Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients (NCT00844597), a non-randomized phase 1, phase 2 study. The primary outcome is Safety and Tolerability.

2. Clinical Question

The registry describes a Phase I/II study of AVI-4658, also identified in the record as an exon 51-directed Morpholino oligomer. Its stated primary aim was assessment of safety and tolerability. The primary endpoint is a participant count, not a measure of the amount of dystrophin produced or a direct measure of clinical benefit.

AVI-4658 was administered at six recorded weekly dose levels: 0.5 mg/kg/wk, 1.0 mg/kg/wk, 2.0 mg/kg/wk, 4.0 mg/kg/wk, 10.0 mg/kg/wk, and 20.0 mg/kg/wk. Each cohort description specifies 12 weekly intravenous infusions. The registry also names pharmacokinetics and efficacy over 12 weeks of dosing among the secondary outcomes, but the posted record does not give their results.

Because the allocation was non-randomized and the study model was single-group, the cohort structure does not establish a like-for-like comparison between dose levels. The record supports describing the safety counts recorded for each cohort; it does not support a causal claim that differences between cohorts were due to dose.

3. Trial Design

The registry describes a completed Phase I/II study with non-randomized allocation, no masking, and a single-group model. Enrollment is recorded as 19. The study began in 2009-01, and primary completion is recorded as 2010-06. These administrative details do not by themselves show how many participants contributed to each individual outcome; the adverse-event record gives cohort-specific risk counts.

Six cohorts received AVI-4658 for injection at 0.5 mg/kg/wk, 1.0 mg/kg/wk, 2.0 mg/kg/wk, 4.0 mg/kg/wk, 10.0 mg/kg/wk, or 20.0 mg/kg/wk. The cohort descriptions specify 12 weekly intravenous infusions in 50 mL of normal saline solution over a 60-minute period. No placebo or other concurrent control is listed. Since allocation was non-randomized, the dose cohorts should not be treated as randomized arms or as a controlled dose comparison.

The primary outcome is safety and tolerability, defined as the number of participants with at least one treatment-emergent adverse event considered possibly related to the investigational drug. Its timeframe is baseline to 6 months. The defined population is the safety population: any patient who received at least one dose of study drug. The adverse-event information also reports counts for serious and other adverse events by cohort, but those counts do not substitute for a reported result for the primary endpoint as defined.

Pharmacokinetics, including mean peak plasma concentration after administration, and efficacy over 12 weeks of dosing are listed as secondary outcomes. Specific numerical results for those outcomes are not reported in the registry record. The registry does not report the protocol’s sample-size justification, a detailed statistical analysis plan, or the procedures used to assign participants to dose cohorts.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population - Any patient who received at least one dose of the 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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Safety and Tolerability, measured over Baseline to 6 months.

The primary endpoint counts participants who experienced at least one treatment-emergent adverse event that was considered possibly related to the investigational drug. The registry sets the assessment period from baseline to 6 months and defines the safety population as patients who received at least one dose of study drug. This is a participant-level event count: it records whether a participant met the endpoint, rather than how many separate events that participant experienced.

Safety endpoints of this kind are used to describe adverse experiences occurring during treatment and follow-up, and to support monitoring of tolerability. The qualification “possibly related” is part of the registry’s endpoint definition; it is not equivalent to proof that the drug caused an event. The record does not describe the method used to assess relatedness or how disagreements about relatedness were handled.

The posted adverse-event data separately give counts of participants with serious adverse events and with other adverse events. Those categories are informative for safety description, but they are not interchangeable with the primary endpoint: the primary definition specifically concerns treatment-emergent events considered possibly related to study drug. A numerical result for that defined endpoint is not reported in the registry record. Therefore, the cohort-level serious and other event counts should not be presented as the primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins by matching the analysis to the design. This study is recorded as non-randomized, unmasked, and single-group. Its six cohorts received different AVI-4658 dose levels, but the record does not describe random assignment. A comparison of cohort counts is therefore descriptive, not a randomized estimate of the effect of changing dose. General statistical principle: random allocation can help balance measured and unmeasured characteristics between comparison groups; without it, cohort differences may reflect participant characteristics, treatment choices, or other factors as well as the intervention.

What does a participant count tell us?

The primary endpoint is a count of participants with at least one qualifying event. For this type of endpoint, each participant is classified according to whether the event definition was met during the specified observation period. A count is easy to interpret, but its meaning depends on the population included, the event definition, and the period during which events were observed. Here, the registry defines the safety population as patients who received at least one dose and sets the primary timeframe from baseline to 6 months. The posted record does not give a numerical result for the primary endpoint, so no cohort-specific count for that precise definition can be interpreted.

The adverse-event listing instead supplies separate counts for participants with serious events and other events. These are also participant counts, but they answer different questions from the primary endpoint. An event may be categorized by seriousness and separately assessed for its relationship to study drug. The record does not say that every serious event was considered possibly related, nor that every other event met the primary endpoint definition. Treating these categories as equivalent would change the endpoint being discussed.

Why do the cohort counts need caution?

General statistical principle: observed counts are subject to sampling uncertainty. When the number of participants at risk in a cohort is limited, a count can change substantially with the experience of a small number of participants. The serious-event counts are presented against cohort risk counts of 4, 2, 2, 3, 4, and 4. The record gives no confidence intervals around those counts and no inferential comparison across doses. A count of zero in a cohort does not establish that the underlying chance of an event is zero; it means no affected participant is recorded for that cohort in the posted data.

General statistical principle: a confidence interval expresses the uncertainty around an estimate under a specified statistical model. It is not a guarantee that the true value lies within the interval, and its interpretation depends on the method and assumptions used. No confidence intervals are reported for these adverse-event counts, so the precision of any estimated event frequency cannot be assessed from the registry record. No p-values are reported either. Without a stated analysis and inferential result, the cohort counts should not be described as statistically significant or statistically indistinguishable.

What would a comparison require?

A dose comparison would need a clearly defined estimand: the outcome being compared, the relevant populations, and the contrast of interest. It would also require an analysis that accounts for the non-randomized allocation and explains how differences between cohorts were handled. Those details are not reported in the registry record. The simple observation that counts differ between cohorts is not itself an adjusted dose effect. General statistical principle: confounding occurs when a factor related to both group assignment and outcome can distort an apparent group difference. The record does not provide enough information to assess or correct for such factors.

The posted record lists 5 outcome measures and 0 analyses. This does not establish what analyses may have been conducted outside the registry; it means analysis results are not recorded there. A statistical plan, including any prespecified comparisons, model choices, handling of repeated observations, or interim analyses, is not reported in the registry record. These methods should not be inferred from the study title or from the presence of several dose cohorts.

How should planning illustrations be understood?

General statistical principle: sample-size planning asks how many participants would be needed under stated assumptions to detect a specified effect with a chosen error rate and power. Such calculations are planning illustrations, not descriptions of observed study results. They do not show that a completed study had a particular probability of detecting its result, and they cannot replace the trial’s actual analysis. Any planning illustration associated with these results uses assumptions stated for that calculation; it is not the study’s own design justification, which is not reported in the registry record. The record does not report an original sample-size justification, so no claim about the rationale for enrollment can be made.

For this study, the planning assumptions describe two-sided significance level 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a stated fraction of the observed effect. Those assumptions do not match the recorded non-randomized, single-group design with six dose cohorts. They should not be interpreted as the design actually used or as observed power. The record does not give inferential results for the primary safety endpoint to support a claim of statistical power or a treatment effect.

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("Open Label Treatment Arm")
n      <- c(19)
events <- c(14)
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  Open Label Treatment Arm  19  14  73.7  48.8  90.9  51.2  88.2  50.9  88.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures and 0 analyses. It names safety and tolerability as the primary outcome and lists pharmacokinetics and efficacy over 12 weeks of dosing as secondary outcomes. Several dose cohorts and outcomes can create multiple opportunities for comparison. General statistical principle: when many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for multiplicity. Whether any correction, hierarchy, or prespecified testing strategy was used is not reported in the registry record.

The analysis plan is not reported, including the choice of statistical tests, whether comparisons were planned across dose cohorts, and whether any interim analyses occurred. No p-values or confidence intervals are reported for the endpoints described in the available record. It is therefore not possible to assess the inferential approach or distinguish prespecified analyses from exploratory ones.

Missing-data methods are not reported in the registry record. It does not describe how incomplete follow-up, missed assessments, withdrawals, or unavailable outcome measurements were handled. The safety population is defined as patients who received at least one dose, but the record does not give a separate analysis-population flow or explain whether all participants in that population contributed complete data for each endpoint.

The registered enrollment of 19 should not be treated as the denominator for every outcome. The adverse-event listings give their own at-risk counts by cohort, while the primary endpoint’s numerical result is not reported. No intention-to-treat population or other efficacy analysis population is described in the record. Without these details, the completeness and consistency of endpoint-specific analyses cannot be assessed.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: post-operative nausea and vomiting (50.0%), fracture of left medial malleolus (33.3%).

The serious adverse-event figures are participant counts within each cohort, with the at-risk count stated alongside them. The registry records 0 of 4 affected participants in Cohort 1, 0 of 2 in Cohort 2, 1 of 2 in Cohort 3, 1 of 3 in Cohort 4, 0 of 4 in Cohort 5, and 0 of 4 in Cohort 6. These counts describe the posted record; they do not establish that an event was caused by AVI-4658 or that the cohorts are comparable.

Other adverse-event counts are 4 of 4 in Cohort 1, 2 of 2 in Cohort 2, 2 of 2 in Cohort 3, 3 of 3 in Cohort 4, 4 of 4 in Cohort 5, and 4 of 4 in Cohort 6. The serious and other categories should be kept distinct. Neither set of counts is the same as the primary endpoint, which requires a treatment-emergent event considered possibly related to study drug.

The listed serious-event terms are Post-Operative Nausea and Vomiting at 50.0% and Fracture of Left Medial Malleolus at 33.3%. The denominator and details behind those percentages are not reported in the registry record. A death count is also not reported in the registry record; that omission does not establish that no deaths occurred.

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

The posted results support a limited descriptive reading: the registry records cohort-level counts for participants with serious adverse events and with other adverse events. The serious-event counts are nonzero in Cohort 3 and Cohort 4, and zero in the other listed cohorts. Other adverse events are recorded for every participant represented in each cohort’s at-risk count. These observations describe the recorded events; they do not by themselves establish cause, comparative risk, or the safety profile in a broader population.

The primary endpoint is defined as the number of participants with at least one treatment-emergent adverse event considered possibly related to the investigational drug, assessed from baseline to 6 months in the safety population. A numerical result for that definition is not reported in the registry record. The serious and other event counts cannot fill that gap because they do not establish the same relatedness criterion. The secondary outcome titles also do not provide numerical evidence of pharmacokinetic or efficacy results.

The study’s non-randomized allocation and single-group model matter when interpreting the dose cohorts. The posted counts are not a controlled comparison, and differences between cohorts cannot be attributed to dose on the basis of these data alone. No adjusted analyses, confidence intervals, or p-values are reported in the registry record. As a result, the precision and statistical significance of any between-cohort difference cannot be assessed.

The record also does not report the sample-size rationale, missing-data procedures, or detailed statistical plan. Those omissions limit assessment of how the outcomes were planned and analyzed. Any sample-size calculations presented as planning illustrations are not observed power and do not show what the trial was designed to detect. Overall, the record documents the study design and selected safety counts, but it does not establish a comparative treatment effect or provide the numerical primary endpoint result.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its dose cohorts can look like a comparison while lacking the features needed for a randomized comparison. The registry records six AVI-4658 dose levels, but allocation was non-randomized and the study model was single-group. Cohort-specific counts therefore offer descriptive information, not a clean estimate of what would have happened to comparable participants at a different dose or without treatment.

It also illustrates why endpoint definitions matter. The primary outcome is not simply “any adverse event”; it counts participants with a treatment-emergent event considered possibly related to study drug over the stated timeframe. Seriousness, event occurrence, and suspected relationship are separate dimensions. The posted serious and other event counts cannot be substituted for the primary endpoint when its result is not reported.

The small cohort-level at-risk counts make careful treatment of uncertainty especially important. A zero count is not proof of zero underlying risk, and a difference between observed counts is not proof of a dose effect. Confidence intervals, inferential comparisons, and adjustment methods are not reported, so precision and statistical significance cannot be evaluated from the registry record.

Finally, this record demonstrates the distinction between a trial’s administrative status, its listed outcomes, and reported analysis results. The study is marked completed, but the primary endpoint result and detailed analysis methods are not reported. Completion status alone does not resolve missing statistical information. For readers, the central lesson is to separate what the record counts from what its design and analyses can support.

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 most direct limitation is that the numerical result for the registered primary endpoint is not reported in the registry record. Although serious and other adverse-event counts are listed by cohort, they do not identify which events were considered possibly related to study drug. The primary safety question therefore cannot be answered from those counts alone.

The design is non-randomized, unmasked, and single-group, with no concurrent control listed. Dose cohorts should not be treated as exchangeable groups. The record does not report how participants entered cohorts, whether baseline characteristics differed, or whether analyses adjusted for any differences. Accordingly, apparent variation across dose levels cannot be attributed to dose from the posted information.

At-risk counts for the adverse-event listings are limited within each cohort. No confidence intervals or statistical comparisons are reported, and the record does not explain how missing event information or incomplete follow-up was handled. A death count is not reported in the registry record. The listed percentages for serious-event terms lack reported denominator details.

The protocol’s sample-size justification, statistical analysis plan, multiplicity procedures, and interim-analysis methods are not reported in the registry record. The record also does not provide numerical results for the named secondary outcomes. These gaps prevent a full assessment of the planned analysis, uncertainty, and completeness of outcome reporting. The registered enrollment of 19 does not replace outcome-specific cohort denominators or a documented analysis population.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients — NCT00844597.
• Registry record last updated 2015-10-06; status last verified 2015-09.
• Results first posted 2015-10-06.
• 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

The registry record describes a completed Phase I/II study of AVI-4658 in selected patients with Duchenne muscular dystrophy and a frame-shift mutation amenable to exon 51 skipping. It records non-randomized allocation, no masking, a single-group model, and enrollment of 19. The study began in 2009-01, with primary completion in 2010-06.

Participants were assigned to six dose cohorts, with each cohort description specifying 12 weekly intravenous infusions. The primary outcome is the number of participants with at least one treatment-emergent adverse event considered possibly related to the study drug from baseline to 6 months, in the safety population. A numerical result for that endpoint is not reported in the registry record.

Cohort-level counts for serious and other adverse events are recorded, but they do not provide a randomized comparison or establish drug causation. Numerical results for the named secondary outcomes, detailed analysis methods, and missing-data procedures are not reported in the registry record.