This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP2) (NCT04077437), a randomized phase 3 study. The primary outcome is Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04077437 |
| Phase | Phase 3 |
| Condition | Posttraumatic Stress Disorder |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 121 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Resilient Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
People with posttraumatic stress disorder of moderate or greater severity. The registry summary describes the intended population as people with at least moderate PTSD. The posted primary outcome includes 53 participants in the MDMA-assisted psychotherapy arm and 50 in the placebo-with-psychotherapy arm.
Intervention
MDMA-assisted psychotherapy, using midomafetamine HCl with manualized psychotherapy. The intervention description specifies an initial dose of 80 to 120 mg and a supplemental half-dose of 40 or 60 mg, respectively, 1.5 to 2 hrs after the initial dose.
Comparator
Inactive placebo with manualized psychotherapy. The registry summary describes three placebo-with-therapy sessions, alongside the psychotherapy schedule used in the trial.
Primary question
How did CAPS-5 total severity scores change from baseline to the primary endpoint, described as 18 weeks post baseline post enrollment confirmation, in each randomized arm? The registry reports an arm-specific estimate for each group, rather than a posted between-arm estimate or test of the treatment contrast.
The central statistical question is whether the observed symptom-score changes differ between the randomized groups, and how precisely that difference is estimated. The CAPS-5 measures PTSD symptom severity, with higher scores representing greater severity. A negative change therefore represents a decline in the score from baseline. The posted results give least-squares mean changes and confidence intervals separately for the two arms. Those arm-specific summaries describe changes within each group; by themselves they do not quantify the randomized contrast between groups.
The trial also lists change in the Adapted Sheehan Disability Scale total score as a secondary outcome. The registry record does not report a result for that outcome in the material. The primary question should therefore be read as a question about the posted CAPS-5 results, not as a summary of all symptom, functioning, or safety outcomes.
3. Trial Design
MAPP2, registered as NCT04077437, is a randomized, double-blind, placebo-controlled, multisite phase 3 study. Its design is listed as parallel-group, with triple masking recorded in the registry. The record does not identify which specific roles were masked, so the masking label should not be expanded into assumptions about participants, clinicians, assessors, or analysts.
The trial enrolled 121 participants and is marked completed. The registry lists a start date of 2020-09-02 and a primary completion date of 2022-10-30. Resilient Pharmaceuticals is identified as the sponsor. These record details describe the trial's registration and status; they do not by themselves establish how every participant proceeded through treatment or follow-up.
The experimental arm received midomafetamine, also referred to in the intervention description as MDMA, together with manualized psychotherapy. The placebo comparator received inactive placebo with manualized psychotherapy. According to the brief summary, participants first had three preparatory sessions without study drug, followed by three sessions of MDMA-assisted therapy or placebo with therapy. Each medication session was followed by three integrative therapy sessions without study drug. The arm description specifies an initial dose of 80 to 120 mg, followed by a supplemental half-dose 1.5 to 2 hrs later; the placebo arm is described as inactive placebo combined with manualized psychotherapy.
The primary outcome is change from baseline to the stated primary endpoint in CAPS-5 total severity score. The timeframe is recorded as baseline to 18 weeks post baseline post enrollment confirmation. The primary outcome results include 53 participants in the experimental arm and 50 in the placebo arm. These outcome counts are not the same as the overall enrollment figure, and the registry record does not explain the difference in this result entry.
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
| Stage | Experimental: MDMA-assisted Psychotherapy | Placebo Comparator: Placebo With Psychotherapy |
|---|---|---|
| STARTED | 53 | 51 |
| COMPLETED | 52 | 42 |
| NOT COMPLETED | 1 | 9 |
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.
| Characteristic | Unit | Experimental: MDMA-assisted Psychotherapy | Placebo Comparator: Placebo With Psychotherapy | Total |
|---|---|---|---|---|
| Participants analysed | 53 | 51 | 104 | |
| Age, Continuous | years | 38.2 (SD 11.0) | 39.9 (SD 9.6) | 39.1 (SD 10.3) |
| Sex: Female, Male: Female | Participants | 32 | 42 | 74 |
| Sex: Female, Male: Male | Participants | 21 | 9 | 30 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 17 | 11 | 28 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 36 | 39 | 75 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 1 | 1 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 2 | 2 |
| Race (NIH/OMB): Asian | Participants | 5 | 6 | 11 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 1 | 1 |
| Race (NIH/OMB): Black or African American | Participants | 5 | 3 | 8 |
| Race (NIH/OMB): White | Participants | 37 | 32 | 69 |
| Race (NIH/OMB): More than one race | Participants | 6 | 7 | 13 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Baseline PTSD Duration | years | 16.3 (SD 14.3) | 16.1 (SD 12.4) | 16.2 (SD 13.3) |
| Baseline CAPS-5 Dissociative Subtype | Participants | 13 | 11 | 24 |
6. Primary Endpoint
The registry lists the primary outcome as Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5), measured over Baseline to 18 weeks post baseline post enrollment confirmation.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | score on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change from baseline in the Clinician Administered PTSD Scale for DSM-5, abbreviated CAPS-5. It is a 30-item semi-structured interview about PTSD in the past month, anchored to a traumatic event defined under DSM-5. The record says the assessment produces a total severity score based on PTSD domains, as well as a categorical rating indicating whether diagnostic criteria are met.
The total severity score ranges from 0 to 80, with higher values indicating greater symptom severity. The posted primary result concerns the continuous total severity score, not the categorical diagnosis. A change score expresses how the measured score at the endpoint differs from baseline; a negative change means the score moved downward. It does not, on its own, show whether each participant improved, whether diagnostic criteria were no longer met, or how symptoms changed in other domains.
CAPS-5 is used in this trial as a clinician-administered measure of PTSD symptom severity. Such a measure allows the trial to compare score changes over the specified follow-up period. The registry reports least-squares mean changes with 95% confidence intervals for each arm. The record does not report a between-arm estimate for the primary endpoint in this result entry, so the arm-specific changes should not be mistaken for the estimated randomized treatment contrast.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
For the MDMA-assisted psychotherapy arm, the posted least-squares mean change in CAPS-5 total severity score was -23.69, with a 95% confidence interval from -26.94 to -20.44; the result entry lists 53 participants. For the placebo-with-psychotherapy arm, the posted least-squares mean change was -14.78, with a 95% confidence interval from -18.28 to -11.28; the entry lists 50 participants. Because higher CAPS-5 scores indicate greater symptom severity, negative changes correspond to lower scores at the primary endpoint than at baseline in each arm.
These are estimates of change within each arm. The intervals describe uncertainty around each arm-specific least-squares mean under the analysis that generated the posted results. They are not confidence intervals for the difference between arms. The registry result entry does not provide a between-arm estimate, its confidence interval, or a test statistic or p-value. Consequently, the posted arm summaries alone do not establish the size or precision of the randomized comparison. Comparing two arm-specific changes by eye is not a substitute for a direct treatment-contrast analysis.
The outcome counts are 53 and 50, while overall enrollment is 121. The record does not explain the accounting of participants in this outcome result or specify the analysis population. The counts should therefore be read as the participants associated with the posted arm summaries, not as proof of a particular inclusion, exclusion, or missing-data rule.
The intervals around the arm estimates convey uncertainty about those means. They do not describe the range of individual participant changes, and they do not indicate that every participant had a change close to the arm mean. Nor do they address all possible sources of uncertainty, such as measurement limitations or differences between trial participants and other populations.
A secondary outcome is change in Adapted Sheehan Disability Scale total score. The registry record lists that outcome but does not report its result in this entry. The record lists two outcome measures and zero statistical analyses. It does not report an inferential analysis of the primary contrast in the registry entry summarized by these results. The conclusions that can be drawn are therefore limited to the posted descriptive arm-specific changes and their confidence intervals, rather than a complete assessment of the trial's comparative efficacy or safety.
The figures should be interpreted as results at the specified primary endpoint, not as evidence about longer-term outcomes. The registry record does not report a longer follow-up result in this primary outcome entry. Likewise, the posted CAPS-5 means do not answer the trial's safety question; serious and other adverse event counts are reported separately and require their own interpretation.
9. Statistical Methods Explained
The primary outcome is continuous: CAPS-5 total severity is recorded as a score, and the result is expressed as change from baseline. The registry identifies the reported parameter as a least-squares mean and the accompanying uncertainty measure as a 95% confidence interval. The posted arm estimates are -23.69 (95% confidence interval -26.94 to -20.44) for MDMA-assisted psychotherapy and -14.78 (95% confidence interval -18.28 to -11.28) for placebo with psychotherapy.
What does a least-squares mean represent?
In general, a least-squares mean is a model-based estimate of an average, often called a marginal mean. Depending on the statistical model, it may account for selected variables or features of the analysis. The registry record does not report the model specification, covariates, or adjustment set used to obtain these estimates. It is therefore not possible to identify what, if anything, the posted means adjust for. They should be described using the registry's stated label rather than treated as confirmed raw arithmetic averages.
How should a confidence interval be read?
In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision for that estimate than a wider interval would, all else being equal. The intervals posted are attached to each arm's mean change. They do not give the uncertainty for the difference between the arms. A direct comparison needs its own estimate and uncertainty interval, which are not reported in this result entry.
The confidence intervals are also not ranges within which individual participants' changes are expected to fall. An average can be estimated with some precision even while individual responses vary. The registry entry does not give the participant-level distribution of changes or a measure of within-arm variation, so that variation cannot be characterized from the posted means and intervals alone.
Why does the randomized contrast matter?
In general, randomization supports a comparison between assigned groups by reducing the influence of systematic baseline differences on average, subject to the conduct and analysis of the trial. The principal comparative quantity is the difference in outcomes between groups, estimated according to a defined analysis. Separate within-group changes do not reveal that contrast with its uncertainty. Both groups received psychotherapy, and the placebo group also had a baseline-to-endpoint score change. The arm-specific results therefore need a direct between-arm analysis to quantify the relative change associated with assignment to the two trial conditions.
The record lists a continuous endpoint, a least-squares mean, and 95% confidence intervals, but no statistical analyses are listed. Details such as the exact model, handling of baseline score, variance assumptions, participant inclusion rules, and treatment of missing observations are not reported in the registry record. Without those details, the modeling choices and their implications cannot be independently evaluated from the registry entry.
What does the sample-size illustration mean?
General sample-size calculations estimate how many participants would be needed under specified assumptions to detect a target effect with a chosen power and significance level. Any planning illustrations accompanying the results are not observed trial outcomes and are not the trial's original design justification. The described illustration uses the observed effect as a reference, varies the fraction of that effect to detect, assumes equal allocation, uses a two-sided significance level of 0.05, and applies a normal approximation. Such assumptions are planning choices, not evidence that the trial had a particular probability of detecting an effect after it was conducted. They must not be described as observed power.
The registry record does not report the original sample-size justification or the assumptions used to plan the trial. The illustration cannot fill that gap. In general, planning estimates depend on assumptions about the target effect and statistical variability; changing those assumptions changes the estimated sample size. They do not establish the precision or validity of the result actually observed.
What can be inferred from the posted results?
The arm-specific confidence intervals quantify uncertainty about the reported means under the corresponding analysis. They do not provide a significance test of the treatment comparison. No p-value or direct contrast estimate is reported in the registry result entry. A reader should distinguish the descriptive movement in each group from a statistical estimate of the difference attributable to assignment. The absence of a reported contrast in this record is a reporting limitation, not evidence that the contrast was zero or that it was statistically significant.
The term “recalculated” can refer generally to simple unadjusted calculations from posted summary statistics, but no recalculated treatment contrast is needed to describe these results. The posted arm means and confidence intervals should remain clearly distinguished from any unadjusted calculation, and no new comparison value should be inferred by subtracting the arm means. The registry record does not flag a discrepancy between a sponsor analysis and a recalculation; the sponsor's own analysis would take precedence if a discrepancy were reported.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists one primary CAPS-5 change outcome and one secondary outcome: change in Adapted Sheehan Disability Scale total score. It also states that there are two outcome measures and zero analyses. The primary result entry provides arm-specific CAPS-5 estimates, but the registry record does not report a statistical test or direct estimate for the randomized contrast. It does not report a result for the secondary outcome in this entry.
When a study assesses multiple outcomes or conducts multiple statistical tests, multiplicity can increase the chance of a false-positive finding if results are interpreted without an appropriate strategy. In general, a prespecified hierarchy, adjustment procedure, or other analysis plan can clarify how multiple comparisons are handled. The registry record does not report whether an adjustment was used, whether outcomes were arranged in a testing hierarchy, or how the primary and secondary outcomes were intended to contribute to conclusions. The multiplicity approach is therefore not reported in the registry record.
The record does not describe how missing outcome values were handled, whether participants were analyzed according to randomized assignment, what analysis population was used, or whether sensitivity analyses were conducted. It also does not report the amount or pattern of missing CAPS-5 data. The distinction between overall enrollment of 121 and the outcome counts of 53 and 50 cannot be explained from this entry alone. No assumptions about exclusions, withdrawal, imputation, or follow-up completion should be inferred from those figures.
These omissions limit assessment of the statistical analysis, but they do not establish that a particular procedure was or was not used outside the registry record. The relevant analysis-population definitions, missing-data methods, and multiplicity handling are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| MDMA-assisted Therapy | 0 | 53 | 0.0% |
| Placebo With Therapy | 0 | 51 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| MDMA-assisted Therapy | 0 of 53 |
| Placebo With Therapy | 0 of 51 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| MDMA-assisted Therapy | 53 of 53 |
| Placebo With Therapy | 49 of 51 |
Most frequent non-serious adverse event terms
| Event term | Organ system | MDMA-assisted Therapy | Placebo With Therapy |
|---|---|---|---|
| Headache | Nervous system disorders | 38 of 53 | 31 of 51 |
| Muscle tightness | Musculoskeletal and connective tissue disorders | 31 of 53 | 13 of 51 |
| Suicidal ideation | Psychiatric disorders | 18 of 53 | 21 of 51 |
| Nausea | Gastrointestinal disorders | 24 of 53 | 11 of 51 |
| Insomnia | Psychiatric disorders | 19 of 53 | 15 of 51 |
| Anxiety | Psychiatric disorders | 15 of 53 | 12 of 51 |
| Decreased appetite | Metabolism and nutrition disorders | 19 of 53 | 5 of 51 |
| Fatigue | General disorders | 14 of 53 | 9 of 51 |
| Dizziness | Nervous system disorders | 15 of 53 | 8 of 51 |
| Hyperhidrosis | Skin and subcutaneous tissue disorders | 18 of 53 | 3 of 51 |
The serious adverse event entries report 0 events among 53 participants at risk in the MDMA-assisted therapy group and 0 among 51 participants at risk in the placebo-with-therapy group. Deaths are recorded as 0 in both groups. No serious adverse event terms are listed. These are the serious-event counts in the registry record; they do not establish that no other events occurred or that no safety concerns are possible.
The record also reports other adverse events for 53 of 53 participants in the MDMA-assisted therapy group and 49 of 51 participants in the placebo-with-therapy group. These are separate from the serious adverse event counts. The registry entry does not provide event descriptions in the serious-event term list, and the figures alone do not show the nature, timing, duration, severity, or number of events experienced by each participant. Nor do they quantify a causal difference between the randomized groups.
In general, adverse-event counts depend on the definitions and collection procedures used in a trial. The registry record does not provide further detail about those procedures. The counts should be read as reported observations within the listed groups, not as a complete assessment of comparative safety or as a prediction of risks outside the trial.
12. What the Result Does, and Does Not, Mean
The posted primary outcome shows a decline in mean CAPS-5 total severity score from baseline to the stated endpoint in both randomized arms. The MDMA-assisted psychotherapy arm has a least-squares mean change of -23.69, with a 95% confidence interval from -26.94 to -20.44. The placebo-with-psychotherapy arm has a least-squares mean change of -14.78, with a 95% confidence interval from -18.28 to -11.28. Given the scale's direction, negative changes indicate lower measured symptom severity at the endpoint than at baseline for the reported arm means.
Those estimates do not, on their own, show the comparative effect of assignment to MDMA-assisted psychotherapy versus placebo with psychotherapy. The registry record does not report the direct between-arm contrast or its confidence interval or p-value in this result entry. It would be inappropriate to treat the separate within-arm estimates as if they were a randomized comparison or to make a new numerical contrast from them.
The result is also specific to the CAPS-5 total severity score and the stated follow-up timeframe. It does not tell whether participants met diagnostic criteria at the endpoint, since the posted result is a continuous score change and no categorical result is given. It does not describe individual participant outcomes, longer-term symptom trajectories, or results for the secondary disability measure. Those results are not reported in the registry record.
The listed adverse event counts provide a separate record of observed events in the trial groups. They do not settle questions about the nature or comparative risk of events, and zero serious events in the listed groups does not imply zero risk in other settings. Overall, the registry information supports a careful description of the reported arm-specific score changes and event counts, while leaving key elements of comparative inference and analysis detail unavailable.
13. Why This Trial Matters Statistically
This trial is statistically notable for its randomized, placebo-controlled, parallel-group design and its use of a clinician-administered continuous symptom measure as the primary outcome. Random allocation and a concurrent comparison group are important design features for estimating differences between assigned treatment conditions. The inclusion of psychotherapy in both arms also means that the central comparison concerns the two trial regimens, not psychotherapy versus no psychotherapy.
The results illustrate why within-arm change and between-arm effect are different quantities. Both groups have negative mean CAPS-5 changes, but the principal randomized question requires a direct estimate of the difference between the groups and its uncertainty. The registry result entry reports only the arm-specific means and confidence intervals. Without a posted contrast, readers cannot judge the comparative estimate's precision or use a reported test to assess compatibility with a null difference.
The endpoint also provides a useful example of how a scale's direction affects interpretation: lower CAPS-5 scores represent lower symptom severity, so a negative change indicates a reduction in the arm mean. That is a statement about the reported score, not a claim about every participant, diagnostic status, or the clinical importance of a particular change.
Finally, the registry record makes clear that safety results, secondary outcomes, and analysis details require separate attention. The outcome entry and adverse-event counts answer different questions, while missing information about multiplicity, missing data, and the analysis population limits a complete statistical appraisal. These distinctions matter when translating a trial record into a precise account of what the reported numbers do and do not establish.
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 main limitation for interpreting the primary result is that the registry record gives arm-specific least-squares mean changes but does not report the direct comparison between randomized arms. It also does not provide a p-value or confidence interval for that contrast. As a result, the comparative estimate and its precision cannot be assessed from this outcome entry.
Important analysis details are not reported in the registry record. These include the statistical model and covariates, the analysis population, how missing observations were handled, and whether sensitivity analyses were conducted. Although the primary outcome entry lists 53 and 50 participants, the record does not explain how those counts relate to overall enrollment of 121 or describe the disposition of other participants for this analysis.
The entry lists a secondary disability outcome but does not report its result. It also does not describe the approach to multiplicity or provide a result for the categorical CAPS-5 diagnosis. The primary endpoint is limited to change in continuous total severity score from baseline to the recorded endpoint; this does not establish longer-term outcomes or individual-level response patterns.
The adverse-event record gives group counts but no serious-event terms, and it does not characterize event types, timing, or severity beyond the serious-event classification. The information therefore cannot serve as a complete comparative safety analysis. These limitations concern what is reported in the registry record and do not establish what may be available in other documents.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP2) — NCT04077437.
- Registry record last updated 2025-06-06; status last verified 2025-05.
- Results first posted 2023-10-11.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT04077437 is a completed randomized, double-blind, placebo-controlled, multisite phase 3 parallel-group study sponsored by Resilient Pharmaceuticals. It enrolled 121 participants and compares MDMA-assisted psychotherapy with placebo and psychotherapy for posttraumatic stress disorder of moderate or greater severity.
The primary endpoint is change in CAPS-5 total severity score from baseline to the stated endpoint at 18 weeks post baseline post enrollment confirmation. The registry reports least-squares mean changes of -23.69 (95% confidence interval -26.94 to -20.44; 53 participants) for MDMA-assisted psychotherapy and -14.78 (95% confidence interval -18.28 to -11.28; 50 participants) for placebo with psychotherapy. The record does not report a direct between-arm estimate in this result entry.
Change in Adapted Sheehan Disability Scale total score is listed as a secondary outcome. Serious adverse events and deaths are recorded as 0 in both groups. Further details about the analysis plan, missing data, analysis populations, multiplicity, and secondary-outcome results are not reported in the registry record.