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 The Qure Study: Q-fever Fatigue Syndrome - Response to Treatment (NCT01318356), a randomized phase 4 study. The primary outcome is Checklist Individual Strength (CIS).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01318356 |
| Phase | Phase 4 |
| Condition | Q Fever, Fatigue Syndrome, Chronic, Coxiella Infection |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 156 |
| Arms in the primary outcome | 3 |
| Lead sponsor | Radboud University Medical Center |
| Results posted | Yes |
2. Clinical Question
Population
The study concerns people with Q-fever Fatigue Syndrome (QFS), in the context of Q fever, chronic fatigue syndrome and Coxiella infection. The primary outcome is described as an intention-to-treat analysis. The registry does not give further eligibility details or a more specific description of the participants in the outcome record.
Intervention
The treatment strategies named in the record are cognitive behavioral therapy (CBT) and long-term doxycycline treatment. The arm descriptions do not provide further details about how either intervention was delivered, including treatment schedules or accompanying care.
Comparator
The reported comparison arms include placebo for the doxycycline strategy and CBT as a separate treatment arm. The registry does not describe the placebo or provide details about how the interventions were masked. It records the trial as double-masked.
Primary question
The primary question is whether the treatment strategies differ in fatigue severity at 24 weeks after treatment start, measured using the fatigue-severity subscale of the Checklist Individual Strength (CIS). Higher CIS scores indicate greater fatigue. The registry reports arm means and 95% confidence intervals, but does not post a formal analysis or pairwise treatment estimates.
The registry describes the objective as assessing two treatment strategies for fatigue and disabilities in QFS: long-term doxycycline or CBT. The posted results include a placebo arm as well as the CBT and doxycycline arms. The primary outcome record presents results for all three arms, which permits a descriptive reading of each reported mean and its uncertainty interval. It does not, by itself, establish the result of a randomized comparison between any two arms.
The clinically framed question is about fatigue severity at the specified follow-up, not every aspect of QFS or disability. Sickness Impact Profile total score and Symptom Checklist 90 are listed as secondary outcomes, but their results are not included in the posted outcome values. The registry record therefore offers a focused, incomplete account of the outcomes: the CIS means are reported, while detailed results for the other listed measures and formal comparisons are not.
3. Trial Design
The Qure Study is recorded as a Phase 4, randomized, double-masked, parallel-group trial sponsored by Radboud University Medical Center. The registry lists an enrollment of 156. It records a study start of 2011-04, primary completion of 2015-09 and status as completed. These registry fields describe the trial as registered; they do not establish when all analyses were conducted or whether the results were published elsewhere.
The interventions listed are cognitive behavioral therapy, doxycycline and placebo. The arm-level primary-outcome results are reported for Cognitive Behavioral Therapy, Doxycycline and Placebo. The trial’s brief summary frames its objective as assessing long-term doxycycline or CBT for fatigue and disabilities in QFS. The registry does not provide a detailed account of treatment delivery, allocation procedures, masking procedures, adherence, follow-up contacts or other care during the trial.
The primary outcome is the mean score on the CIS fatigue-severity subscale at 24 weeks after treatment start. The stated analysis population is intention-to-treat. The registry reports means and 95% confidence intervals for the three arms. It does not post a formal statistical analysis, pairwise treatment estimates or the model used to produce the reported estimates. Thus, the arm summaries can be described, but they do not answer all the inferential questions that a comparison of randomized groups might address.
Two secondary outcomes are named: Sickness Impact Profile (SIP) Total Score and Symptom Checklist 90 (SCL90). The registry record does not report their results. Nor does it report protocol details, the planned sample-size justification, interim analyses or a statistical analysis plan. These omissions limit how fully the design and the relationship between planned and reported analyses can be assessed from the registry record alone.
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: 156 patients signed informed consent and were randomized; of these, 155 started treatment, either doxycycline (n = 52), placebo (n = 52), or CBT (n = 51). One patient refused double-blind randomization after allocation to the medication group, and received no treatment.
Overall Study
| Stage | Cognitive Behavioral Therapy | Doxycycline | Placebo |
|---|---|---|---|
| STARTED | 51 | 52 | 52 |
| COMPLETED | 43 | 49 | 50 |
| NOT COMPLETED | 8 | 3 | 2 |
Analysis population for the primary outcome, as defined in the registry: Intention-to-treat analysis
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 | Cognitive Behavioral Therapy | Doxycycline | Placebo | Total |
|---|---|---|---|---|---|
| Participants analysed | 51 | 52 | 52 | 155 | |
| Age, Continuous | years | 43.3 (SD 13.7) | 43.6 (SD 10.2) | 44.6 (SD 12.3) | 43.8 (SD 12.1) |
| Sex: Female, Male: Female | Participants | 25 | 29 | 20 | 74 |
| Sex: Female, Male: Male | Participants | 26 | 23 | 32 | 81 |
| Race and Ethnicity Not Collected | Participants | — | — | — | 0 |
| Region of Enrollment: Netherlands | participants | 51 | 52 | 52 | 155 |
| Sickness Impact Profile 8 total score | scores on a scale | 1369.4 (SD 646.7) | 1304.9 (SD 537.7) | 1295.1 (SD 593.7) | 1322.8 (SD 591.1) |
| Checklist Individual Strength, subscale fatigue | scores on a scale | 49.7 (SD 4.7) | 51.4 (SD 4.7) | 50.2 (SD 4.8) | 50.36 (SD 4.9) |
| Symptom Checklist 90 total score | scores on a scale | 156.4 (SD 35.0) | 152.2 (SD 31.4) | 159.1 (SD 41.0) | 155.6 (SD 36.0) |
| Duration of symptoms | months | 40 (22 to 59) | 36 (24.25 to 57) | 37.50 (25.50 to 50.75) | 39 (24 to 54) |
6. Primary Endpoint
The registry lists the primary outcome as Checklist Individual Strength (CIS), measured over 24 weeks after start of treatment.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | score on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is fatigue severity measured using the fatigue-severity subscale of the Checklist Individual Strength questionnaire. The subscale contains 8 items, each using a 7-point Likert scale. Its stated score range is 8-56, and higher scores indicate a higher level of fatigue. The record identifies a cutoff score of 35 for classifying patients as severely fatigued. The reported outcome is the mean CIS score, with a 95% confidence interval, at 24 weeks after treatment start.
A continuous score can preserve gradations in fatigue severity rather than reducing the outcome to a category. A mean describes the average score in an arm, while the confidence interval communicates uncertainty around that estimate. The continuous outcome therefore offers a summary of fatigue severity across the stated analysis population, but it does not show the distribution of individual scores or how many participants crossed the severity cutoff.
The endpoint is relevant to the stated objective because the study focuses on fatigue in QFS. It is not a direct measure of every disability or symptom associated with the condition. SIP Total Score and SCL90 are listed as secondary outcomes, but their values are not reported in the registry record. The record does not explain the choice of the CIS subscale beyond identifying fatigue severity as the primary outcome.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted CIS means at 24 weeks are 31.6 for Cognitive Behavioral Therapy, 40.8 for Doxycycline and 37.8 for Placebo. Because higher scores indicate greater fatigue, the arm means describe different average fatigue-severity levels at that time point. The CBT arm’s reported mean is lower than the means in the other two arms; the doxycycline arm’s mean is higher than the placebo arm’s mean. These are descriptive statements about the reported summaries, not estimates of treatment effects from a formal comparison.
The 95% confidence intervals are 28.0 to 35.1 for CBT, 37.3 to 44.3 for doxycycline and 34.3 to 41.2 for placebo. A confidence interval expresses uncertainty about an estimated mean under the analysis used. It is not a range containing every participant’s score, and it does not by itself provide a test of the difference between treatment arms. The registry does not give confidence intervals for between-arm differences, p-values or adjusted estimates. Therefore, the arm means and their intervals should not be treated as a complete inferential comparison.
The cutoff of 35 gives context for interpreting the score scale, but the reported outcome is a mean. A group mean cannot show how many participants were classified as severely fatigued, nor can it reveal how many individuals improved, worsened or stayed the same. The registry does not post counts by cutoff category or participant-level changes from baseline. It also does not report baseline CIS values in the outcome record, so the reported follow-up means should not be described as changes from baseline.
The record identifies the primary analysis population as intention-to-treat, but does not describe how missing outcome data were handled or how many outcome observations contributed to each estimate. It reports arm sizes alongside the means, but those figures do not resolve whether every participant contributed an outcome. The registry record lists no posted analyses. Consequently, the available results support a descriptive reading of the arm summaries, while important inferential details remain unavailable.
There are no registry-posted results for the listed secondary outcomes. The CIS findings therefore cannot be taken as a complete account of the trial’s planned assessment of fatigue and disabilities. The trial status is completed, but completion does not fill gaps in the statistical reporting. Interpretation should stay with the outcome, follow-up and summary measures actually recorded, without inferring statistical significance, clinical importance or a definitive treatment effect.
9. Statistical Methods Explained
The registry reports a mean for a continuous outcome and a 95% confidence interval for each arm. A mean is a measure of the average score. It is useful for summarizing a continuous scale, but it conceals variation among individual participants: the same mean could arise from different patterns of scores. A confidence interval describes the precision of an estimate under the assumptions of the analysis. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. It does not show the full range of participant outcomes.
What does the 95% confidence interval convey?
In general, a 95% confidence interval is produced by a method intended to cover the underlying quantity in 95% of repeated samples when its assumptions hold. For this trial, the reported intervals surround arm means, not treatment differences. Comparing whether intervals overlap is not a substitute for a direct test or interval for the difference between arms. The registry does not report those direct comparison estimates, so the means and intervals should not be used to claim that a pairwise difference is statistically significant or not significant.
Why does the scale’s direction matter?
The record states that higher CIS scores indicate more fatigue. This direction gives meaning to the reported arm means: a lower mean represents a lower average fatigue-severity score, while a higher mean represents a higher average score. The scale ranges from 8-56, and the record identifies 35 as the cutoff for severe fatigue. These properties help interpret the score, but the cutoff does not transform the reported mean into a count of people above or below that threshold.
What can randomization and masking add?
In general, random allocation is intended to make treatment groups comparable at the point of assignment, on average, and can support a causal interpretation of a properly conducted comparison. Masking is intended to reduce certain influences on care, outcome assessment or reporting. The registry records this study as randomized and double-masked, but does not describe the procedures used to generate or conceal allocation or how masking was maintained. Those details are not reported in the registry record, so the design labels alone do not establish how these safeguards operated in practice.
How should the intention-to-treat label be read?
In general, an intention-to-treat analysis aims to analyze participants according to their randomized assignment, regardless of treatment received. This preserves the original randomized comparison when applied as planned. The registry names intention-to-treat as the analysis population for the primary outcome, but does not explain the handling of missing scores, treatment discontinuation, nonadherence or other deviations. The label therefore communicates the stated analysis population, not the detailed implementation of the analysis.
What can be said about the posted comparisons?
The registry supplies arm-level summaries rather than formal pairwise comparisons. The results record includes means, confidence intervals and arm sizes, but lists no posted analyses. The registry also indicates that values are missing or not estimable for a two-arm comparison of this continuous endpoint. No recalculated pairwise estimate is therefore available from the posted summary statistics. Without a treatment-difference estimate and its uncertainty, the arm means cannot quantify the size or precision of a randomized contrast.
How do the planning assumptions differ from trial results?
Any sample-size planning illustration based on the observed effect is a planning exercise, not an observed trial outcome and not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation, with the target effect set as a stated fraction of the observed effect. These assumptions do not describe the trial’s original design unless the registry says so; the planned sample-size justification is not reported in the registry record. Such an illustration cannot replace an analysis of the trial data, and its assumptions should not be mistaken for evidence that the trial had a particular level of power.
Over-dispersion is a general concern when outcome variability is greater than a model assumes: standard errors can then be too small and confidence intervals too narrow if the model does not account for the extra variability. That concept is not evidence that over-dispersion occurred in this trial. The registry does not report the model, distributional diagnostics or variance assumptions used to obtain the CIS summaries. Similarly, the record does not report adjustment for baseline scores or other covariates, so no such adjustment should be presumed.
Good statistical interpretation separates the measured outcome, the estimated arm summaries and the comparison of interest. Here, the score definition and arm means are reported, while key elements of formal inference are absent. General statistical principles explain what the summaries can convey, but they cannot supply missing analysis details or establish results that the registry does not report.
10. Multiplicity, Missing Data and Analysis Populations
The registry names the CIS fatigue-severity score as the primary outcome and lists SIP Total Score and SCL90 as secondary outcomes. Although the record indicates 3 outcome measures, it posts values only for the CIS outcome in the results. Results for the listed secondary outcomes are not reported in the registry record. No multiplicity adjustment or hierarchy among secondary outcomes is reported.
In general, testing multiple outcomes or comparisons can increase the chance of a false-positive finding if each is assessed separately without an appropriate plan. A prespecified outcome hierarchy or multiplicity adjustment can address that issue, but neither is described in the registry record. The absence of posted secondary results also means the reported CIS means cannot be interpreted as a complete summary of all outcome findings.
The primary outcome is labeled intention-to-treat, but missing-data procedures are not reported in the registry record. The reported arm sizes do not establish how many scores were available at the 24-week assessment, whether all randomized participants contributed to the means, or how missing scores were handled. The registry does not describe imputation, sensitivity analyses or reasons for missingness. These gaps limit assessment of potential bias from incomplete outcome data.
The registry lists no posted analyses. It does not report a statistical analysis plan, prespecified contrasts, adjustment for baseline scores or the model behind the confidence intervals. The protocol’s sample-size justification and interim analyses are also not reported in the registry record. Accordingly, it is not possible from this record to assess whether all analyses followed a prespecified plan or how multiplicity and missing data were addressed.
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 |
|---|---|---|---|
| Cognitive Behavioral Therapy | 0 | 50 | 0.0% |
| Doxycycline | 0 | 52 | 0.0% |
| Placebo | 2 | 52 | 3.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cognitive Behavioral Therapy | 0 of 50 |
| Doxycycline | 0 of 52 |
| Placebo | 0 of 52 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cognitive Behavioral Therapy | 42 of 50 |
| Doxycycline | 51 of 52 |
| Placebo | 45 of 52 |
Most frequent serious adverse event terms
| Event term | Organ system | Cognitive Behavioral Therapy | Doxycycline | Placebo |
|---|---|---|---|---|
| Urosepsis | Renal and urinary disorders | 0 of 50 | 0 of 52 | 1 of 52 |
| Cardiological symptoms | Cardiac disorders | 0 of 50 | 0 of 52 | 1 of 52 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cognitive Behavioral Therapy | Doxycycline | Placebo |
|---|---|---|---|---|
| Infection | Infections and infestations | 29 of 50 | 22 of 52 | 26 of 52 |
| Gastointestinal | Gastrointestinal disorders | 5 of 50 | 31 of 52 | 27 of 52 |
| Other | General disorders | 18 of 50 | 24 of 52 | 13 of 52 |
| Muskuloskeletal | Musculoskeletal and connective tissue disorders | 14 of 50 | 22 of 52 | 17 of 52 |
| Skin | Skin and subcutaneous tissue disorders | 5 of 50 | 20 of 52 | 10 of 52 |
| Neurological | Nervous system disorders | 6 of 50 | 13 of 52 | 10 of 52 |
| Laboratorial | Investigations | 0 of 50 | 14 of 52 | 7 of 52 |
| Bone and teeth | Musculoskeletal and connective tissue disorders | 1 of 50 | 3 of 52 | 2 of 52 |
| Allergic reaction | Immune system disorders | 0 of 50 | 0 of 52 | 0 of 52 |
Serious events with the highest arm-level rate: urosepsis (1.9%), cardiological symptoms (1.9%).
The registry reports serious adverse events for each arm. The count is 0 for Cognitive Behavioral Therapy, 0 for Doxycycline and 2 for Placebo; the record reports no deaths in any arm. These are counts as recorded in the registry, not estimates of comparative risk. The serious-event terms listed are Urosepsis at 1.9% and Cardiological symptoms at 1.9%. The record does not connect those listed terms to a specific treatment arm in the information.
In general, adverse-event counts need context, including the observation period, event definitions, severity criteria and completeness of reporting. The registry does not provide further details about these aspects in the posted safety record. A count of zero does not prove that no harm was possible; it means no serious adverse events are recorded for that arm in this registry entry. Conversely, the presence of recorded events does not establish that treatment caused them.
The record also reports other adverse events affecting 42 participants in the CBT arm, 51 in the doxycycline arm and 45 in the placebo arm. These figures are distinct from the serious-event counts and should not be treated as event totals unless the registry defines them that way. The registry does not provide event-level detail for these other adverse events in the information recorded. These safety summaries are descriptive and do not replace a comparative safety analysis.
12. What the Result Does, and Does Not, Mean
The registry record shows that the reported mean CIS fatigue-severity scores at 24 weeks differ across the CBT, doxycycline and placebo arms. The scores’ direction is clear: higher values mean greater fatigue. The accompanying 95% confidence intervals communicate uncertainty around each reported mean, but they are not intervals for differences between treatment groups. The available summaries therefore describe the arm-level outcome values without establishing the magnitude or statistical uncertainty of a randomized treatment contrast.
The record does not support claims about whether any treatment works or fails to work. It does not post pairwise estimates, p-values or a formal primary-outcome analysis. A comparison of arm means alone does not establish that any observed difference is attributable to treatment, and the registry’s stated design labels cannot substitute for the missing analysis details. The results also do not show individual change, the proportion meeting the severe-fatigue cutoff or the distribution of scores within each arm.
The primary outcome is one measure of fatigue severity at a particular follow-up. It is not a complete measure of disability, overall health or every symptom associated with QFS. The listed secondary outcomes, SIP Total Score and SCL90, have no reported results in the registry entry. The safety information is likewise limited to the recorded adverse-event counts and terms; it does not provide a full comparative assessment of harms.
These limitations do not make the posted results unusable. They define what can be said precisely: the registry reports arm means, confidence intervals and adverse-event summaries for a completed randomized trial. They also define what remains uncertain: the formal between-arm effects, the handling and extent of missing outcome data, the secondary-outcome findings and the detailed statistical methods. Conclusions beyond those posted results would require information not reported in the registry record.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of the difference between arm summaries and a treatment comparison. The registry provides means and confidence intervals for a continuous outcome in three arms. Those quantities make the observed scale values readable, but the main comparative question concerns differences between randomized groups. Without estimates and uncertainty intervals for those differences, the descriptive summaries do not complete the inferential task.
The outcome’s direction and scale also matter. Higher CIS scores indicate more fatigue, and the registry specifies the score range and a cutoff for severe fatigue. A mean is a compact summary, but it cannot show how participants are distributed around that cutoff or whether changes were concentrated in a subset. This is a general reason to distinguish a continuous group average from individual-level response or a threshold-based outcome.
The record also illustrates why an intention-to-treat label should be read alongside information about missing data. Naming the target population is useful, but the number of observations contributing to an endpoint and the handling of unavailable scores affect interpretation. Those details are not reported in the registry record. Similarly, naming secondary measures does not communicate their findings when results are absent, and the possibility of multiple outcomes makes a reported analysis plan relevant.
Finally, randomized and double-masked design labels describe important features of the trial, but statistical interpretation depends on knowing how the design was implemented and how outcomes were analyzed. The record leaves those details incomplete. The distinction between reported estimates, unreported methods and general statistical principles is therefore central to reading this trial without overstating what its registry results 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 registry entry has important limitations for interpreting the primary outcome. It reports arm means and 95% confidence intervals, but does not give pairwise treatment estimates, p-values or a formal analysis. It also lists values as missing or not estimable for a two-arm comparison of this continuous endpoint. As a result, the reported summaries do not quantify the primary randomized contrasts.
The record identifies an intention-to-treat analysis but does not report missing-data procedures, the number of outcome observations contributing to each estimate, reasons for missingness or sensitivity analyses. It does not report baseline CIS values or explain whether the displayed means were adjusted for baseline scores or other covariates. These omissions make it difficult to assess the analysis population and the precision of the estimates beyond the stated confidence intervals.
The registry names two secondary outcomes but does not report their results. It does not report a statistical analysis plan, the planned multiplicity strategy, a sample-size justification or interim analyses. Arm descriptions are blank, and the intervention details, allocation procedures and masking procedures are not described beyond the trial’s design labels. The registry record also does not provide detailed definitions or follow-up context for the adverse-event summaries.
Finally, the reported primary outcome is a mean score at 24 weeks. The registry does not provide individual trajectories, score distributions, changes from baseline or the number of participants above the severe-fatigue cutoff. These limits mean the entry supports a focused account of the posted summaries, not a full reconstruction of the trial conduct or analysis.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: The Qure Study: Q-fever Fatigue Syndrome - Response to Treatment — NCT01318356.
- Registry record last updated 2021-06-23; status last verified 2021-06.
- Results first posted 2021-06-23.
- 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.
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18. Record Summary
The Qure Study is recorded as a completed, randomized, double-masked, parallel-group Phase 4 trial sponsored by Radboud University Medical Center. The registry lists enrollment of 156 and records the study start as 2011-04 and primary completion as 2015-09. The interventions are CBT, doxycycline and placebo.
The primary outcome is the mean CIS fatigue-severity score at 24 weeks after treatment start, with higher scores indicating greater fatigue. The registry reports arm means and 95% confidence intervals for the CBT, doxycycline and placebo groups, and identifies the primary population as intention-to-treat. It lists SIP Total Score and SCL90 as secondary outcomes, but does not report their results.
The registry does not post formal analyses or pairwise treatment estimates, and it does not report detailed statistical methods, missing-data procedures or a statistical analysis plan. Safety results include serious adverse-event counts and no recorded deaths. The entry therefore provides descriptive outcome and safety summaries, with important comparative and methodological details not reported in the registry record.