A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) (NCT03254485), a randomized phase 2 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs.

2. Clinical Question

The clinical question therefore has two parts in the study description: whether IW-1973 affects exercise capacity in people with HFpEF, and what adverse events occur during treatment. The primary outcome addresses the second part by counting participants with events that began or worsened after study drug administration. Investigators assessed whether events were related to study drug. An event’s appearance during treatment does not, by itself, establish that the drug caused it.

Exercise capacity was an important efficacy focus in the study objective. The record also lists change from baseline in 6-minute walk distance and ventilatory efficiency, and CPET responders, as secondary outcomes. However, results for these efficacy measures are not reported in the registry record. The posted information therefore does not answer whether exercise capacity changed or how IW-1973 compared with placebo on those measures.

3. Trial Design

This was a Phase 2, randomized, quadruple-masked, parallel-group study. The official title describes a placebo-controlled evaluation of different doses of IW-1973 over 12 weeks in people with HFpEF. The brief study description says treatment was administered daily for approximately 12 weeks. The record lists IW-1973 and a placebo oral tablet as interventions; the placebo was intended to match the experimental drug.

The registry lists enrollment as 196. It records the study as completed, with a start date of 2017-11-07 and a primary completion date of 2019-08-19. The record identifies Akebia Therapeutics as sponsor. These administrative details describe the registered study and do not establish how many participants contributed data to each particular outcome.

Randomization assigns participants to treatment groups by chance, helping reduce systematic differences between groups. Masking is intended to limit the influence of knowledge about assigned treatment on participants’ experience, care, or assessment. The record says masking was quadruple but does not identify which roles were masked. A parallel design means participants are assigned to a group and followed within that group rather than crossing between treatments.

The safety outcome used the safety population: randomized participants who received at least one dose of study drug. The time window for the primary outcome ran from Day 1 up to Day 113. The registry lists a placebo arm and an IW-1973 high-dose arm, but the adverse-event data use the labels Placebo, Praliciguat 10 mg, Praliciguat 20 mg, and Praliciguat 40 mg. The relationship between the IW-1973 arm description and these Praliciguat labels is not reported in the registry record, so those labels cannot be reconciled from the posted information.

The record does not report the allocation ratio, the randomization procedure, stratification factors, detailed eligibility criteria, or the roles included in quadruple masking. Those design details should not be inferred from the general study description.

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 196 participants were enrolled in the study. Participants enrolled under protocol amendment 2 (or earlier) were randomized in a 1:1:1:1 ratio to 10 milligrams (mg) praliciguat, 20 mg praliciguat, 40 mg praliciguat, or placebo. Participants enrolled under protocol amendment 3 were randomized in a 1:1 ratio to either 40 mg praliciguat or placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population consisted of all randomized participants who took at least 1 dose of study drug.

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: Intent-To-Treat (ITT) Population: The ITT Population consisted of all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs, measured over Day 1 up to Day 113.

The primary outcome counts participants with treatment-emergent adverse events (TEAEs) and participants with study-drug-related TEAEs. A TEAE is an adverse event that began or became more severe after study drug was administered. The record defines adverse events as untoward medical occurrences in a participant given a pharmaceutical product; an event does not have to be caused by the treatment to qualify. Investigators assessed the causal relationship to study drug.

The outcome is reported as a count of participants, not as a measure of exercise capacity or a direct measure of how severe an event was. Its timeframe is Day 1 up to Day 113, and its population is the safety population of randomized participants who took at least one dose. Counting participants with events can describe how many people experienced at least one event, but it does not by itself convey the number of events per person, duration, seriousness, or the uncertainty around a treatment comparison.

Safety outcomes are used to characterize undesirable medical occurrences during treatment and to identify patterns that may warrant closer assessment. This is especially relevant in a study evaluating a drug, because observed events need to be documented whether or not investigators judge them related to treatment. The registry record lists both TEAEs and study-drug-related TEAEs, but does not provide a single summarized comparison across treatment groups for this primary outcome.

The study’s stated efficacy focus was peak exercise capacity. That is distinct from the registered primary safety outcome. The listed secondary outcomes include change from baseline in 6-minute walk distance, change from baseline in ventilatory efficiency, and CPET responders at Week 12. Their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, quadruple-masked, parallel-group Phase 2 study. The primary outcome is a count of participants with treatment-emergent adverse events and study-drug-related events. The posted information does not include a complete statistical analysis plan, inferential results, or a single summarized comparison for that outcome.

What does randomization contribute?

In general, randomization assigns treatment by chance rather than by investigator or participant choice. Its statistical purpose is to reduce systematic differences between groups at the start of a trial. It does not guarantee that groups will be identical, especially in a study with uneven group sizes, and it does not eliminate uncertainty. The registry record does not report the allocation ratio, randomization method, or any stratification factors.

Masking can reduce the influence of treatment knowledge on care, event reporting, and outcome assessment. The record identifies quadruple masking but does not say which participant, clinical, or analytic roles were masked. Therefore, the label indicates the stated masking level, but the exact implementation is not reported in the registry record.

What does a count outcome tell the reader?

The primary outcome counts participants who experienced events. A participant count differs from an event count: a person could experience more than one event, while a participant-level measure generally records whether the person had an event in the specified category. The registry specifies that the number of participants with TEAEs and study-drug-related TEAEs is presented. It does not provide event-level detail or a single combined treatment contrast for these categories.

In general, counts should be interpreted alongside the number of participants at risk and the rules defining the outcome and observation period. The posted safety data give group-specific numbers at risk and counts, but simple comparisons of counts do not adjust for differences in group size, exposure time, or other factors. A formal comparison would require a specified statistical method and its assumptions. The method used for the posted safety data is not reported in the registry record.

Over-dispersion is a general concern for count data when observed variability is greater than a basic statistical model expects. It can arise when participants have different underlying event risks or when events cluster within people. This matters because a model that understates variability can produce uncertainty estimates that are too narrow. The record does not state that a count model was used, nor does it report a model for recurrent events. No conclusion about over-dispersion or its handling can be made from the posted counts alone.

How should uncertainty be assessed?

In general, a confidence interval conveys uncertainty around an estimate under the chosen statistical model. A hypothesis test summarizes how compatible the observed data are with a specified null hypothesis, given the model and assumptions. Neither a confidence interval nor a p-value is reported for a single primary-outcome comparison in the registry record. The record notes that the outcome has several categories or time points and is not reduced to one comparison. The counts therefore should not be treated as a statistically tested treatment effect.

For binary outcomes, a treatment comparison may be expressed using measures such as a risk difference or a relative measure. These are general possibilities, not results reported for this study. No new comparative measure should be inferred from the posted counts. The study’s safety results also include serious-event counts and listed event terms, but their presentation does not itself specify a statistical contrast.

What is the role of the efficacy outcomes?

The study objective refers to peak exercise capacity. The record lists change from baseline in 6-minute walk distance, change from baseline in ventilatory efficiency, and CPET responders at Week 12 as secondary outcomes. These outcomes differ in scale and interpretation: continuous change outcomes describe shifts in measured values, whereas a responder outcome classifies participants according to a response definition. The registry record does not provide the result values, responder definition, analysis methods, or uncertainty estimates for these efficacy outcomes.

In general, analysis of change from baseline may account for baseline measurements in different ways, and choices can affect precision and interpretation. A responder analysis depends on a prespecified threshold or rule. The relevant methods for these outcomes are not reported in the registry record, so the analysis approach cannot be reconstructed from the outcome titles.

What do planning illustrations mean?

General sample-size illustrations can show how a future study’s planned size might vary with the effect size to detect, significance level, allocation, and statistical assumptions. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is described as a stated fraction of the observed effect. Such values are planning illustrations, not observed power and not evidence that the original study was designed using those assumptions. The registry record does not report the trial’s own sample-size justification or design assumptions.

For count outcomes, planning requires a model and assumptions about event occurrence and variability. General methods may be sensitive to group allocation, the expected event frequency, and over-dispersion. The applicable model and any trial-specific assumptions are not reported in the registry record. The listed planning approach cannot substitute for the sponsor’s original design documentation.

Overall, the posted information supports a descriptive reading of the safety counts and a description of the planned outcomes. It does not provide the statistical procedures needed to infer adjusted treatment effects or quantify their precision.

10. Multiplicity, Missing Data and Analysis Populations

The study lists more than one outcome: the primary safety outcome includes TEAEs and study-drug-related TEAEs, and the record also lists efficacy outcomes concerning walking distance, ventilatory efficiency, and CPET responders. Multiple outcomes create a general multiplicity issue: testing many hypotheses can increase the chance of at least one apparently positive result when no true effect exists. Researchers may address this with a prespecified testing sequence, adjusted significance thresholds, or other strategies. The multiplicity approach for this trial is not reported in the registry record.

The record says the primary outcome has several categories or time points and is not reduced to one comparison. It does not provide a single primary-outcome effect estimate or test result. The handling of multiple comparisons within that outcome, or across primary and secondary outcomes, is not reported. The record also does not report whether interim analyses were planned or conducted.

Missing-data handling is not reported in the registry record. For the efficacy outcomes, the record does not describe how missing follow-up measurements, withdrawals, or incomplete exercise tests were handled. It also does not give outcome-specific analysis populations for those measures. For the primary safety outcome, the stated population is the safety population of randomized participants who took at least one dose. The record does not describe further rules for participants with incomplete safety follow-up.

The registry identifies the study as randomized and names the safety population, but does not report whether an intention-to-treat, per-protocol, or other population was used for efficacy analyses. It also does not give a statistical analysis plan or the procedures used to address missing data. These omissions limit assessment of whether the analyses followed prespecified methods and how robust the findings might be to alternative assumptions.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dyspnoea (2.2%), non-cardiac chest pain (2.2%), atrial fibrillation (1.1%), cardiac failure acute (1.1%), pneumonia (1.1%).

The serious adverse-event counts are 9 for Placebo, 0 for Praliciguat 10 mg, 0 for Praliciguat 20 mg, and 10 for Praliciguat 40 mg. The corresponding numbers at risk are 90, 7, 7, and 91. These figures are counts, not estimates adjusted for group size, follow-up, or other factors. The record also lists other adverse-event counts of 58, 4, 6, and 68 for those groups, respectively, with the same numbers at risk.

The group labels are important: the study description names IW-1973, while the safety listing names Praliciguat doses. The registry record does not explain this difference. The counts should therefore be read using the labels as posted rather than assuming a relationship that the record does not establish.

The listed serious-event terms include dyspnoea and non-cardiac chest pain at 2.2% each, and atrial fibrillation, acute cardiac failure, pneumonia, and anaemia at 1.1% each. The record gives these percentages but does not specify group-specific context for each term in the listed summary. The entries do not establish that an event was caused by study drug. The investigator’s relatedness assessment is a separate judgment, and no causal conclusion follows from a serious event being reported during the study.

One death is listed in the Praliciguat 40 mg group, with none listed in the other groups. The record does not provide a cause or a treatment-relatedness assessment for that death. Raw counts alone do not establish comparative safety or explain the clinical circumstances of individual events.

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

The registry record establishes that this was a completed randomized, masked, placebo-controlled Phase 2 study with a stated focus on IW-1973, safety, and exercise capacity in HFpEF. It identifies a primary safety outcome based on participants with TEAEs and study-drug-related TEAEs, and it lists selected adverse-event counts. It also names secondary exercise-related outcomes.

What the record does not establish is whether IW-1973 changed exercise capacity, whether the safety outcomes differed statistically between groups, or how precise any treatment contrast was. The primary outcome is not reduced to one comparison, and no corresponding effect estimate, confidence interval, or test result is reported. Results for the listed secondary outcomes are not reported in the registry record. Thus, the study objective and outcome titles should not be mistaken for evidence of an observed efficacy result.

Adverse-event counts are useful descriptive information, but they do not by themselves establish that a treatment caused an event or that one group had greater risk. Interpretation depends on group size, time under observation, event definitions, assessment methods, and uncertainty. The posted information gives numbers at risk and counts, but does not provide an inferential comparison or enough detail to evaluate all these factors.

The difference between the IW-1973 study description and the Praliciguat labels in the safety data also limits straightforward interpretation. The registry record does not explain the naming difference. It should not be resolved by assuming that the terms refer to the same intervention.

These results therefore describe what the registry lists, not a complete evaluation of benefit and harm. They do not justify a treatment recommendation or a conclusion that IW-1973 does or does not work. A fuller interpretation would require the outcome results, analysis methods, uncertainty estimates, and clarification of the safety-group labels, none of which are reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable because its stated scientific objective emphasizes exercise capacity, while its registered primary outcome is safety-focused. That distinction matters when readers assess what the primary analysis could answer. A safety count can describe adverse events during treatment, but it cannot directly answer whether exercise capacity changed. The registry also lists exercise-related secondary outcomes, whose results are not reported in the registry record.

The safety results illustrate why raw counts should not be interpreted in isolation. The listed groups have different numbers at risk, including small dose groups alongside larger groups. Counts can appear different partly because the number of participants contributing to them differs. A meaningful treatment comparison requires a clearly defined estimand, an appropriate analysis, and an expression of uncertainty, none of which is reported as a single primary-outcome comparison in the registry record.

The record also demonstrates the importance of consistent intervention naming. The study description refers to IW-1973, while the safety-group labels refer to Praliciguat. Without an explanation in the registry record, readers cannot confidently map those safety data to the named study intervention. Clear intervention labels are essential for interpreting results and comparing them with other evidence.

Finally, a completed study record is not necessarily a complete statistical report. Registration details and selected event counts can document important aspects of a trial, but readers also need outcome estimates, confidence intervals, analysis populations, missing-data methods, and multiplicity procedures to judge the strength and precision of findings. Their absence means that the record supports a limited descriptive account, not a full inferential evaluation.

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 principal limitation for interpretation is that the primary safety outcome is not presented as one treatment comparison. The record notes several categories or time points, but does not provide a summarized effect estimate, confidence interval, or test result. Consequently, the size and precision of any between-group difference cannot be assessed from the posted primary-outcome information.

The safety data use Praliciguat dose labels, whereas the trial description names IW-1973 and an IW-1973 high-dose arm. The registry record does not explain whether or how these labels correspond. This naming discrepancy complicates attribution of the listed safety counts to the intervention as described.

The listed group sizes are uneven, with much smaller numbers at risk in the 10 mg and 20 mg groups than in the Placebo and 40 mg groups. Raw counts across such groups are not direct comparative estimates. The posted information does not provide an adjusted analysis or group-specific uncertainty estimates for these safety outcomes.

The registry record does not report detailed eligibility criteria, the allocation ratio, randomization procedures, masking roles, the statistical analysis plan, missing-data methods, or multiplicity procedures. It also does not report results for the exercise-capacity outcomes named in the study objective and secondary outcomes. No conclusion about efficacy or the precision of efficacy estimates can be drawn from the outcome titles alone.

Finally, the serious-event summary lists terms and percentages without enough context to establish their group distribution or causal relationship to treatment. The reported death count is not accompanied by a cause or relatedness assessment. These limitations mean the posted record offers only a partial view of safety and does not support a complete benefit-risk assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) — NCT03254485.
• Registry record last updated 2022-09-15; status last verified 2022-08.
• Results first posted 2022-09-15.
• 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

The registry record describes a completed, randomized, quadruple-masked, parallel-group Phase 2 study of IW-1973 versus placebo in people with HFpEF. The stated objective concerned safety and efficacy over approximately 12 weeks, including peak exercise capacity. Enrollment is listed as 196.

The registered primary outcome counts participants with TEAEs and study-drug-related TEAEs from Day 1 up to Day 113 in the safety population. The posted safety data list serious and other adverse-event counts, but use Praliciguat dose labels rather than the IW-1973 label used in the study description. The relationship between these labels is not reported in the registry record.

The record does not give one summarized comparison for the primary outcome or report results for the listed exercise outcomes. Statistical methods for missing data, multiplicity, and efficacy analyses are also not reported. The posted information therefore supports a descriptive account of the registered design and selected safety counts, but not a statistical conclusion about efficacy or comparative treatment effects.