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 Hydroxychloroquine, Carboplatin, Paclitaxel, and Bevacizumab in Recurrent Advanced Non-Small Cell Lung Cancer (NCT00728845), a non-randomized phase 1, phase 2 study. The primary outcome is Recommended Phase II Dose of Hydroxychloroquine and Carboplatin When Administered With Paclitaxel and Bevacizumab (Phase I).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00728845 |
| Phase | Phase 1, Phase 2 |
| Condition | Lung Cancer |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 8 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Medicine and Dentistry of New Jersey |
| Results posted | Yes |
2. Clinical Question
Population
Patients with recurrent advanced non-small cell lung cancer. The condition is listed as lung cancer, and the brief summary describes the intended population as patients with recurrent advanced disease.
Intervention
Hydroxychloroquine given with carboplatin and paclitaxel. Bevacizumab was included for patients eligible to receive it; the registry also describes a cohort for patients ineligible for bevacizumab.
Comparator
There was no randomized control group. The registry lists separate treatment cohorts according to bevacizumab eligibility, so they are not a like-for-like comparison.
Primary question
The phase I objective was to identify the recommended phase II dose of hydroxychloroquine and carboplatin when administered with paclitaxel and bevacizumab. The registry says early termination left insufficient data to assess this endpoint.
The study asked whether hydroxychloroquine could be combined with a chemotherapy regimen, with bevacizumab included for eligible patients, and what dose would be recommended for later study. Its stated purpose also included assessing side effects and how well the medicines worked in recurrent advanced non-small cell lung cancer. These are distinct questions: dose selection concerns whether a regimen can be taken forward at a specified dose, while measures of tumor progression and survival address disease outcomes.
The registry describes two cohorts rather than a randomized comparison. Cohort 1 included bevacizumab-eligible patients, and Cohort 2 included patients ineligible for bevacizumab. Both cohorts were assigned hydroxychloroquine, carboplatin, and paclitaxel; bevacizumab was added in Cohort 1. Because eligibility determined cohort membership, differences between the cohorts could reflect patient characteristics or eligibility as well as treatment. The record does not support interpreting them as an estimate of the effect of adding bevacizumab.
The primary question cannot be answered from the posted endpoint result: the registry explicitly reports that the study was terminated early and that insufficient data were collected to assess the recommended-dose outcome. The record therefore describes the intended clinical and dose-finding questions, but does not establish a recommended dose or provide a reported estimate of treatment benefit.
3. Trial Design
This was a phase I/II, non-randomized, unmasked, parallel study. The registry reports enrollment of 8 participants and status as terminated. The listed start date is 2008-06-16, and the primary completion date is 2010-12-21. These record dates describe the study timeline; they do not imply that the planned outcome assessments were completed.
The treatment assignment was organized into cohorts based on bevacizumab eligibility. Cohort 1 was for bevacizumab-eligible patients and included hydroxychloroquine, carboplatin, paclitaxel, and bevacizumab. Cohort 2 was for bevacizumab-ineligible patients and included hydroxychloroquine, carboplatin, and paclitaxel without bevacizumab. The descriptions specify treatment on Day 1 and cycles every 3 weeks for 4-6 cycles. For Cohort 1, the listed regimen includes paclitaxel 200mg/m2 IV over 3 hours, carboplatin AUC= 6 IV over 15-30 min, bevacizumab 15 mg/kg IV over 90 min, and hydroxychloroquine 200 mg PO BID. For Cohort 2, the listed regimen includes paclitaxel 200mg/m2 IV over 3 hours, carboplatin AUC= 6 IV over 15-30 min, and hydroxychloroquine 200 mg PO BID.
The phase I primary outcome was the recommended phase II dose of hydroxychloroquine and carboplatin when administered with paclitaxel and bevacizumab. The stated timeframe was follow-up for the duration of phase I treatment, an average of 18 weeks. However, the primary outcome population field says the study was terminated early and insufficient data were collected to assess the outcome.
Phase II outcomes listed in the record were time to progression, progression-free survival at 1 year, and overall survival. The registry lists 5 outcome measures in total, but no analyses are listed. The statistical plan, including any dose-escalation rules, assignment procedures beyond the eligibility-based cohorts, or analysis methods, is not reported in the registry record. The study’s non-randomized structure limits causal comparisons between the 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
| Stage | Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | Hydroxychloroquine, Carboplatin, Paclitaxel |
|---|---|---|
| STARTED | 8 | 0 |
| COMPLETED | 8 | 0 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Study was terminated early and insufficient data were collected to assess this outcome measure.
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 | Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | Hydroxychloroquine, Carboplatin, Paclitaxel | Total |
|---|---|---|---|---|
| Participants analysed | 8 | 0 | 8 | |
| Age, Categorical: <=18 years | Participants | 0 | — | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 4 | — | 4 |
| Age, Categorical: >=65 years | Participants | 4 | — | 4 |
| Age, Continuous | years | 63.3 (SD 8.4) | — | 63.3 (SD 8.4) |
| Sex: Female, Male: Female | Participants | 3 | — | 3 |
| Sex: Female, Male: Male | Participants | 5 | — | 5 |
| Region of Enrollment: United States | participants | 8 | — | 8 |
6. Primary Endpoint
The registry lists the primary outcome as Recommended Phase II Dose of Hydroxychloroquine and Carboplatin When Administered With Paclitaxel and Bevacizumab (Phase I), measured over Followed for the duration of the phase 1 treatment, an average of 18 weeks.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the recommended phase II dose of hydroxychloroquine and carboplatin when administered with paclitaxel and bevacizumab. This is a dose-selection endpoint, not a direct measure of tumor response, progression, or survival. In general, early-phase dose-finding studies use tolerability and safety information to decide what dose merits further study. A recommended dose is therefore a decision informed by observed treatment experience; it is not, by itself, evidence that a regimen improves a clinical outcome.
The registry gives a phase I treatment-duration timeframe, described as an average of 18 weeks. It does not report the criteria used to select a recommended dose, the dose levels evaluated, rules for increasing or reducing doses, or the specific toxicity thresholds used for dose decisions. Those methods are not reported in the registry record, so the intended endpoint can be identified but its operational definition cannot be reconstructed from this record.
Most importantly, the registry states that the study was terminated early and insufficient data were collected to assess this outcome measure. No recommended dose or endpoint estimate is reported. The listed primary endpoint should therefore be understood as the question the study planned to answer, not as an achieved dose recommendation. The record also lists phase II outcomes related to disease progression and survival, but those do not replace the missing phase I dose result.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The clearest result in the registry is a limitation on what can be concluded: the trial ended early, and the primary dose-finding endpoint was not assessable because insufficient data were collected. The registry does not report a recommended phase II dose. This is not a result showing that a dose was unsuitable, nor does it identify a dose as suitable; the endpoint was not established in the record.
The study enrolled 8 participants, while the adverse-event record lists 8 participants at risk in the bevacizumab-containing cohort and 0 at risk in the cohort without bevacizumab. The record does not explain why the second cohort has zero participants at risk, so that entry should not be treated as evidence about the safety or efficacy of its regimen. Nor should the overall enrollment count be interpreted as a complete analysis population for each endpoint without further information about participant disposition and evaluability.
The registry lists 5 outcome measures and identifies time to progression, progression-free survival at 1 year, and overall survival as phase II outcomes. It lists no analyses. No numerical estimates for these clinical outcomes are reported in the registry record, so treatment effects, event timing, and precision cannot be assessed from the posted results. The absence of an analysis is not equivalent to a finding of no effect.
The cohorts were formed by bevacizumab eligibility and treatment assignment was non-randomized. Consequently, a simple comparison between the bevacizumab-containing and bevacizumab-free cohorts would not isolate the effect of bevacizumab. Eligibility itself may be associated with differences between participants, and the record does not provide information that would allow those differences to be addressed. The registry identifies the arms as unsuitable for a like-for-like control comparison.
The safety entries are also limited. In the bevacizumab-containing cohort, 2 participants are listed as having serious adverse events, and 8 are listed as having other adverse events. Two serious-event terms are listed at 12.5% each. These are registry summaries, not comparative safety estimates. The absence of participants at risk in the other cohort makes a between-cohort safety comparison especially uninformative. The record does not report deaths for either group.
In general, an estimate is more informative when its uncertainty and the number of observations contributing to it are available. Here, there is no reported primary endpoint estimate or associated confidence interval, and the registry lists no analysis results. The appropriate interpretation is therefore descriptive: the trial intended to study dose selection and later clinical outcomes, but the posted record does not establish those outcomes. It supports neither a positive nor a negative conclusion about treatment effectiveness.
9. Statistical Methods Explained
Clinical trial methods should be read in light of the question they are designed to answer. This study combined an early-phase dose question with planned later-phase clinical outcome questions. The phase I primary endpoint concerned a recommended dose; the listed phase II endpoints concerned time to progression, progression-free survival at 1 year, and overall survival. These outcomes require different definitions and analyses. The registry lists the outcomes but does not provide results or analysis descriptions for them.
What does non-randomized allocation mean?
In a randomized trial, chance determines treatment assignment according to a defined randomization procedure. Randomization can help make groups comparable, on average, with respect to measured and unmeasured baseline characteristics. This record describes allocation as non-randomized. It also describes cohorts determined by bevacizumab eligibility. The record does not report a random allocation procedure, and the cohorts should not be treated as randomized treatment groups.
This distinction matters because a difference between cohorts could have several explanations. It could be related to treatment, eligibility, participant characteristics, or other factors. The registry does not provide a design or analysis that separates those explanations. In particular, the cohort receiving bevacizumab and the cohort not receiving it are not a like-for-like control comparison. Describing their listed treatments does not establish the effect of adding or omitting bevacizumab.
What does a dose-finding endpoint represent?
A recommended dose is a dose selected for further evaluation using the evidence gathered during early-phase treatment. In general, dose-finding work considers whether treatment can be delivered and what adverse effects occur, together with prespecified decision rules. The record identifies the recommended phase II dose as the primary endpoint, but it does not report the dose-selection algorithm, dose levels, dose-limiting toxicity definition, or decision thresholds. It is therefore not possible to reproduce or evaluate the dose-selection process from the registry record.
The endpoint is not a direct efficacy measure. A dose recommendation does not show whether a treatment improves survival or delays progression. Conversely, a planned progression or survival outcome cannot stand in for a missing dose recommendation. The registry lists both types of questions, but says that early termination left insufficient data to assess the primary dose endpoint and lists no analyses for the outcomes.
How should precision be understood?
In general, a confidence interval describes a range of values compatible with the observed data under a statistical model and procedure. A narrow interval indicates greater precision than a wide interval, while a wide interval leaves more uncertainty about the underlying quantity. No confidence interval for the primary endpoint or phase II outcomes is reported in the registry record. Without an estimate and its uncertainty, the magnitude and precision of any treatment effect cannot be assessed.
The enrollment count alone does not provide the information needed to calculate precision. For time-to-event outcomes, the number and timing of events, follow-up, censoring, and analysis population matter. The registry lists time to progression, progression-free survival at 1 year, and overall survival, but does not report their estimates, event counts, or analysis details. The statistical analysis plan and handling of censoring are not reported in the registry record.
What do planning illustrations mean?
In general, sample-size planning illustrations describe how many participants or events a hypothetical future study might require under stated assumptions. Such illustrations depend on assumptions about the effect to detect, statistical significance level, allocation, and analysis approach. They are planning scenarios, not observations from the trial and not evidence that the trial had a particular probability of finding a result. A sample-size illustration based on an observed effect should not be interpreted as observed power.
The registry record does not report the trial’s own sample-size justification or statistical design assumptions. It also does not report a calculated treatment effect on which to base a trial-specific interpretation of planning scenarios. Any planning values should therefore be read as illustrations under their stated assumptions, not as a reconstruction of the study’s original design or an estimate of the certainty of its findings.
Why do safety counts need context?
Adverse-event counts describe events recorded for participants within the stated group and observation framework. A serious adverse event is a distinct category from other adverse events; the entries should not be combined or treated as interchangeable. Counts depend on who was included, how events were defined and collected, and the period during which participants were observed. The registry provides group counts but does not describe those collection and analysis details.
In general, a count in a small or incomplete cohort can be unstable and may not represent the frequency expected in a broader population. A percentage listed for an event term is a descriptive registry value, not a comparison of treatment risks. Comparisons also require groups with appropriate membership and follow-up. Here, one cohort has no participants listed at risk, and cohort allocation was non-randomized, so the record does not support a comparative safety analysis.
The main methodological conclusion is that the registry identifies the intended design and outcomes but does not report enough analysis information to estimate dose, efficacy, or comparative safety. The planned phase I/II structure should not be mistaken for a completed analysis of both phases.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists multiple outcomes: the phase I recommended-dose endpoint and phase II outcomes for time to progression, progression-free survival at 1 year, and overall survival. When a study evaluates multiple outcomes or makes repeated statistical tests, multiplicity can increase the chance of a chance finding. General approaches include specifying a primary outcome in advance, setting a testing hierarchy, or adjusting the interpretation of multiple tests. The statistical plan for multiplicity, if any, is not reported in the registry record.
The primary outcome is identified, but its assessment was not completed: the registry says the study was terminated early and insufficient data were collected. The record lists no analyses, and it does not provide results for the phase II outcomes. Consequently, there are no reported outcome estimates on which to assess multiplicity adjustments, confidence intervals, or the consistency of findings across endpoints.
The record does not report how missing observations, incomplete follow-up, withdrawals, or participants who did not complete treatment were handled. It also does not describe analysis populations, such as whether analyses were based on enrollment, treatment received, or endpoint evaluability. Those details are important because missingness and exclusions can affect both the estimated outcome and its interpretation. The available information does not support assumptions about why data are absent or how they were handled.
In general, early termination can leave planned analyses under-informative, but the reason for termination and any interim monitoring procedures are not reported in the registry record. It is not possible to infer that a formal interim efficacy analysis occurred or that stopping followed a prespecified statistical boundary. The registry’s statement of insufficient data should be read as a report that the primary endpoint could not be assessed, not as a statistical finding for or against treatment.
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 |
|---|---|---|---|
| Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | 2 | 8 | 25.0% |
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 |
|---|---|
| Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | 8 of 8 |
| Hydroxychloroquine, Carboplatin, Paclitaxel | 0 of 0 |
Most frequent serious adverse event terms
| Event term | Organ system | Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | Hydroxychloroquine, Carboplatin, Paclitaxel |
|---|---|---|---|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e | Infections and infestations | 1 of 8 | 0 of 0 |
| Dyspnea (shortness of breath) | Respiratory, thoracic and mediastinal disorders | 1 of 8 | 0 of 0 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab | Hydroxychloroquine, Carboplatin, Paclitaxel |
|---|---|---|---|
| Leukocytes (total WBC) | Blood and lymphatic system disorders | 7 of 8 | 0 of 0 |
| Neuropathy: sensory | Nervous system disorders | 7 of 8 | 0 of 0 |
| Neutrophils/granulocytes (ANC/AGC) | Blood and lymphatic system disorders | 6 of 8 | 0 of 0 |
| Fatigue (asthenia, lethargy, malaise) | General disorders | 6 of 8 | 0 of 0 |
| Hemoglobin | Blood and lymphatic system disorders | 5 of 8 | 0 of 0 |
| Hair loss/alopecia (scalp or body) | Skin and subcutaneous tissue disorders | 5 of 8 | 0 of 0 |
| Weight loss | General disorders | 5 of 8 | 0 of 0 |
| Hypertension | Cardiac disorders | 5 of 8 | 0 of 0 |
| Platelets | Blood and lymphatic system disorders | 4 of 8 | 0 of 0 |
| Constipation | Gastrointestinal disorders | 4 of 8 | 0 of 0 |
Serious events with the highest arm-level rate: infection (documented clinically or microbiologically) with grade 3 or 4 neutrophils (anc <1.0 x 10e (12.5%), dyspnea (shortness of breath) (12.5%).
The serious adverse-event record lists the bevacizumab-containing cohort with 8 participants at risk and 2 affected. The cohort without bevacizumab is listed with 0 participants at risk and 0 affected. The registry also lists 8 participants at risk and 8 affected for other adverse events in the bevacizumab-containing cohort, with 0 at risk and 0 affected in the other cohort. The record does not report deaths for either cohort.
Two serious-event terms are listed, each at 12.5%: infection documented clinically or microbiologically with Grade 3 or 4 neutrophils (ANC <1.0 x 10e, and dyspnea (shortness of breath). The first registry term is incomplete as displayed, so its wording should not be extended beyond the recorded description.
These entries are descriptive counts, not evidence of comparative risk. The zero at-risk entry for the second cohort means the record offers no observed safety denominator for that group; it does not establish that the regimen had no adverse events. The registry does not report event ascertainment details, exposure duration by participant, or a comparative safety analysis. The listed event percentages should be read as registry summaries rather than as estimates that can be generalized beyond the recorded cohort.
12. What the Result Does, and Does Not, Mean
The result that can be stated directly is that the registry reports early termination and insufficient data to assess the primary recommended-dose endpoint. It does not report a recommended phase II dose. The record also lists phase II outcomes, but no analyses are listed, and no numerical results for time to progression, progression-free survival at 1 year, or overall survival are reported.
This does not demonstrate that the regimen was ineffective, and it does not demonstrate that the regimen was effective. Without an assessable endpoint estimate and an analysis of the planned clinical outcomes, the record cannot establish the magnitude or direction of a treatment effect. A missing result is not equivalent to a null result. Similarly, no comparative conclusion can be drawn from the safety entries.
The trial’s non-randomized, eligibility-based cohorts also constrain interpretation. The cohort receiving bevacizumab and the cohort not receiving bevacizumab were formed according to eligibility, rather than random assignment. Any apparent differences would therefore not isolate the contribution of bevacizumab. The registry itself identifies the arms as not being a like-for-like control comparison.
The adverse-event counts document events in the listed bevacizumab-containing cohort, but do not establish comparative safety. The other cohort has no participants listed at risk, and the registry does not provide a full account of safety observation or analysis methods. Event terms and percentages should be read as descriptive record entries, not as proof of a treatment effect or a population-level risk.
In general, interpretation of a clinical trial requires alignment between the question, the endpoint, the analysis population, and the uncertainty around the estimate. The registry identifies the study’s intended questions and some observed safety counts, but does not supply the primary endpoint result or phase II analyses. The most defensible conclusion is therefore about the limits of the available evidence: the planned dose and clinical outcome questions remain unanswered in the registry record.
13. Why This Trial Matters Statistically
This trial matters statistically because it illustrates the difference between a planned endpoint and an assessable result. A registry can identify a primary dose-selection question and planned phase II outcomes while still documenting that the primary endpoint could not be evaluated. Reading the study as a completed efficacy test would go beyond what the record reports.
It also shows why treatment cohorts should not automatically be treated as comparison groups. The cohorts differed by bevacizumab eligibility, and allocation was non-randomized. Statistical comparisons between them would mix treatment differences with possible differences related to eligibility and participant characteristics. Without a randomized design or a reported adjustment strategy, the effect of bevacizumab cannot be separated from those factors.
The safety summary provides another useful interpretive lesson: counts need denominators and context. One cohort has participants listed at risk, while the other has none. Those entries do not support a meaningful comparison of event frequency. Likewise, a listed percentage for a serious-event term is descriptive; it does not by itself quantify a treatment effect or its uncertainty.
Finally, the absence of analyses is not a statistical finding. It means that the registry record does not present estimates for the planned phase II outcomes or an assessable primary dose result. Distinguishing unavailable evidence from evidence of no effect is essential when reading early-phase trials that end before planned assessments can be completed. The record is useful for documenting the study’s design, intended questions, and limited safety summaries, while also making clear that its main statistical questions remain unresolved.
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 is explicit in the registry record: the study was terminated early, and insufficient data were collected to assess the primary endpoint. No recommended phase II dose is reported. The registry also lists no analyses, and does not report results for the planned phase II outcomes. This prevents assessment of the intended dose and clinical outcome questions.
Enrollment was 8, but the record does not give participant disposition by cohort or explain the zero at-risk entry for the cohort without bevacizumab. The adverse-event summary therefore cannot be assumed to represent complete or comparable exposure in both cohorts. The record does not report the analysis populations, follow-up completeness, missing-data handling, or reasons for early termination.
The non-randomized design and eligibility-based cohort assignment limit between-cohort interpretation. The registry does not report methods to adjust for differences between eligible and ineligible participants. It also does not provide a statistical analysis plan, dose-escalation rules, dose-limiting toxicity definition, multiplicity approach, or interim analysis procedures. These aspects are not reported in the registry record and should not be inferred from the phase labels or endpoint names.
Although adverse-event counts and serious-event terms are listed, definitions, ascertainment procedures, exposure-adjusted analyses, and event-level details are not reported. The record does not report deaths. The available safety summary therefore supports only a limited description of the recorded entries, not a broad or comparative safety conclusion.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Hydroxychloroquine, Carboplatin, Paclitaxel, and Bevacizumab in Recurrent Advanced Non-Small Cell Lung Cancer — NCT00728845.
- Registry record last updated 2017-05-23; status last verified 2017-04.
- Results first posted 2013-11-25.
- 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
NCT00728845 was a non-randomized, unmasked, parallel phase I/II study of hydroxychloroquine with carboplatin and paclitaxel, with bevacizumab for eligible participants with recurrent advanced non-small cell lung cancer. The registry reports enrollment of 8 and status as terminated.
The primary phase I endpoint was the recommended phase II dose of hydroxychloroquine and carboplatin with paclitaxel and bevacizumab. The registry states that early termination left insufficient data to assess this endpoint. Phase II outcomes listed were time to progression, progression-free survival at 1 year, and overall survival; no analyses are listed.
The adverse-event record lists participants and events for the bevacizumab-containing cohort, while the other cohort has 0 participants at risk. The cohorts were based on bevacizumab eligibility and are not a like-for-like control comparison. The registry record documents the intended study questions but does not establish a dose recommendation, clinical outcome effect, or comparative safety result.