Cryotherapy vs. LEEP to Treat Cervical Intraepithelial Neoplasia (CIN) 2/3 Among HIV-positive Women: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cryotherapy vs. LEEP to Treat Cervical Intraepithelial Neoplasia (CIN) 2/3 Among HIV-positive Women (NCT01298596), a randomized na study. The primary outcome is Recurrence of Cervical Intraepithelial Neoplasia Among HIV-positive Women.

2. Clinical Question

The clinical question is framed as a comparison of two procedures in the same broad population, rather than as a comparison with no treatment. The primary outcome is recurrence, and the registry records the number of participants with that outcome in each arm. This makes the posted primary result a comparison of event counts and proportions at the stated follow-up, not a time-to-event estimate. The registry record does not provide a more detailed definition of recurrence, the criteria used to establish it, or the assessment schedule within the 2-year period.

The shedding objective concerns a different outcome and a shorter follow-up period. It should not be treated as another measure of recurrence: it asks about HIV-1 shedding from the cervix, whereas the primary outcome concerns cervical intraepithelial neoplasia returning. Although the registry lists shedding as a secondary outcome, it does not report a result for that outcome. The clinical question can therefore be described from the registry aims and posted recurrence data, but the listed secondary objective cannot be interpreted as an observed comparison.

3. Trial Design

The registry describes a completed, randomized, parallel-group trial with no masking. Enrollment was 400, with 200 participants assigned to cryotherapy and 200 assigned to LEEP in the posted primary outcome. The trial is listed as phase NA. The sponsor was the University of Washington. The registry records a start date of 2011-06 and primary completion in 2016-10.

In a parallel-group design, participants are assigned to one intervention arm and outcomes are compared between the groups. Random allocation is intended to support a fair comparison by reducing systematic differences in how participants enter each group. The registry identifies the allocation as randomized, but the sequence-generation method, allocation-concealment procedures, and details of implementation are not reported in the registry record. The registry lists masking as none; it does not describe whether outcome assessors were masked separately from participants or clinicians.

The two interventions were procedures rather than medicines. Cryotherapy freezes the diseased part of the cervix using a cryoprobe and carbon dioxide or nitrous oxide gas. LEEP removes the diseased part using a low-voltage electrified wire loop. These descriptions identify the general procedures, but the registry record does not specify operator training, procedural variations, or any additional care delivered alongside either intervention.

The primary outcome timeframe is 2 years. The registry also describes cervical HIV-1 shedding as a secondary outcome to be compared over 3 weeks. The completed status indicates that the trial is recorded as completed, but it does not by itself establish that every planned outcome was reported. One secondary outcome is listed, while a result for it is not reported in the registry record. The original protocol, detailed analysis plan, interim monitoring approach, recruitment flow, and reasons for any missing outcomes are not reported in the registry record.

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 Recurrence of Cervical Intraepithelial Neoplasia Among HIV-positive Women, measured over 2 years.

The primary endpoint is recurrence of cervical intraepithelial neoplasia among HIV-positive women after treatment, assessed over 2 years. The registry labels the measure as a count of participants. The posted values therefore give the number of participants with recurrence in each arm, rather than a recurrence time or an average number of recurrences per participant. The record does not describe the operational definition of recurrence, how it was confirmed, or how participants were assessed throughout follow-up.

A recurrence endpoint addresses whether the condition returns after the procedure. It is useful for comparing outcomes that matter to the study question across treatment groups. Because the measure is recorded as participants with an event, the arm counts can be considered alongside the numbers assessed in each arm. The posted counts are 60 of 200 for cryotherapy and 37 of 200 for LEEP; the registry also reports proportions of 0.3 and 0.185, respectively. Those summaries describe the observed primary outcome in this record. They do not give details about when recurrence occurred or whether participants experienced more than one event.

As a general statistical point, a binary endpoint reduces each participant’s follow-up to whether the defined event was recorded or not. That can make a group comparison straightforward to communicate, but it omits information about event timing and about the course of disease. The registry’s endpoint description does not indicate whether recurrence was assessed using pathology, clinical examination, or another method, so those details cannot be inferred. The separate shedding objective is not part of this primary endpoint and has no posted result in the registry record.

7. Results Posted in the Registry

• Loop Electrosurgical Excision Procedure: 18.5% (37/200) versus 30.0% (60/200) on control; risk difference -11.5 percentage points (95% CI -19.8 to -3.2), risk ratio 0.62 (0.43–0.88); unadjusted two-proportion z-test p = 0.007.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a randomized parallel-group comparison mean?

The registry identifies the study as randomized, with a parallel model and no masking. In a randomized trial, allocation is intended to make the treatment groups comparable at the time of assignment, on average, so differences in outcomes can be examined in relation to the assigned intervention. A parallel-group structure means the two groups receive different procedures and are compared over follow-up. Randomization does not guarantee that every characteristic is exactly balanced, and it does not remove the need to describe follow-up, outcome measurement, and analysis choices.

The registry record does not describe how the allocation sequence was generated or concealed. It also does not report masking beyond the designation of none. These details can affect the risk of selection or measurement bias, but they cannot be evaluated from the record alone. The fact that the procedures are described does not establish whether all participants received the assigned procedure as planned or whether additional care differed between arms.

How is the primary result represented?

The primary endpoint is a count of participants with recurrence over 2 years. The posted counts are 60 in the cryotherapy arm and 37 in the LEEP arm, with 200 participants in each arm. The proportions reported in the comparison are 0.3 for cryotherapy and 0.185 for LEEP. A proportion uses the number of participants with the event relative to the number in the group. In general, binary-outcome analyses compare the frequency of participants with an event between groups, and may report an absolute difference, a relative risk, or an odds ratio.

The posted risk difference is -0.115 for LEEP relative to cryotherapy, with a confidence interval from -0.198 to -0.032. The risk ratio is 0.617, with a confidence interval from 0.430 to 0.884. The odds ratio is 0.530, with a confidence interval from 0.332 to 0.846. These measures answer related but distinct questions. A risk difference expresses an absolute contrast; a risk ratio compares event proportions; an odds ratio compares event odds. The interpretation depends on the measure and which arm is used as the reference. Here the comparison is stated for LEEP relative to cryotherapy, so the negative risk difference indicates a lower observed proportion in the LEEP arm.

The registry reports an unadjusted p-value of 0.007. In general, an unadjusted test compares groups without accounting for additional covariates in a model. The record does not report a covariate-adjusted analysis or the method used to produce the posted comparison, apart from identifying the p-value as unadjusted. A p-value is not a measure of effect size, and it does not establish that a result is important in clinical terms. It addresses compatibility between the data and a null hypothesis under the assumptions of the test.

What does a confidence interval add?

In general, a confidence interval describes a range of estimates compatible with the observed data under a specified statistical procedure. Its position indicates the direction of the estimated contrast, and its span communicates uncertainty. For the risk difference, the interval extends from -0.198 to -0.032. Since the entire reported interval is negative under the LEEP-relative-to-cryotherapy direction, the interval is consistent with a lower observed recurrence proportion in the LEEP arm. The interval does not incorporate every possible source of uncertainty, such as errors in outcome classification or incomplete follow-up, unless the analysis specifically models those sources.

What is not established by the posted analysis?

The record lists zero analyses. It does not report a model specification, analysis population, treatment of missing outcomes, handling of protocol deviations, or interim analyses. The presence of a reported p-value and confidence intervals does not fill in those missing methods. In general, an intention-to-treat analysis keeps participants in the groups to which they were randomized, while a per-protocol analysis focuses on participants who followed a specified protocol; the registry does not state which population was used. It is therefore not possible to label the posted estimates as intention-to-treat or per-protocol from the registry record.

Multiplicity refers, in general, to the increased chance of a chance-positive finding when many hypotheses are tested. This trial lists a primary recurrence outcome and a secondary shedding outcome. The registry record does not describe a multiplicity adjustment, hierarchy among outcomes, or a prespecified testing strategy. It also does not provide a result for the listed shedding outcome, so there is no posted secondary estimate to interpret alongside the primary result.

Why do over-dispersion and time-to-event methods not define this outcome?

As a general concept, over-dispersion arises when variability in count data exceeds what a chosen model expects; methods designed for over-dispersed counts can then improve uncertainty estimates. The primary outcome recorded is a number of participants with a binary event, not a recurrent-event count or an average count per participant. The registry does not report an over-dispersion analysis. Similarly, a time-to-event analysis uses the timing of events and can account for censoring under stated assumptions. The posted endpoint is a participant count over a 2-year timeframe, and the registry does not report event-time estimates or a time-to-event method.

The displayed estimates should consequently be read as summaries of the posted binary outcome comparison. They offer a description of recurrence counts and uncertainty for that comparison, but they do not disclose all the methods needed to reproduce or fully audit the analysis. Protocol-level definitions, analysis specifications, and participant-level information are not reported in the registry record.

10. Confidence Intervals and Precision

The principal absolute-effect estimate is a risk difference of -0.115 for LEEP relative to cryotherapy. Its confidence interval ranges from -0.198 to -0.032. The interval is entirely negative, which is consistent with a lower observed recurrence proportion in the LEEP arm under this direction of comparison. The unadjusted p-value is 0.007. The interval and p-value address statistical uncertainty under their respective methods; they do not establish the clinical importance of the contrast or account for limitations not included in the analysis.

Relative-effect estimates are also reported. The risk ratio is 0.617, with a confidence interval from 0.430 to 0.884. The odds ratio is 0.530, with a confidence interval from 0.332 to 0.846. These intervals also lie below the value representing no relative difference. The three effect measures use different scales, so their numerical values should not be compared directly as if they meant the same quantity. Each is an expression of the contrast based on the posted event counts.

In general, a confidence interval is a way to show how precisely an effect has been estimated under the model and data used. A narrower interval indicates less sampling uncertainty than a wider interval on the same scale, while an interval spanning a broad range allows more possible effect sizes. The registry does not state the confidence level or the exact method used to construct these intervals. Nor do the intervals reflect uncertainty about how recurrence was defined, the completeness of follow-up, or possible differences in outcome ascertainment unless those issues were incorporated into the analysis.

The equal arm sizes of 200 participants and the observed event counts are useful context for reading precision, but they do not eliminate uncertainty. The posted estimates apply to the trial population and its recorded follow-up; they should not be treated as exact predictions for other settings or participants.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect and are not the trial’s original sample-size justification. The registry record does not report the trial’s own design assumptions or sample-size justification. The planning assumptions stated for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect.

The 80% power column gives the number of participants per arm in a planning scenario designed to have an 80% chance of detecting the selected effect under those assumptions, if that effect is the one that truly applies and the analysis assumptions hold. The 90% power column describes the corresponding planning target for a 90% chance. Power is a property of a planned study under assumed conditions; it is not a measure of how likely the observed result is to be true.

For the full observed effect, the illustration lists 217 participants per arm for 80% power and 290 per arm for 90% power. For planning at 75% of the observed effect, it lists 402 participants per arm for 80% power and 538 per arm for 90% power. For planning at 50% of the observed effect, it lists 938 participants per arm for 80% power and 1,255 per arm for 90% power. These are planning values, not observed enrollment or trial results. Smaller effects need more participants to detect, all else equal, which is why the illustrated requirements rise as the assumed fraction of the observed effect gets smaller. This is not observed power.

The planning curve should be read in the same way as the listed planning scenarios: it represents how required group size changes under the stated assumptions as the target effect changes. It does not document the assumptions used when the trial was originally designed, and it cannot establish what sample size would be appropriate for a new study without specifying its own target effect and design.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.300; treatment proportion p₁ = 0.185; average p̄ = 0.242.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6061 = 1.1880.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6006 = 0.5055.
4. n = (1.1880 + 0.5055)² / (-0.1150)² = 216.9, rounded up to 217 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.3                          # control proportion
p1 <- 0.185                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1298596)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 217 (80% power), 290 (90% power)
 75% of observed effect: n per arm = 402 (80% power), 538 (90% power)
 50% of observed effect: n per arm = 938 (80% power), 1,255 (90% power)
power.prop.test: 216.9 
Simulated power at n = 217 per arm: 0.806 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists recurrence of cervical intraepithelial neoplasia as the primary outcome and cervical HIV-1 shedding as a secondary outcome. It states that recurrence is assessed over 2 years and that shedding is assessed over 3 weeks. The recurrence comparison has posted estimates, but a result for the listed secondary shedding outcome is not reported in the registry record. A secondary outcome without a posted result cannot be interpreted as showing either a difference or no difference.

Multiplicity is a general statistical concern when multiple outcomes, timepoints, or subgroup comparisons are tested. With many tests, the chance of at least one apparently unusual result may increase. A prespecified hierarchy or adjustment can address that concern, but the registry record does not report a multiplicity strategy, a testing hierarchy, or an adjustment. It is not possible to tell from the record whether such methods were specified elsewhere or used in the trial.

The record lists zero analyses. It does not describe the statistical analysis population or say whether the primary analysis followed randomized assignment, included only participants with observed outcomes, or used another approach. In general, an intention-to-treat population retains participants in their randomized groups, while a per-protocol population applies criteria about adherence or eligibility after randomization. Neither can be attributed to this trial based on the registry record.

Missing-data methods, follow-up completeness, the number of participants assessed for the endpoint, and the handling of participants with unknown recurrence status are not reported in the registry record. The posted arm sizes are 200 each, but the record does not explain whether those counts represent all randomized participants, all treated participants, or those included in the endpoint analysis. Interim analyses and stopping rules are also not reported in the registry record. These omissions make it difficult to assess whether missing outcomes or repeated testing could affect the interpretation of the posted estimate.

14. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hiv complications (2.5%).

The serious adverse event figures list 5 affected participants among 200 at risk in the cryotherapy arm and 2 among 200 at risk in the LEEP arm. The other adverse event figures list 2 affected participants among 200 at risk in the cryotherapy arm and 0 among 200 at risk in the LEEP arm. These are counts recorded for the two groups; the registry does not provide event-level descriptions for all of these counts or explain whether participants could contribute more than one event.

The record lists HIV complications at 2.5% among the top serious adverse event terms. It does not identify the treatment arm associated with that percentage in the listed term, so it should not be assigned to either arm. Death counts are not reported in the registry record.

These figures describe the adverse event entries in the registry, not a complete comparative safety analysis. The record does not state how events were defined, how long safety was monitored, how severity or relatedness was assessed, or whether all events were collected in the same way across arms. Raw counts should therefore be read with their denominators and reporting context, rather than as definitive evidence of a difference in safety between procedures.

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

The posted primary data show recurrence in 60 of 200 participants assigned to cryotherapy and 37 of 200 assigned to LEEP. The registry reports proportions of 0.3 and 0.185, respectively, and a risk difference of -0.115 for LEEP relative to cryotherapy. The confidence interval for that difference ranges from -0.198 to -0.032, and the unadjusted p-value is 0.007. The data therefore describe a lower observed recurrence proportion in the LEEP arm in this trial record, with uncertainty represented by the reported interval.

This result does not by itself determine whether one procedure should be selected for an individual or establish a treatment recommendation. The registry record does not report detailed eligibility criteria, the full outcome definition, how recurrence was assessed, completeness of follow-up, or the analysis population. Those features matter when judging how well the posted comparison represents the intended population and how robust the estimate is to missing or misclassified outcomes. The trial is randomized, but details of allocation procedures and the analysis plan are not reported in the registry record.

The result also does not answer the secondary question about HIV-1 shedding. Although the registry describes that outcome and a 3-week timeframe, it does not report a numerical finding for it. Likewise, recurrence counts do not show when events occurred, whether repeated events occurred, or the course of disease between treatment and the end of follow-up.

As a general interpretation principle, statistical evidence and clinical importance are related but distinct. A p-value and confidence interval describe aspects of sampling uncertainty under assumptions; they do not weigh benefits, harms, feasibility, preferences, or consequences for particular patients. The adverse event counts are limited registry summaries and do not provide a detailed safety comparison. The appropriate meaning of the posted result is therefore a description of the recorded recurrence contrast in this randomized trial, alongside the specific uncertainties and unreported details in the registry record.

16. Why This Trial Matters Statistically

This trial is statistically informative because it compares two active procedures using randomized allocation and reports a binary recurrence outcome over a stated follow-up period. The equal posted arm sizes and event counts allow the recurrence comparison to be expressed in several complementary ways: as a risk difference, risk ratio, and odds ratio. Each measure emphasizes a different scale, making it possible to distinguish an absolute contrast from relative contrasts without treating them as interchangeable.

The example also illustrates why effect estimates should be read together with their uncertainty. The risk difference is -0.115, and its confidence interval ranges from -0.198 to -0.032. The unadjusted p-value is 0.007. The estimate communicates the direction and size of the recorded contrast on the risk-difference scale, while the interval shows the range of values compatible with the data under the analysis method. Neither alone supplies a complete assessment of clinical importance.

The record is also useful for teaching the difference between a result and a design assumption. The sample-size illustrations are based on the observed effect and explicit planning assumptions, while the registry record does not report the original sample-size justification. Those illustrations cannot be interpreted as the trial’s original design or as evidence that the observed result had a particular probability of success before the study began.

Finally, the registry highlights the importance of reporting beyond a primary p-value. Analysis populations, missing-data methods, outcome definitions, multiplicity handling, and a result for the listed secondary shedding outcome are not reported in the registry record. These omissions do not erase the reported recurrence comparison, but they limit what can be established about its analysis and broader interpretation. A careful statistical reading therefore uses the posted estimates while keeping the distinction between reported results, general statistical concepts, and unreported methods clear.

17. 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 details needed to assess the recurrence estimate are not reported in the registry record. These include a detailed definition of recurrence, the method used to confirm it, the assessment schedule, and the completeness of follow-up. The primary outcome is stated as a count of participants over 2 years, so the registry does not show event timing or repeated recurrence information. It is also not clear from the record whether all randomized participants contributed to the posted outcome counts.

The registry identifies the study as randomized and unmasked but does not report sequence generation, allocation concealment, or any masking of outcome assessors. Because the procedures differ, masking may be difficult, but the registry does not describe how the potential for assessment bias was addressed. Treatment delivery details, operator experience, protocol deviations, and care outside the procedures are also not reported in the registry record.

The record does not report the analysis population, missing-data methods, adjustment variables, or sensitivity analyses. It lists zero analyses and does not provide an analysis plan or multiplicity strategy. The primary comparison is accompanied by an unadjusted p-value, but the registry does not describe whether other analyses were conducted. The listed secondary outcome, cervical HIV-1 shedding, has no reported result. These gaps mean that the posted recurrence estimates cannot be evaluated against a fully described prespecified statistical plan.

Finally, detailed participant characteristics and eligibility criteria are not reported in the registry record. The scope to which the results may apply beyond the enrolled trial population cannot be assessed from the recurrence summary alone. The adverse event counts also lack detailed definitions, duration, and attribution information. These are limitations of the available registry description, not evidence that any particular procedure or analysis was inadequate.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Cryotherapy vs. LEEP to Treat Cervical Intraepithelial Neoplasia (CIN) 2/3 Among HIV-positive Women — NCT01298596.
• Registry record last updated 2019-11-12; status last verified 2019-10.
• Results first posted 2019-10-18.
• 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.

21. Record Summary

NCT01298596 is a completed, randomized, parallel-group trial comparing cryotherapy with LEEP among HIV-positive women with cervical intraepithelial neoplasia. The registry lists enrollment of 400, no masking, and phase NA. The primary outcome is recurrence over 2 years, recorded as a count of participants.

The posted recurrence counts are 60 of 200 for cryotherapy and 37 of 200 for LEEP. The risk difference for LEEP relative to cryotherapy is -0.115, with a confidence interval from -0.198 to -0.032; the unadjusted p-value is 0.007. The registry also lists cervical HIV-1 shedding as a secondary outcome over 3 weeks, but a result for that outcome is not reported in the registry record.

The registry does not report detailed analysis populations, missing-data methods, outcome ascertainment procedures, multiplicity handling, or the original sample-size justification. The available estimates describe the posted recurrence comparison, while these unreported details limit further assessment.