and deaths for three dose-group entries, as well as a list of serious-event terms and percentages. These are useful descriptive details about the safety experience recorded in the study.

They do not establish a causal relationship between treatment and any particular event. The registry’s adverse-event definition explicitly allows events that are not considered related to study drug, and the summary does not provide relatedness results. Nor do the different dose-group counts establish that one dose is safer than another. The study is not randomized, and the listed entries should not be read as independent control and treatment arms.

The record also lists blood-pressure outcomes, including changes from baseline and response or control targets, but does not report analyzed results for them. As a result, the registry information does not support a conclusion about the magnitude or precision of blood-pressure changes. It also does not provide reported p-values or confidence intervals for the safety counts.

In general, a study’s findings need to be interpreted in light of its design, outcome definitions, analysis methods and completeness of follow-up. Several of those details are not reported in the registry record, including the full statistical plan and handling of missing data. The appropriate reading is therefore limited: the record reports descriptive safety counts in a treated population, but it does not supply a randomized comparison, causal attribution, or analyzed blood-pressure effects.

13. Why This Trial Matters Statistically

This study illustrates why statistical interpretation begins with design, not just with the size of a count. The registry records a single-group, open-label study with a sequence of medication exposures. Although the safety summaries use several dose-group labels, they are not randomized arms. Treating them as direct comparators would imply a design feature that the registry record does not report.

It also illustrates the value of distinguishing outcome definitions. The primary endpoint separates adverse events, serious adverse events and death. Seriousness is defined by consequences and medical significance, while an adverse event need not be judged related to the study drug. These distinctions help readers understand what the counts represent and what they cannot establish.

The record further shows the difference between listing outcomes and reporting analyses. It names blood-pressure outcomes as secondary measures, but the number of analyses is recorded as zero. A listed endpoint is not itself evidence of an analyzed result. Similarly, general assumptions for a sample-size planning illustration should not be confused with the trial’s own design justification or observed statistical power.

For clinical researchers and biostatisticians, the central lesson is to connect each result to its population, denominator, design and analysis. Descriptive counts can convey the recorded safety experience, but without a randomized comparator, reported uncertainty estimates, or details of missing-data handling, their scope is limited. Clear separation of what the record reports from what it does not report is essential to avoid overstating the evidence.

14. 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 record does not report a randomized control group or masking, so the dose-group entries cannot support a like-for-like treatment comparison. The stated study design is single group, and the arm description indicates sequential medication exposure. The description of force titration is incomplete, ending before the full dose information is given. The reasons for differences in the numbers at risk across the entries are not reported in the registry record.

The record reports descriptive safety counts but no inferential estimates, confidence intervals or p-values for these outcomes. It does not report analyzed results for the listed blood-pressure outcomes, even though those outcomes appear among the secondary measures. The number of analyses is recorded as zero. Consequently, there is no reported estimate of the precision of the safety summaries and no reported analysis of blood-pressure change or response.

Further limitations are the lack of reported detail about the statistical analysis plan, interim analyses, missing-data handling, and event relatedness. The registry record defines the treated population but does not provide a fuller account of follow-up completeness or explain how incomplete observations were treated. The sample-size planning assumptions are described as an illustration and do not constitute a reported justification for this study’s enrollment. These limitations constrain interpretation to the safety counts and event terms recorded in the registry.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Long Term Safety Study to Test the Combination of Aliskiren/ Amlodipine / Hydrochlorothiazide in Participants With Essential Hypertension — NCT00667719.
• Registry record last updated 2021-06-07; status last verified 2021-05.
• Results first posted 2021-06-07.
• 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.

18. Record Summary

NCT00667719 is a completed Phase 3, open-label, multicenter, single-group study in participants with essential hypertension. Enrollment was 564. The registry record lists a study start date of 2008-06-05 and a primary completion date of 2009-10-05, and describes a 28 to 54-week study.

The primary outcome counts participants with adverse events, serious adverse events and death over 54 weeks in a treated population. The registry reports three dose-group safety entries, with counts for serious events, other events and deaths, and lists several serious-event terms with percentages. Blood-pressure changes and response or control targets are listed as secondary outcomes, but analyzed results are not reported in the registry record. The design does not provide a randomized, like-for-like comparison among the dose-group entries.