One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study (NCT00580788), a non-randomized early/phase 1 study. The primary outcome is Dose Limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

This was an early-phase 1, non-randomized, single-group study of PTHrP (1-36). The registry describes the study as a dose-escalation investigation and gives four infusion levels: 2, 4, 5, and 6 picomoles/kg/hr, each administered for one week. Enrollment was 14. Although several dose levels are listed, the study is not a randomized comparison, and no concurrent control group is described. Differences between dose groups therefore cannot be read as if treatment allocation had created comparable groups.

The registry identifies masking as single, but does not report who was masked or how masking was implemented. The record also does not describe the sequence of dose cohorts, rules for moving between levels, stopping criteria, or whether dose assignment depended on earlier participants' outcomes. These details should not be inferred from the dose-escalation label alone.

The study started in 2008-01, had a primary completion date of 2009-12, and is listed as completed. The study summary describes healthy human volunteers and says the investigators intended to assess whether PTHrP altered bone formation, as well as its direct influence on bone-turnover markers and plasma 1,25 (OH)2 vitamin D regulation. The registry lists 1,25 Vitamin D, 24 Hour Urine Calcium, Tubular Maximum of Phosphorous (TmP/GFR), sNTX, sCTX, P1NP, BSAP, and Parathyroid Hormone (1-84) among the secondary outcomes. It lists 13 outcome measures and 16 analyses. The record does not report the detailed statistical plan, analysis populations, or results for those measures.

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:

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.

6. Primary Endpoint

The registry lists the primary outcome as Dose Limiting Toxicity (DLT), measured over 12 hours after the infusion was started then q 8 hours for 7 days.

The primary endpoint was dose-limiting toxicity (DLT), measured as a count of participants meeting the protocol definition. The registry says assessments began 12 hours after the infusion was started and then occurred q 8 hours for 7 days. A DLT required one major criterion or two minor criteria, each rated at ≥ 2 on a scale of 0-5.

The major criteria were symptomatic orthostatic hypotension, defined as a systolic BP fall >30 mm/hg; tachycardia, defined as pulse > 120; hypertension, defined as systolic BP >160 mm/hg on 2 occasions; hypercalcemia, defined as serum calcium ≥ 12 mg/dl; and hypophosphatemia, defined as serum phosphorous < 1.5 mg/dl. Minor criteria included symptoms such as flushing, nausea, abdominal or muscle cramps, dizziness, lightheadedness, and palpitations.

In general, a dose-limiting toxicity endpoint is used in early-phase dose escalation to capture unacceptable toxicity during treatment and inform assessment of dose tolerability. Here, the defined threshold combines clinical symptoms, vital signs, and laboratory findings. The registry record does not report how many participants met the DLT definition at any dose, so the endpoint's observed values and the resulting dose assessment are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary participant-level outcome: each participant either meets the defined DLT threshold or does not. The registry describes the endpoint unit as participants and the measure as a number. In general, a binary endpoint reduces a complex clinical observation to whether a prespecified event definition was reached. That can make event counting clear, but interpretation still depends on the event definition, observation period, and completeness of monitoring.

For this study, the event definition combines major and minor criteria. One major criterion is sufficient, while two minor criteria are required; criteria must be rated at ≥ 2 on a scale of 0-5. The major criteria span blood pressure, pulse, calcium, and phosphorous, while the minor criteria include symptoms. This composite approach treats several different manifestations as part of the same endpoint. In general, composite endpoints should be interpreted with attention to which components contribute to events, since components can differ in clinical meaning and frequency. The registry record does not report component-level DLT counts.

The stated monitoring schedule began 12 hours after infusion started and continued q 8 hours for 7 days. Repeated observation matters because an event could occur at different points during an infusion. In general, a participant-level count of whether any DLT occurred during a monitoring window does not describe when it arose, how long it persisted, or whether multiple criteria occurred together. Those details are not reported in the registry record. Nor does the record report how assessments were handled if a scheduled observation was missed.

Because the outcome is a count of participants with an event, a natural descriptive summary would be the number meeting DLT criteria at each dose level and the corresponding number assessed. The registry record does not report those primary outcome counts. It consequently does not support a dose-specific event-rate estimate or an uncertainty interval for DLT. In general, intervals around event rates help convey the imprecision that can arise when few participants are observed; they do not remove the limitations of a non-randomized design.

Allocation is listed as non-randomized and the model as single-group. In general, random allocation helps balance measured and unmeasured participant characteristics across comparison groups, while non-randomized allocation may leave group differences that influence outcomes. Here, no concurrent control is described, so the dose groups should not be treated as a randomized treatment-versus-control contrast. The dose-escalation sequence and rules are not reported in the registry record, and the adverse-event group labels are not explicitly linked to dose names.

The record lists a single masking arrangement, but does not specify who was masked, which procedures were masked, or how masking was maintained. In general, masking can reduce the influence of expectations on assessments or reporting, but its protection depends on what was masked and whether the masking was successful. The registry record does not provide enough detail to evaluate those points.

The registry describes 13 outcome measures and 16 analyses, including the primary DLT endpoint and secondary measures related to vitamin D regulation, urine calcium, phosphate handling, bone turnover, and parathyroid hormone. In general, evaluating multiple outcomes creates a multiplicity issue: if many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for that. The record does not report whether any adjustment was planned or used, which outcomes were designated for formal inference, or how repeated measurements were modeled.

The record also includes sample-size assumptions for planning illustrations: two-sided significance level 0.05, equal allocation between two arms, normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. Such illustrations are planning calculations, not observed power. They do not establish that the study had adequate power, and equal allocation between two arms does not describe the reported single-group, non-randomized design. The registry record does not report a sample-size justification for the trial itself or the values needed to assess the planning illustrations. The sample-size assumptions should therefore be kept separate from the trial's actual enrollment and results.

Finally, analysis methods depend on which participants and observations are included. In general, an analysis population may be defined by enrollment, treatment received, completion of monitoring, or availability of outcome measurements; different definitions can yield different summaries. The registry record does not report the analysis population, missing-data approach, or handling of participants who might not complete the infusion or assessments. These are important details for interpreting any endpoint estimate, but cannot be reconstructed from the record.

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("Group 1", "Group 2", "Group 3", "Group 4")
n      <- c(3, 6, 3, 2)
events <- c(0, 0, 2, 2)
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  Group 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Group 2  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Group 3  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2
ARM  Group 4  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 16 analyses. The primary endpoint is DLT; listed secondary outcomes include 1,25 Vitamin D, 24 Hour Urine Calcium, TmP/GFR, sNTX, sCTX, P1NP, BSAP, and Parathyroid Hormone (1-84). The record does not state which secondary outcomes were formal confirmatory targets, how the analyses correspond to the outcome measures, or whether a multiplicity adjustment was planned or used.

In general, multiplicity arises when several outcomes, time points, groups, or hypotheses are examined. Without a prespecified strategy, isolated findings across many analyses can be difficult to distinguish from chance patterns. The registry record does not report an approach to controlling multiplicity or prioritizing results. This limits interpretation of any secondary analyses, even if individual values are available elsewhere.

The record does not report a missing-data method, the number of participants with evaluable data for each outcome, or the analysis populations. It also does not describe how missed monitoring assessments or incomplete infusions were handled. In general, missing observations can affect both the number of participants included and the interpretation of an event count, particularly when missingness is related to tolerability or outcome status. No particular missing-data mechanism can be assumed from the registry record.

The primary endpoint results themselves are not reported in the registry record. Thus, no primary analysis estimate, missingness assessment, or multiplicity context can be evaluated from the posted record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event entries report zero participants with serious adverse events in each group. The numbers listed at risk for serious events are 3 in Group 1, 6 in Group 2, 3 in Group 3, and 2 in Group 4. For other adverse events, the entries list zero affected participants in Group 1, zero in Group 2, one in Group 3, and two in Group 4; the corresponding numbers at risk are 3, 6, 3, and 2. The registry record does not report deaths in these entries.

These are group-level counts, not a comparison against a control treatment. The study is non-randomized, and the registry does not identify which dose corresponds to each group label in the adverse-event record. The absence of reported serious events in these entries does not establish that no other safety outcomes occurred, nor does it answer the primary DLT endpoint question. The record does not report the primary DLT counts or explain the relationship between DLT and the adverse-event categories. Small group counts also mean that the entries alone provide limited information about how frequently events might occur beyond the observed participants.

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

The registry record establishes that this was an early-phase, non-randomized dose-escalation study of a one-week continuous intravenous PTHrP infusion, with four dose levels listed and enrollment of 14. It defines a DLT using clinical signs, symptoms, and laboratory thresholds, and describes frequent monitoring during the infusion period. Those design details clarify what the investigators intended to assess.

The primary endpoint results are not reported in the registry record. No DLT count by dose, estimated maximum safe dose, or uncertainty interval is available in the record. Therefore, the posted information does not show whether a dose met the investigators' safety objective or whether the endpoint varied across dose levels. The adverse-event counts are not a replacement for the DLT results because the registry presents them separately and does not explain their correspondence.

The adverse-event entries report no serious adverse events among participants listed at risk, alongside other-event counts that differ across the four group labels. These observations describe the recorded participants only. They should not be interpreted as proof that serious events cannot occur, or as a definitive comparison of the dose levels. No concurrent control is described, and group assignment was not randomized.

The study summary describes intended assessment of bone formation, bone-turnover markers, and vitamin D regulation, and the registry lists secondary outcomes in these areas. However, their results are not reported in the registry record. The available information therefore cannot establish a biological effect of PTHrP on these measures, nor can it support conclusions about clinical benefit. Overall, the record is informative about the planned question, endpoint definition, and recorded adverse-event counts, but does not contain the primary outcome results needed to answer the main dose-escalation question.

14. Why This Trial Matters Statistically

This trial illustrates a central statistical challenge in early-phase dose escalation: the main question concerns safety at particular exposure levels, while the number of participants available at each level is limited. The registry lists enrollment of 14 across four described infusion levels. Such a design is primarily structured around dose assessment, rather than a randomized comparison of treatment with a control. The distinction matters because dose-group patterns do not have the same interpretation as effects estimated from comparable randomized groups.

The DLT definition also shows why endpoint specification is consequential. It combines vital-sign changes, laboratory thresholds, and symptoms under a rule based on major and minor criteria. A single participant-level count can be useful for dose assessment, but the component events may differ in type and significance. Reporting component counts, timing, and the number assessed would help readers understand what drove the overall endpoint. Those DLT results are not reported in the registry record.

The record lists many outcome measures and analyses alongside the primary endpoint. That breadth can be valuable in a study examining bone formation, bone turnover, and mineral regulation, but it makes a clearly stated analysis plan and multiplicity approach important. The registry record does not report those details. It also does not report the analysis populations or missing-data methods, which are needed to understand how observations contributed to results.

Finally, the available safety entries demonstrate the difference between reporting a count and establishing a general safety profile. Counts describe what was recorded among participants in the listed groups; they do not, by themselves, establish how a treatment compares with a control or how precisely a rate is known. Since the primary endpoint results are absent, the record underscores the importance of complete outcome reporting for interpreting even a clearly defined early-phase question.

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.

Several trial-specific limitations constrain interpretation. First, the registry record does not report the primary DLT results. The central outcome counts by dose, the number evaluable for that outcome, and any estimate of the maximal safe dose are therefore unavailable. The adverse-event entries cannot fill that gap because their relationship to the DLT definition is not described.

Second, allocation was non-randomized, the model is listed as single-group, and no concurrent comparator is described. The record does not report how participants were assigned among dose levels, whether groups were comparable at baseline, or the rules governing escalation. Group differences cannot be interpreted as an unbiased causal dose effect based on the record alone.

Third, the safety entries use group labels that are not explicitly mapped to the four stated doses. They report counts at risk and affected, but deaths are not reported in the registry record. The record also does not give component-level DLT information, timing of events, or detail on incomplete monitoring.

Fourth, although 13 outcome measures and 16 analyses are listed, the statistical analysis plan, multiplicity handling, missing-data methods, and analysis populations are not reported in the registry record. The registry's planning assumptions do not substitute for a trial-specific sample-size justification, which is not reported in the registry record. These limitations leave key aspects of both the primary analysis and the secondary outcome interpretation unresolved.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study — NCT00580788.
• Registry record last updated 2016-02-11; status last verified 2016-02.
• Results first posted 2016-02-11.
• 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.

19. Record Summary

The registry describes an early-phase 1, non-randomized, single-group study of continuous intravenous PTHrP (1-36) for one week. Four dose levels are listed: 2, 4, 5, and 6 picomoles/kg/hr. Enrollment was 14; the study is listed as completed, with a start date of 2008-01 and primary completion date of 2009-12.

The primary endpoint was participant count meeting a defined DLT threshold during repeated monitoring. The record describes secondary measures related to vitamin D, calcium, phosphate handling, bone turnover, and parathyroid hormone. Adverse-event entries list no serious events in the four groups and other-event counts of zero, zero, one, and two affected participants, respectively. The primary DLT results, detailed statistical plan, missing-data methods, and dose-to-group mapping are not reported in the registry record.