protocol synopsis
10.0 statistical considerations 10.1 study

To determine whether treating anal high-grade intraepithelial neoplasia (HSIL) is effective in reducing the incidence of anal cancer in HIV-infected men and women.  
10.1.2 Secondary objectives
- To determine the safety of infrared coagulation, electrocautery, imiquimod, laser, and 5- fluorouracil treatments for anal HSIL.  
- To assess the responsiveness (sensitivity to change) and clinical significance of the A-HRSI subscales by comparing change scores within groups of participants as defined by participant responses to the PGIC item.
10.1.3 Exploratory objectives Collect clinical specimens and data to create a bank of well-annotated specimens that will enable correlative science: a) Identification of viral factors in HSIL progression to cancer; b) identification of host factors in HSIL progression to cancer; c) identification of biomarkers of HSIL progression to cancer and d) identify medical history and behavioral risk factors for HSIL progression to cancer. Ancillary study aims are outlined in Section 2.6.  
10.1.4 Quality of Life Objectives
- Primary QOL Objective: To compare arms in terms of changes in physical symptoms and impacts from T2 to T3, adjusting for T1.  
- Secondary QOL Objective: To compare arms in terms of changes in psychological symptoms from T3 to T4, adjusting for T1.  
- Exploratory QOL Objective: To assess of long-term HR-QoL changes in physical symptoms/impacts and psychological symptoms from T4 through the subsequent T5-T8 follow-ups overall and by arm.
protocol synopsis
10.2 sample size/accrual rate

For this study we are assuming an incidence rate of anal cancer of 100/100,000 among all HIV-infected men and women, which by definition includes those with and without prevalent anal SIL. We are assuming that the obligate anal cancer precursor is HSIL, and that all cases of cancer develop from HSIL. If half of the population develops HSIL then the incidence of cancer among those with HSIL would be expected to be 200/100,000. Of note, in their meta-analysis, Machalek et al estimated that 1/377 HIV-infected MSM progress from anal HSIL to anal cancer each year (16). This is equivalent to 265/100,000 per year. All participants must have HSIL to be enrolled in the ANCHOR study and thus we estimate that an incidence of 200/100,000 among study participants in the active monitoring arm is conservative to perform an intent-to-treat (ITT) analysis of our primary objective. The ITT analysis will include all randomized study participants, including those who fail treatment of anal HSIL in the treatment arm, and those who develop new, metachronous lesions, which may or may not have been fully treated at the end of study
protocol synopsis
follow-up.

Sample size estimates were based on using a log-rank test to compare the treatment and active monitoring arms under the following assumptions: three-year accrual period, five years of follow-up, 5% annual drop-out rate for both arms, and 7% annual drop-in rate for the active monitoring arm (116)(117). The 7% annual drop-in rate is the rate at which participants in the active monitoring arm opt to have treatment for HSIL. The 5% annual dropout rate includes individuals who are lost to follow-up or who die over the course of the study. For both drop-ins and drop-outs, observation time will be censored at the time of drop-in or drop-out. The annual incidence rates of anal cancer were assumed to be constant over time. To detect a difference between an annual incidence of anal cancer of 0.2% (200/100,000) in the active monitoring arm and 0.05% in the treatment arm at the two-sided 0.05 significance level with power of 0.90 will require 2529 study participants per arm for a total of 5058 study participants. Under these assumptions, the expected number of events is 7.0 and 23.7 in the treatment and active monitoring arms, respectively. The power that we would attain under a range of assumptions is shown in the table that follows. Assuming that we enroll 2529 in each arm (5058 total), power was estimated for three levels of incidence rates for the active monitoring arm, and 3 levels of drop-in rate from the control to the treatment arm under the following assumptions:
- Constant hazard rates (incidence rates) over time for both groups  
- Two-sided 0.05 significance level
- Sample size of 5058 evenly divided between treatment and active monitoring arms
- 3-year accrual period and minimum follow-up period of 5 years
- Annual drop-out rate of 5% for both observation and treatment arms - No drop-ins from treatment to active monitoring arm.  
- Drop-in rate of 7% from observation to treatment
- Alternative hypothesis is a 75% reduction in the incidence of anal cancer from the active monitoring arm  
Table 10-A: Power associated with varying drop-out rates and drop-in rates from the active monitoring arm with fixed sample size (N=5058), two-sided significance level of 0.05, incidence rate for the active monitoring arm (200/100,000) and the treatment arm (50/100,000)  
Drop-out  
rate  
Drop-in rate from the active monitoring arm to the treatment arm  
7% 10% 15%  
5% 90.0 84.9 74.6  
10% 85.0 79.4 69.2 15% 79.2 73.5 63.7 20% 72.8 67.2 58.3  
Please note that the exact incidence of progression to cancer among HIV-infected individuals is not known. We have estimated 200/100,000 as described above (data shown in bold in the table), but the estimate of Machalek et al yields an estimate of 265/100,000. We believe that the recruitment goal is a bit larger than it needs to be but should serve to ensure that we will have sufficient power for the primary study objective. We will monitor the incidence of anal cancer in both arms on a regular basis, and can either discontinue the trial early if the numbers warrant it as determined by the DSMB, or extend follow-up beyond 5 years if cancer is developing at a rate lower than projected. Over the course of the recruitment period, we estimate that we will need to screen 11065 men to diagnose 4426 (40%) with anal HSIL. We estimate that we will need to screen 6320 women to find 632 (10%) with anal HSIL. The proportion of HIV-infected men and women expected to have HSIL was based on multiple studies of HSIL prevalence demonstrated on biopsy, as determined using HRA. An assumption of 40% prevalence of HSIL among HIVinfected men is conservative based on the literature (118)(119)(120)(121) as is the estimate of 10% prevalence among HIV-infected women (122). Although the study of HSIL in women showed 9% with anal HSIL, that estimate only included women who were referred for HRA because of abnormal cytology. Women in that study with normal cytology were not referred for HRA. Since it is well known that anal cytology underestimates the true grade of disease, and some high-risk individuals with normal anal cytology may have anal HSIL (121)(123), the 9% figure represents a low-end estimate of the prevalence of HSIL among HIV-infected women.  
| year follow-up   | Anal cancer incidence per  100,000   | Dropout  rate  (%)   |     |      |    |    |
|------------------|--------------------------------------|----------------------|-----|------|----|----|
| Events Active    |                                      |                      |     |      |    |    |
| Monitoring  Arm  | Drop-in rate from  the active        |                      |     |      |    |    |
| Active           | monitoring arm to                    |                      |     |      |    |    |
| monitoring       | the treatment arm                    |                      |     |      |    |    |
| Arm              |                                      |                      |     |      |    |    |
| Events           |                                      |                      |     |      |    |    |
| Treatment Arm    |                                      |                      |     |      |    |    |
| Power  (%)       | Treatment Arm                        |                      |     |      |    |    |
| 78.8             | 17.8                                 | 5.2                  | 150 | 37.5 | 5  | 7  |
| 72.1             | 15.3                                 | 4.4                  | 150 | 37.5 | 10 | 7  |
| 72.1             | 16.7                                 | 5.2                  | 150 | 37.5 | 5  | 10 |
| 65.6             | 14.4                                 | 4.4                  | 150 | 37.5 | 10 | 10 |
| 90.0             | 23.7                                 | 7.0                  | 200 | 50   | 5  | 7  |
| 85.0             | 20.4                                 | 5.9                  | 200 | 50   | 10 | 7  |
| 84.9             | 22.2                                 | 7.0                  | 200 | 50   | 5  | 10 |
| 79.4             | 19.2                                 | 5.9                  | 200 | 50   | 10 | 10 |
| 95.6             | 29.6                                 | 8.7                  | 250 | 62.5 | 5  | 7  |
| 92.4             | 25.4                                 | 7.4                  | 250 | 62.5 | 10 | 7  |
| 92.3             | 27.8                                 | 8.7                  | 250 | 62.5 | 5  | 10 |
| 88.3             | 23.9                                 | 7.4                  | 250 | 62.5 | 10 | 10 |  
The sample size of 5058 evenly divided between treatment and active monitoring arms was based on detecting a difference in the incidence of anal cancer of 200/100,000 in the active monitoring arm and 50/100,000 in the treatment arm at the two-sided 0.05 significance level assuming a 5% annual dropout rate across both arms, and a drop-in rate from the active monitoring arm to the treatment arm of 7%. The following table shows the power estimates for changing levels of dropout rate (5%, 10%, 15% and 20%) and changing levels of drop-in rate from the active monitoring to the treatment arm (7%, 10%, 15%). Study participants randomized to the active monitoring arm who drop-in to the treatment will be followed, if feasible, to determine if they develop anal cancer.  
| treatment arm (50/100,000)  Drop-out rate Drop-in rate from the active monitoring arm to the treatment arm 7% 10% 15%  5% 90.0 84.9 74.6 10% 85.0 79.4 69.2  15% 79.2 73.5 63.7  20% 72.8 67.2 58.3   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
protocol synopsis
10.3 stratification factors

Randomization will be stratified by study site, nadir CD4 count (less than or equal to 200, greater than 200), and lesion size at baseline (greater than 50%, less than or equal to 50% of anal canal/perianal region). Nadir CD4 count will be self-reported; if the participant's lowest CD4 count is unknown (specifically or categorically), the site may rely on a positive history of opportunistic infections as a surrogate to categorize the participant as having a CD4 count less than or equal to 200. In order to document lesion size at baseline, the site must report this stratification factor based on the clinician's evaluation of these results as documented in the source. Three zones are to be evaluated for extent: 1) from the squamocolumnar junction (SCJ)/transformation zone (TZ) to the dentate line; 2) dentate line to the verge; and 3) the verge outward to the perianus. If any one of these zones have HSIL involvement of more than 50% , or if two of these zones have more than 25% HSIL involvement, the participant is considered to have more than 50% extent of HSIL. Lesions do not have to be contiguous to qualify for this definition. The site must report this stratification factor based on the clinician's evaluation of these results as documented in the source.
protocol synopsis
10.4 statistical analysis 10.4.1 primary

The primary analysis population for this study will be the ITT population which will include all randomized study participants. For each study participant, time to anal cancer will be defined as the time from randomization to diagnosis of anal cancer, and censored at the date of last follow-up. The log-rank test will be used to compare the treatment and control arms with respect to time to detection of anal cancer. For each arm, the hazard rate and its 95% confidence interval will be estimated. The proportional hazards model will be used to assess the association of study site, lesion size, and nadir CD4 level with time to detection of anal cancer.  
10.4.2 Analysis of safety of anal HSIL treatments Adverse events will be summarized at the event level and at the participant level by type of adverse event and severity grade for each of the treatments (infrared coagulation, laser, electrocautery, imiquimod, and 5- fluorouracil treatments), for the treatment arm as a whole and for the active monitoring arm over the course of study participation. For adverse events that occur in more than 5% of any of the treatments, the Poisson rates will be used to estimate the number of adverse events per unit time and the binomial proportion and its 95% confidence interval will be used to estimate the proportion of participants who reported the event.
protocol synopsis
10.5 quality of life analyses

This substudy will use the PGIC item to document change between the second and third follow-up time points (T2 and T3): "Since the last time you completed a questionnaire, how would you rate your OVERALL QUALITY OF LIFE?", marked on a 7-point scale from "Very much worse" to "Very much better" with a mid-point of "No Change". Each patient will be categorized into one of 3 groups: change for the worse (a response of "Very much worse", "Moderately worse", or "A little worse"), no change ("About the Same"), and change for the better ("A
little better", "Moderately better", and "Very much better"). Changes in the AHRSI scores will also be calculated (T2 scores minus baseline scores).  
Responsiveness is supported if changes in the A-HRSI scores correspond reliably with the anticipated changes between the three groups. This will be analyzed by a one-way ANOVA on the changes in the A-HRSI scores across the 3 groups ("worse", "no change", and "better"). The PGIC item has been used with recall periods up to 6 weeks. It may or may not work for recall periods exceeding 6 weeks. We will collect the dates of assessments and thus can assess for trends in PGIC item. A sample size of 90 will support 80% power if the three groups differ by a standardized change of 0.46, in a one-way ANOVA. We estimated the statistical power by running a simulation where the "worsened" group had a mean change in A-HRSI score of -0.46 (simulated from a standard normal of mean=-0.46 and standard deviation=1.0), the "no change" group had a mean change of 0.0, and the "improved" group had a mean change of +0.46. Additional statistical assumptions included a two-sided type-I error rate of 5%, a correlation of 0.35 between the assessment scores, and n=30 in each of the 3 groups. We understand that this change of ±0.46 may be optimistic. If the changes are only ±0.30, then it will support 80% at a type-I error rate of 0.31 (i.e., considerably reduced confidence in rejecting the null). To allow for 10% dropout, 100 participants (50 in each study arm) will be enrolled in the substudy. Additionally, the standardized response mean (SRM) will be computed as the mean change in subscale scores divided by the standard deviation of change scores within each change category. The purpose of this statistic is to examine the extent to which patients' quality of life change over time. Values greater than 0.8 will be considered large and values between 0.5 and 0.8 will be considered moderate. The amount of time spent on each ePRO item screen will be descriptively summarized in order to evaluate participant behavior in completing the questionnaire via the ePRO tool, as well as to verify that the ePRO application is 10.5.2 QoL objective In the final implementation of quality of life assessment as measured by the AHRSI will occur at 8 time points: Pre-randomization (T1), within 2-7 days (T2) and at 4 weeks of treatment/randomization (T3), and then yearly out to 5 years (T4-T8). The primary endpoint for the QoL objective is changes in physical symptoms and impacts from T2 to T3, adjusting for T1. It is anticipated that participants assigned to the treatment arm will experience significant reduction in physical symptoms and impacts from T2 to T3 versus those in the active monitoring arm. The secondary endpoint for the QoL objective is changes in psychological symptoms from T3 to T4, adjusting for T1. Due to potential uncertainty related to lack of treatment for those in the active monitoring arm, it is anticipated that participants assigned to the active monitoring arm will experience significant increases in psychological symptoms from T3 to T4 versus those in the treatment arm. The exploratory endpoint is the assessment of long-term HR-QoL changes in physical symptoms/impacts and psychological symptoms from T4 through the subsequent T5-T8 follow-ups. In the table below, we show the minimum difference that can be detected with 150, 200, and 250 participants per arm in mean A-HRSI physical symptoms and physical impacts subscale change scores (T3 minus T2) using an analysis of covariance adjusting for the covariate baseline subscale to test for differences between arms at a one-sided 0.025 significance level with approximately 90% power. A one-sided alpha of 0.025 was selected for each comparison to maintain an overall one-sided alpha level of 0.05 after a Bonferroni adjustment for two comparisons. The details of the A-HRSI and subscales may be found in Section 2.3.11.
protocol synopsis
table 10-d smallest differences that

time points according to treatment group for various scenarios based on pilot data with 90% power using a one-sided alpha of 0.025  
| Minimum difference that can be  detected with given sample size  (per arm): n=150 n=200 n=250                                                                       |       |      |      |      |      |      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|------|------|------|------|------|
| Primary (T3 vs. T2):  Physical Symptoms                                                                                                                             | 0.025 | 0.78 | 0.29 | 0.29 | 0.25 | 0.23 |
| Physical Impacts                                                                                                                                                    | 0.025 | 1.09 | 0.22 | 0.43 | 0.37 | 0.33 |
| Secondary (T4 vs. T3): Psychological Impacts                                                                                                                        | 0.05  | 1.34 | 0.17 | 0.50 | 0.43 | 0.39 |
| SD=standard deviation  Note: Estimates of SD and R2  were from responsiveness substudy. Endpoint Alpha SD for  (1-sided) change  score R2 with  baseline  covariate |       |      |      |      |      |      |  
Our plan is to target 250 participants per arm to allow for screen failures in consented participants and nonresponse. In the A-HRSI scale responsiveness study 16% of consented participants were screen failures, and 12% of eligible participants did not return at either follow-up. The above table shows that with 150-200 participants per arm we would be able to detect differences of roughly 0.3 to 0.4 unit change on the two primary endpoints of change in physical symptoms and physical impacts. Although the timing of T2 and T3 are somewhat different compared to the responsiveness substudy, the minimum differences that can be detected are smaller than the changes observed in the responsiveness substudy for those with worse ECOG PS scores compared to those with no change (mean group differences of 0.43 and 0.53 for the two subscales, section 2.3.11). Data for the QOL primary endpoints (physical symptoms and physical impacts) will each be analyzed using an analysis of covariance (ANCOVA) with the dependent variable being change in subscale (T3 score minus T2 score) and independent variables for arm and baseline subscale score. A similar approach will be used for analyzing change (T4 score minus T3 scores) in psychological impacts. The exploratory endpoint will be analyzed in a mixed model repeated measures ANCOVA with change from baseline calculated at each follow-up visit (T4 through T8) for each subscale and baseline subscale included as a covariate. Arms will be compared across time points by testing the main effect for arm. Additionally, the interaction between time and arm will be examined and trajectories over time, according to arm and specific treatments, will be explored using graphs and posthoc tests at specific follow-up times using model-based contrasts.  
Procedures to address missing data. As stated above, we are targeting 250 participants per arm to allow for screen failures and varying survey response rates over time with the goal of obtaining evaluable data from n=150-200 per arm, which still allows for meaningful effects to be detected with 90% power (Table 10-D). We would not anticipate missing questionnaire to be differential with respect to known and unknown factors between arms due to randomization. However, as a sensitivity analysis, we plan to use regression-based, multiple random imputations for the primary and secondary endpoints assuming questionnaire are missing not a random (MNAR). We will use participant characteristics and baseline A-HRSI measurements in this predictive model. The analysis will then be carried out in multiple data sets, and the results combined using standard methods to produce arm effect estimates with standard errors that incorporate the imputation error. We will also compare participant characteristics for evaluable and unevaluable participants for each primary and secondary endpoint.
protocol synopsis
10.6 sars-cov-2 ancillary study analyses

Aim 1: Determine the prevalence of SARS-CoV-2 detection in anal and oropharyngeal swabs among people living with HIV (PLWH) being screened for the ANCHOR study. The prevalence of SARS-CoV-2 in anal swabs and in oropharyngeal swabs will be estimated using the binomial proportion and its 95% confidence interval. With a sample size of 400 for each swab type and a hypothesized prevalence rate of 10%, the 95% confidence interval for the SARS-CoV-2 prevalence will be no greater than ±3.0% Aim 2: Determine the relationship in the ANCHOR screening population between prevalent anal SARS-CoV-2 positivity, anal HPV infection, and anal high-grade squamous intraepithelial lesions (HSIL) Fisher's exact tests will be used to compare those screened participants with and without SARS-CoV-2 detected on the anal swab with respect to the prevalence of anal HPV infection and anal HSIL. Aim 3: Determine the 6-month incidence of SARS-CoV-2 detection in anal and oropharyngeal swabs among participants with anal HSIL newly enrolled into the ANCHOR study. For each swab type (anal and oropharyngeal), participants will be divided into two groups: those who tested positive for SARS-CoV-2 at baseline and those who did not. For those who tested positive for SARS-CoV-2 on anal (oropharyngeal) swabs, participants will be categorized as persistent if they test positive on the 6-month anal (oropharyngeal) swab. For each swab type, persistence will be estimated as the binomial proportion of those who tested positive at 6-months divided by those who were positive for SARS-CoV-2 at baseline. The point estimate and 95% confidence interval will be estimated for the binomial proportion. For those who tested negative for SARS-CoV-2 on anal (oropharyngeal) swabs, participants will be categorized as incidence cases if they test positive on the 6-month anal (oropharyngeal) swab. For each swab type, the incidence rate will be estimated as the binomial proportion of those who tested positive at 6-months divided by those who were negative for SARS-CoV-2 at baseline. The point estimate and 95% confidence interval will be estimated for the binomial proportion. Aim 4. Determine the relationship between prevalent or incident SARS-CoV-2 detection and regression of anal HPV infection or HSIL among participants newly enrolled into the ANCHOR study and who are randomized to the monitoring arm. For monitoring arm participants, the incidence of regression of anal HPV infection will be estimated for prevalent and incident SARS-CoV-2 cases using the binomial proportion and its 95% confidence interval. Similarly, the incidence of regression of HSIL will be estimated for prevalent and incidence SARS-CoV-2 cases using the binomial proportion and its 95% confidence interval. Study time frame: We will enroll 400 PLWH who are being screened for ANCHOR over a 5-month period from the start of the study. This should be straightforward since the study typically screens over 200 PLHW/month. To reduce costs will perform the study only at the top 5-6 screening/enrolling sites in ANCHOR, and collectively these sites screen more than 1100 individuals/year. By completing enrollment within 5 months, we will also complete the 6-month follow-up analysis for Aims 3 and 4 within a year of starting the study. We will analyze the data in the last month of the study.
protocol synopsis
10.7 data and safety monitoring

10.7.1 Participant safety will be monitored in accordance with the AMC Data and Safety Monitoring Plan (Appendix VI). The study will be monitored by a Data and Safety Monitoring Board. The DSMB will meet at least annually after study initiation to assess enrollment, retention (drop-out and drop-in rates), and safety data, and may meet more frequently if needed. The DSMB will also review the outcome-based interim analyses described in Section 10.6.2.
protocol synopsis
10.7.2 interim analysis futility and

Three interim analyses of the primary efficacy outcome are planned to assess the futility of achieving a significant result if the study continues and to potentially demonstrate efficacy before all participants are enrolled. The Lan and DeMets spending function was used to specify the O'Brien-Fleming boundaries based on a one-sided log-rank test 0.025. At the final test, an overall two-sided alpha level of 0.05 (which corresponds to a one-sided 0.025 alpha level) and 90% power will be maintained. The boundaries and operating characteristics for the planned analyses are found in the table below. The DSMB will be informed of the results of the interim analysis. Consideration will be given to halting the study if the futility or efficacy boundary is crossed during the interim analysis.  
| Reject H0          |                       |           |               |       |       |
|--------------------|-----------------------|-----------|---------------|-------|-------|
| (Efficacy) Bound Z | Reject H1             |           |               |       |       |
| (Futility) Bound Z |                       |           |               |       |       |
| Analysis           | Information  fraction | Overall   | Overall β (1- |       |       |
| α spent            | power) spent          |           |               |       |       |
| 1 (Interim)        | 0.50                  | Z > 2.963 | Z < 0.332     | 0.002 | 0.020 |
| 2 (Interim)        | 0.75                  | Z > 2.359 | Z < 1.292     | 0.010 | 0.058 |
| 3 (Final)          | 1.00                  | Z > 2.014 | Z < 2.014     | 0.025 | 0.100 |  
At the time of the interim analyses, the ratio of the hazard rate for the treatment arm to the active monitoring arm will be estimated using its point estimate and 95% confidence interval. The target hazard ratio is 0.25. If the efficacy stopping boundary is crossed, then stopping the study for efficacy would be considered if the upper bound of the hazard ratio is less than or equal to 0.50 suggesting that HSIL treatment reduces the anal cancer incidence rate by at least half.
protocol synopsis
10.7.3 drop-out rate and drop-in

The sample size estimate for this study was based on a drop-out rate of 5% annually for both arms, and a drop-in rate of 7% to treatment for participants in the active monitoring arm. On a semi-annual basis, the drop-out and drop-in rates will be calculated for each year of follow-up. The drop-out rate will be defined as the number of participants who drop out in a follow-up year divided by the number of person years observed during that follow-up year. The drop-in rate will be defined as the number of participants in the active monitoring arm who are treated for HSIL (for any reason) in a follow-up year divided by the number of person years observed during that follow-up year in the active monitoring arm. If the drop-out rate exceeds 5 per 100 person-years for two consecutive 6-month periods, the protocol team will be required to implement a corrective action plan to decrease the drop-out rate. If the drop-out rate remains above 5 per 100 personyears for two additional 6-month periods, and would require the accrual duration to be extended more than one year, then the trial would be stopped. If the drop-in rate exceeds 7 per 100 person-years for two consecutive 6-month periods, the protocol team will be required to implement a corrective action plan to decrease the drop-in rate. If the drop-in rate remains above 7 per 100 person-years for two additional 6-month periods, and would require the trial duration to be extended for more than one year, then the trial would be stopped.
protocol synopsis
10.7.4 stopping rules for accrual

The planned duration of accrual is 36 months. With the sample size of 5058, accrual would be completed in 36 months if the accrual rate is 140.5 enrollees/month. On a semi-annual basis, the cumulative accrual will be compared with the projected accrual for that timepoint to determine the proportion of the projected accrual that has been achieved. After 18 months, the proportion of the projected accrual will be calculated as the number of study participants enrolled divided by the cumulative projected number of participants for that time period. If it is less than or equal to 0.20, then the DSMB will be asked to review accrual and to determine with the study team if measures can be taken to greatly improve the accrual rate. If the proportion of projected accrual that has been achieved is greater than 0.20 and less than 0.50, then enrollment will continue for an additional 6 months. At 30 months, if the proportion of the projected accrual that has been achieved remains below 0.50, then the DSMB will consider whether to stop the study due to accrual.
protocol synopsis
10.7.5 dsmb safety review rule

The DSMB will conduct a formal review with recommendations when the rate of grade 3 or higher adverse events that are at least possibly related to a study treatment or procedure exceeds 5%, by arm; accounting for follow-up this would correspond to a rate greater than 5 events per 100 person years. If a safety issue is identified, potential actions the DSMB may consider recommending to address a safety risk may include recommendations to remove any procedures posing excess safety risks from the study, discussing added clinical measures with the protocol team to prevent or address the specific risk if feasible, and/or modification of the expected severe adverse event frequency in the protocol and consent form.
protocol synopsis
11.0 role of data management

Access to the internet data entry system for this study, AdvantageEDCSM, and instructions for recording of study data on CRFs will be provided by the ANCHOR DMC at www.anchordmc.com. Participating institutions are responsible for submitting data and/or data forms via AdvantageEDC in accordance with the ANCHOR Data Entry Guide and specific form instructions, within the timelines specified by the AMC's Standards of Procedure for Site Performance Measures.
protocol synopsis
11.2 data quality

It is the responsibility of the ANCHOR DMC to assure the quality of data for the study. See the AMC Data and Safety Monitoring Plan (Appendix VI) for the study plans for adverse event reporting and data review. This role extends from protocol development to generation of the final study database.
protocol synopsis
11.3 data monitoring

This study will be monitored in compliance with AMC and ANCHOR Study policies and by the Clinical Data Update System (CDUS) Version 3.0. Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). The ANCHOR DMC is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
protocol synopsis
12.0 ethical and regulatory considerations

The principles of Institutional Review Board (IRB) approval and informed consent described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 56) and Department of Health and Human Services (DHHS) regulations for the Protection of Human Participants regulations (45 CFR Part 46) must be followed. IRB approval of the protocol and the informed consent form must be given in writing. The sponsor's designee (ANCHOR DMC) must receive a copy of the letter of approval from the IRB, which specifically approves the protocol and informed consent, before participant enrollment. The IRB must also approve any significant changes to the protocol and documentation of this approval must be sent to the ANCHOR DMC. The IRB must review the research project at least once every 365 days during the duration of the project. Continuing approval of the project must also be given in writing and provided to the ANCHOR DMC. Records of all study review and approval documents must be kept on file by the Investigator and are participant to inspection during or after completion of the study. AEs must be reported to the IRB according to local procedures. The IRB should receive notification of completion of the study and final report within 3 months of study completion and termination. The Investigator will maintain an accurate and complete record of all submissions made to the IRB, including a list of all reports and documents submitted. Written informed consent will be obtained from the participant. The nature, significance, and risks associated with the study must be explained to the participant. The informed consent will describe the purpose of the study, the procedures to be followed, the risks and benefits of participation, all risks of the investigational agent(s) and/or study participation as listed in the model informed consent form, and all other elements of informed consent as required by regulation. A copy of the consent form will be given to the participant to keep. In addition, any institution(s) conducting research according to the guidelines of this protocol is required to adhere to local and national laws and regulations governing the confidentiality and disclosure of health information.
protocol synopsis
12.2 changes to the protocol

Any change or addition to this protocol requires a written protocol amendment that must be approved by CTEP and the Investigator before implementation. All amendments require approval by the IRB of the treating institution. A copy of the written approval of the IRB must be sent to the DMC.
protocol synopsis
12.3 women and minorities

This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium (AMC). As part of their contractual obligations, each participating site within the AMC and the AMC as a whole is required to assure that the participation of women and minority participants reflects the percentage representation of these populations in their geographic region and, for the AMC, the United States as a whole. As such, it is expected that the representation of participants on this trial will reflect the constitution of the respective populations.  
| Sex/Gender                                        |           |           |       |    |       |
|---------------------------------------------------|-----------|-----------|-------|----|-------|
| Ethnic Category                                   | Females   | Males     | Total |    |       |
| Hispanic or Latino                                | 191       | +         | 1,074 | =  | 1,265 |
| Not Hispanic or Latino                            | 567       | +         | 3,226 | =  | 3,793 |
| Ethnic Category: Total of all participants        | 758       | +         | 4,300 | =  | 5,058 |
| Racial Category American Indian or Alaskan Native | 38        | +         | 215   | =  | 253   |
| Asian                                             | 38        | +         | 215   | =  | 253   |
| Black or African American                         | 303       | +         | 1,720 | =  | 2,023 |
| Native Hawaiian or other Pacific Islander         | 38        | +         | 215   | =  | 253   |
| White                                             | 341       | +         | 1,935 | =  | 2,276 |
| Racial Category: Total of all participants        | 758       | +         | 4,300 | =  | 5,058 |
| (A1 = A2)                                         | (B1 = B2) | (C1 = C2) |       |    |       |  
Enter actual estimates, whole numbers only (percentages, fractions, or decimals are not acceptable).  
The totals provided for each Ethnic/gender or Ethnic/total combination must match those given for each Race/gender or Race/total combination (i.e., A1 must match A2, B1 must match B2, and C1 must match C2).
protocol synopsis
13.0 references

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protocol synopsis
appendix i schedule of evaluations

| Participants Randomized to Active Monitoring Arm Visit 0 Screening Visit 1* Randomization Visit 2 6  months 1 Visit 3 12  months Visits 4- 10**                                   | Final  study  visit (60  months  or later) ±4 weeks                                                                                                                                                                                   | Early Study  Discontinuation       |    |    |    |    |    |
|-----------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|----|----|----|----|----|
| Within 4  weeks of                |                                                                                                                                                                                                                                       |       |    |    |    |    |    |
| Information  Visit                | Every 6  months                                                                                                                                                                                                                       |       |    |    |    |    |    |
| Within 1- 12 weeks  of  Screening | ±4                                                                                                                                                                                                                                    |       |    |    |    |    |    |
| weeks                             |                                                                                                                                                                                                                                       |       |    |    |    |    |    |
| ±4                                |                                                                                                                                                                                                                                       |       |    |    |    |    |    |
| weeks                             | ±4                                                                                                                                                                                                                                    |       |    |    |    |    |    |
| weeks                             |                                                                                                                                                                                                                                       |       |    |    |    |    |    |
| Informed consent                  | X2                                                                                                                                                                                                                                    |       |    |    |    |    |    |
| Demographics                      | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| Medical history                   | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| Concurrent meds                   | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  | X  |
| Physical exam3                    | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Inguinal node exam                | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  | X  |
| Risk factor questionnaire         | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| Quality of Life  questionnaires4  | T1                                                                                                                                                                                                                                    | T2 T3 |    |    |    |    |    |
| Performance status                | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| CBC w/diff, platelets5            | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| HIV documentation                 | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| HIV viral load, CD4 level         | X6                                                                                                                                                                                                                                    | X6    | X6 | X6 | X6 |    |    |
| Anal cytology7                    | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Digital anorectal exam            | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  | X  |
| High resolution anoscopy          | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  | X  |
| Anal swabs8                       | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Anal biopsy9                      | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Adverse event evaluation          | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Urine HCG10                       | X                                                                                                                                                                                                                                     |       |    |    |    |    |    |
| Blood for biorepository11         | X                                                                                                                                                                                                                                     | X     | X  | X  | X  | X  |    |
| Oropharyngeal swab12              | X                                                                                                                                                                                                                                     | X     |    |    |    |    |    |
| *                                 | Screening evaluations for Visit 0 may be performed at Visit 1 (except informed consent, the anal swab for cytology, the  screening HRA, and anal biopsies), provided that all Visit 0 evaluations are performed before randomization. |       |    |    |    |    |    |  
1 Clinicians may elect to perform HRA and biopsy lesions between any of the 6-month visits if cancer is suspected. Visits that occur between regularly scheduled 6-month visits will be designated with the appropriate visit number and a, b, c, etc.  
2 Informed consent will be obtained 1-6 weeks before randomization, and may be given during a preceding information visit, if done.  
3 Complete physical exam will be performed at baseline. Targeted physical exam will be performed at all subsequent 6-month visits (see Section 8.1.7). Height and weight will be collected at the screening visit only.  
4 For participants who consent to the optional HRQoL substudy (completed in February 2020), the A-HRSI and Patient ECOG PS will be administered via telephone facilitated interview or ePRO platform between time of enrollment and time of randomization (T1). A-HRSI, Patient ECOG PS and PGIC will be administered at least 14 days (2-weeks) postrandomization, and at most 70-days post-randomization (T2). The third HRQoL follow-up will be scheduled to take place at least 71 days (10 weeks + 1 day) post-ANCHOR randomization, and at most 112 days (16 weeks) post-randomization (T3).  
5 CBC with differential and platelets may occur up to 90 days prior to randomization. 6 HIV viral load and CD4 count results are required at Visit 1 (results obtained from routine medical care within six weeks prior to randomization will be acceptable). Results will be collected from routine medical care at annual visits through study discontinuation, if available. Venipuncture may be performed on the day of randomization, even after randomization.  
7 Collect per Section 8.1.10. Leftover material is to be shipped to the ANCHOR Biorepository. 8 One swab stored for DNA. One swab stored for RNA for correlative science studies. These swabs may be collected at the randomization visit if not collected at the screening visit. All swabs will be collected every 6 months on the study.  
9 Screening biopsy must be performed 1-12 weeks prior to Visit 1. Biopsy of HSIL lesions performed at every other 6-month visit (annually). At the final visit, all visible lesions and any prior areas of HSIL that appear to have regressed will be biopsied. If this totals less than 4 biopsies, normal-appearing tissue in remaining quadrants will be biopsied so that a minimum of 4 areas are sampled per Section 4.1. Biopsies may be done at any time if cancer is suspected.  
10 HCG for females of childbearing age potential.  
11 Blood for correlative science studies (serum [red top tube] at all indicated visits, plus plasma and whole blood fraction
[lavender top tube] at Visit 2 only).  
12 Collect only if consented for participation in the SARS-CoV-2 ancillary study at the 5 participating centers. Swabs must be collected at the same visit as anal swab collection.  
| Fluorouracil Cream               |                                                                                                                                                                                                                                       |                                         |                    |                    |                               |                                                     |    |    |
|----------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|--------------------|--------------------|-------------------------------|-----------------------------------------------------|----|----|
| Visit 0                          |                                                                                                                                                                                                                                       |                                         |                    |                    |                               |                                                     |    |    |
| Screening                        | Visit 1* Randomization                                                                                                                                                                                                                                       | Visit  1A, 1B 8, 16  weeks,  ±2  weeks1 | Visit 2 6  months2 | Visit 3 12  months | Visits 4-10** Every 6  months | Final  study  visit (60  months  or later) ±4 weeks | Early  Study  Discontinuation    |    |
| Within 4  weeks of  Information visit                                  | Within 1- 12 weeks  of  Screening                                                                                                                                                                                                     | ±4 weeks                                | ±4                 |                    |                               |                                                     |    |    |
| weeks                            | ±4                                                                                                                                                                                                                                    |                                         |                    |                    |                               |                                                     |    |    |
| weeks                            |                                                                                                                                                                                                                                       |                                         |                    |                    |                               |                                                     |    |    |
| Informed consent                 | X3                                                                                                                                                                                                                                    |                                         |                    |                    |                               |                                                     |    |    |
| Demographics                     | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| Medical history                  | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| Concurrent meds                  | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   | X  |    |
| Physical exam4                   | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Inguinal node exam               | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   | X  | X  |
| Risk factor questionnaire        | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| Quality of Life  Questionnaires5 | T1                                                                                                                                                                                                                                    | T2 T3                                   |                    |                    |                               |                                                     |    |    |
| Performance status               | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| CBC w/diff, platelets6           | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| HIV documentation                | X                                                                                                                                                                                                                                     |                                         |                    |                    |                               |                                                     |    |    |
| HIV viral load, CD4 level        | X7                                                                                                                                                                                                                                    | X7                                      | X7                 | X7                 | X7                            |                                                     |    |    |
| Anal cytology8                   | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Digital anorectal exam           | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   | X  | X  |
| High resolution anoscopy         | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   | X  | X  |
| Anal swabs9                      | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Anal biopsy10                    | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Adverse event evaluation         | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   | X  |    |
| Urine HCG11                      | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Blood for biorepository12        | X                                                                                                                                                                                                                                     | X                                       | X                  | X                  | X                             | X                                                   |    |    |
| Oropharyngeal swab13             | X                                                                                                                                                                                                                                     | X                                       |                    |                    |                               |                                                     |    |    |
| *                                | Screening evaluations for Visit 0 may be performed at Visit 1 (except informed consent, the anal swab for cytology, the  screening HRA, and anal biopsies), provided that all Visit 0 evaluations are performed before randomization. |                                         |                    |                    |                               |                                                     |    |    |  
1 If treatment is tolerated at Visit 1A, clinician will continue treatment for an additional 8 weeks or stop if no HSIL is seen.  
Participant will return for an optional visit at 16 weeks for Visit 1B if treatment is continued.  
2 If biopsies show HSIL clinician may opt to initiate another treatment modality. The schedule for that 6-month block of treatment will vary depending on the modality that will be used. Visits that occur between regularly scheduled 6-month visits will be designated with the appropriate visit number and an interim visit sequence letter a, b, c, etc.  
3 Informed consent will be obtained 1-6 weeks before randomization, and may be given during the preceding information visit, if done.  
4 Complete physical exam will be performed at baseline. Targeted physical exam will be performed at all subsequent 6-month visits, (see Section 8.1.7). Height and weight will be collected at the screening visit only.  
5 For participants who consent to the optional HRQoL substudy (completed in February 2020), the A-HRSI and Patient ECOG PS will be administered via telephone facilitated interview or ePRO platform between time of enrollment and time of randomization (T1). A-HRSI, Patient ECOG PS and PGIC will be administered at least 14 days (2-weeks) postrandomization, and at most 70-days post-randomization (T2). The third HRQoL follow-up will be scheduled to take place at least 71 days (10 weeks + 1 day) post-ANCHOR randomization, and at most 112 days (16 weeks) post-randomization (T3).  
6 CBC with differential and platelets may occur up to 90 days prior to randomization. 7 HIV viral load and CD4 count results are required at Visit 1 (results obtained from routine medical care within six weeks prior to randomization will be acceptable). Results will be collected from routine medical care at annual visits through study discontinuation, if available. Venipuncture may be performed on the day of randomization, even after enrollment into the system.  
8 Collect per Section 8.1.10. Leftover material is to be shipped to the ANCHOR Biorepository. 9 One swab stored for DNA. One swab stored for RNA for correlative science studies. These swabs may be collected at the randomization visit if not collected at the screening visit. All swabs will be collected every 6 months on the study.  
10 Screening biopsy must be performed between 1-12 weeks prior to Visit 1. Biopsies of HSIL lesions performed at each 6month visit. Areas that appear normal following treatment do not require rebiopsy. At the final visit, HSIL lesions and previously treated areas that appear normal will be biopsied (minimum of 4 biopsies per Section 4.2). Biopsies may be done at any time if cancer is suspected.  
11 HCG for females of childbearing potential, as needed prior to treatment. 12 Blood for correlative science studies (serum [red top tube] at all indicated visits, plus plasma and whole blood fraction
[lavender top tube] at Visit 2 only).  
13 Collect only if consented for participation in the SARS-CoV-2 ancillary study at the 5 participating centers. Swabs must be collected at the same visit as anal swab collection.  
| Hyfrecation/Electrocautery, or Laser   |                                                                                                                                                                                                                                       |                                                    |                    |                    |                               |                                                     |    |    |
|----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|--------------------|--------------------|-------------------------------|-----------------------------------------------------|----|----|
| Visit 0                                |                                                                                                                                                                                                                                       |                                                    |                    |                    |                               |                                                     |    |    |
| Screening                              | Visit 1* Randomization                                                                                                                                                                                                                                       | Visit  1A 6  weeks,  ±2  weeks1                    | Visit 2 6  months2 | Visit 3 12  months | Visits 4-10** Every 6  months | Final  study  visit (60  months  or later) ±4 weeks | Early  Study  Discontinuation    |    |
| Within 4  weeks of  Information Visit                                        | Within 1- 12 weeks of  Screening                                                                                                                                                                                                      | ±4                                                 |                    |                    |                               |                                                     |    |    |
| weeks                                  | ±4                                                                                                                                                                                                                                    |                                                    |                    |                    |                               |                                                     |    |    |
| weeks                                  | ±4                                                                                                                                                                                                                                    |                                                    |                    |                    |                               |                                                     |    |    |
| weeks                                  |                                                                                                                                                                                                                                       |                                                    |                    |                    |                               |                                                     |    |    |
| Informed consent                       | X3                                                                                                                                                                                                                                    |                                                    |                    |                    |                               |                                                     |    |    |
| Demographics                           | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| Medical history                        | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| Concurrent meds                        | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   | X  | X  |
| Physical exam4                         | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Inguinal node exam                     | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   | X  | X  |
| Risk factor questionnaire              | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| Quality of life  questionnaires5       | T1                                                                                                                                                                                                                                    | T2 T3                                              |                    |                    |                               |                                                     |    |    |
| Performance status                     | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| CBC w/diff, platelets6                 | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| HIV documentation                      | X                                                                                                                                                                                                                                     |                                                    |                    |                    |                               |                                                     |    |    |
| HIV viral load, CD4 level              | X7                                                                                                                                                                                                                                    | X7                                                 | X7                 | X7                 | X7                            |                                                     |    |    |
| Anal cytology8                         | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Digital anorectal exam                 | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   | X  | X  |
| High resolution anoscopy               | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   | X  | X  |
| Anal swabs9                            | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Anal biopsy10                          | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Biopsy in RNALater11                   | X                                                                                                                                                                                                                                     | Not more than once each 6-month block during study |                    |                    |                               |                                                     |    |    |
| Adverse event evaluation               | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   | X  |    |
| Urine HCG12                            | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Blood for biorepository13              | X                                                                                                                                                                                                                                     | X                                                  | X                  | X                  | X                             | X                                                   |    |    |
| Oropharyngeal swab14                   | X                                                                                                                                                                                                                                     | X                                                  |                    |                    |                               |                                                     |    |    |
| *                                      | Screening evaluations for Visit 0 may be performed at Visit 1 (except informed consent, the anal swab for cytology, the  screening HRA, and anal biopsies), provided that all Visit 0 evaluations are performed before randomization. |                                                    |                    |                    |                               |                                                     |    |    |  
1 As needed, if the participant is having staged procedures or requires an additional treatment of the lesion being ablated in the judgment of the clinician.  
2 If biopsies show HSIL clinician may opt to initiate another treatment modality. The schedule for that 6-month block of treatment will vary depending on the modality that will be used. Visits that occur between regularly scheduled 6-month visits will be designated with the appropriate visit number and an interim visit sequence letter a, b, c, etc.  
3 Informed consent will be obtained 1-6 weeks before randomization, and may be given during the preceding information visit, if done.  
4 Complete physical exam will be performed at baseline. Targeted physical exam will be performed at all subsequent 6-month visits (see Section 8.1.7). Height and weight will be collected at the screening visit only.  
5 For participants who consent to the optional HRQoL substudy (completed in February 2020), the A-HRSI and Patient ECOG PS will be administered via telephone facilitated interview or ePRO platform between time of enrollment and time of randomization (T1). A-HRSI, Patient ECOG PS and PGIC will be administered at least 14 days (2-weeks) postrandomization, and at most 70-days post-randomization (T2). The third HRQoL follow-up will be scheduled to take place at least 71 days (10 weeks + 1 day) post-ANCHOR randomization, and at most 112 days (16 weeks) post-randomization (T3).  
6 CBC with differential and platelets may occur up to 90 days prior to randomization. 7 HIV viral load and CD4 count results are required at Visit 1 (results obtained from routine medical care within six weeks prior to randomization will be acceptable). Results will be collected from routine medical care at annual visits through study discontinuation, if available. Venipuncture may be performed on the day of randomization, even after enrollment into the system.  
8 Collect per Section 8.1.10. Leftover material is to be shipped to the ANCHOR Biorepository. 9 One swab stored for DNA. One swab stored for RNA for correlative science studies. These swabs may be collected at the randomization visit if not collected at the screening visit. All swabs will be collected every 6 months on the study.  
10 Screening biopsy must be performed between 1-12 weeks prior to Visit 1. Biopsies of visible lesions performed at each 6month visit. Areas that appear normal following treatment do not require rebiopsy. At the final visit, HSIL lesions and previously treated areas that appear normal will be biopsied (minimum of 4 biopsies per Section 4.2). Biopsies may be done at any time if cancer is suspected.  
11 One additional biopsy of the lesion with the most severe appearance will be collected prior to ablative treatment and stored in RNALater for banking. This biopsy may be collected beginning at the randomization and not more than once every six months during the study.  
12 HCG for females of childbearing potential, as needed prior to treatment. 13 Blood for correlative science studies (serum [red top tube] at all indicated visits, plus plasma and whole blood fraction
[lavender top tube] at Visit 2 only).  
14 Collect only if consented for participation in the SARS-CoV-2 ancillary study at the 5 participating centers. Swabs must be collected at the same visit as anal swab collection.  
| Participants Randomized to Treatment Arm, Surgery Visit 0 Screening  Visit 1* Randomization1  Visit  Visit 2 1A, 1B2 6 months3 Visit 3 12  months Visits 4-10** Every 6  months                                  | Final  study  visit (60  months  or later) ±4  weeks                                                                    | Early  Study  Discontinuation       |    |    |    |    |    |    |
|----------------------------------|-------------------------------------------------------------------------------------------------------------------------|-------|----|----|----|----|----|----|
| Within 4  weeks of  Information Visit                                  | ±4 weeks                                                                                                                |       |    |    |    |    |    |    |
| Within 1-12 weeks of  Screening  | ±4 weeks                                                                                                                | ±4    |    |    |    |    |    |    |
| weeks                            |                                                                                                                         |       |    |    |    |    |    |    |
| Informed consent                 | X4                                                                                                                      |       |    |    |    |    |    |    |
| Demographics                     | X                                                                                                                       |       |    |    |    |    |    |    |
| Medical history                  | X                                                                                                                       |       |    |    |    |    |    |    |
| Concurrent meds                  | X                                                                                                                       | X     | X  | X  | X  | X  | X  | X  |
| Physical exam5                   | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Inguinal node exam               | X                                                                                                                       | X     | X  | X  | X  | X  | X  | X  |
| Risk factor questionnaire        | X                                                                                                                       |       |    |    |    |    |    |    |
| Quality of life  questionnaires6 | T1                                                                                                                      | T2 T3 |    |    |    |    |    |    |
| Performance status               | X                                                                                                                       |       |    |    |    |    |    |    |
| CBC w/diff, platelets7           | X                                                                                                                       |       |    |    |    |    |    |    |
| HIV documentation                | X                                                                                                                       |       |    |    |    |    |    |    |
| HIV viral load, CD4 level        | X8                                                                                                                      | X8    | X8 | X8 | X8 |    |    |    |
| Anal cytology9                   | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Digital anorectal exam           | X                                                                                                                       | X     | X  | X  | X  | X  | X  | X  |
| High resolution anoscopy         | X                                                                                                                       | X     | X  | X  | X  | X  | X  |    |
| Anal swabs10                     | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Anal biopsy11                    | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Adverse event evaluation         | X                                                                                                                       | X     | X  | X  | X  | X  | X  |    |
| Urine HCG12                      | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Blood for biorepository13        | X                                                                                                                       | X     | X  | X  | X  | X  |    |    |
| Oropharyngeal swab14             | X                                                                                                                       | X     |    |    |    |    |    |    |
| *                                | Screening evaluations for Visit 0 may be performed at Visit 1 (except informed consent, the anal swab for cytology, the |       |    |    |    |    |    |    |  
1 Surgery will be scheduled and should be performed within 2 months. 2 Additional visits may occur between 6-month visits if TUA is being performed in stages. 3 If biopsies show HSIL clinician may opt to initiate another treatment modality. The schedule for that 6-month block of treatment will vary depending on the modality that will be used. Visits that occur between regularly scheduled 6-month visits will be designated with the appropriate visit number and an interim visit sequence letter a, b, c, etc.  
4 Informed consent will be obtained 1-6 weeks before randomization, and may be given during the preceding information visit, if done.  
5 Complete physical exam will be performed at baseline. Targeted physical exam will be performed at all subsequent 6-month visits (see Section 8.1.7). Height and weight will be collected at the screening visit only.  
6 For participants who consent to the optional HRQoL substudy (completed in February 2020), the A-HRSI and Patient ECOG PS will be administered via telephone facilitated interview or ePRO platform between time of enrollment and time of randomization (T1). A-HRSI, Patient ECOG PS and PGIC will be administered at least 14 days (2-weeks) postrandomization, and at most 70-days post-randomization (T2). The third HRQoL follow-up will be scheduled to take place at least 71 days (10 weeks + 1 day) post-ANCHOR randomization, and at most 112 days (16 weeks) post-randomization (T3).  
7 CBC with differential and platelets may occur up to 90 days prior to randomization. 8 HIV viral load and CD4 count results are required at Visit 1 (results obtained from routine medical care within six weeks prior to randomization will be acceptable). Results will be collected from routine medical care at annual visits through study discontinuation, if available. Venipuncture may be performed on the day of randomization, even after enrollment into the system.  
9 Collect per Section 8.1.10. Leftover material is to be shipped to the ANCHOR Biorepository.  
10 One swab stored for DNA. One swab stored for RNA for correlative science studies. These swabs may be collected at the randomization visit if not collected at the screening visit. All swabs will be collected every 6 months on the study.  
11 Screening biopsy must be performed between 1-12 weeks prior to Visit 1. Biopsies of visible lesions performed at each 6-  
month visit. Areas that appear normal following treatment do not require rebiopsy. At the final visit, HSIL lesions and previously treated areas that appear normal will be biopsied (minimum of 4 biopsies per Section 4.2). Biopsies may be done at any time if cancer is suspected.  
12 HCG for females of childbearing potential, as needed prior to treatment. 13 Blood for correlative science studies (serum [red top tube] at all indicated visits, plus plasma and whole blood fraction
[lavender top tube at Visit 2 only).  
14 Collect only if consented for participation in the SARS-CoV-2 ancillary study at the 5 participating centers. Swabs must be collected at the same visit as anal swab collection.
protocol synopsis
health-related quality of life (qol)

| T1                                  |                                                    |                                            |                                             |
|-------------------------------------|----------------------------------------------------|--------------------------------------------|---------------------------------------------|
| Baseline                            | T2                                                 |                                            |                                             |
| 2-7 days postrandomization                                     | T3                                                 |                                            |                                             |
| 4 weeks postrandomization                                     | T4-T8                                              |                                            |                                             |
| Time Point and  Target  Completion  | 12, 24, 36, 48,  and 60 months post  randomization |                                            |                                             |
| Visit 1                             |                                                    |                                            |                                             |
| Randomization                       |                                                    |                                            |                                             |
| Target A-HRSI  completion  window   | 14 to 0 days  before  randomization                | 2 to 7 days after  randomization ± 1 weeks | ± 4 weeks                                   |
| 14 to 0 days  before  randomization | 2 to 10 days  after  randomization                 | 21 to 60 days  after  randomization        | -28 / +56 days of target annual  visit date |
| Window for  accepted forms          |                                                    |                                            |                                             |  
| Karnofsky Performance Scale         | ECOG Performance Status Scale                                      |                                                                                                     |                                                                                                                        |
|-------------------------------------|--------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|
| Percent                             | Description                                                        | Grade                                                                                               | Description                                                                                                            |
| 100                                 | Normal, no complaints, no  evidence of disease.                    | 0                                                                                                   | Normal activity. Fully active, able to  carry on all pre-disease performance                                           |
| Able to carry on normal activity;   | without restriction.                                               |                                                                                                     |                                                                                                                        |
| 90                                  | minor signs or symptoms of  disease.                               | Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able to |                                                                                                                        |
| Cares for self, unable to carry on  | carry out work of a light or  sedentary nature (e.g., light        |                                                                                                     |                                                                                                                        |
| 70                                  | normal activity or to do active  work.                             | housework, office work).                                                                            |                                                                                                                        |
| 80                                  | Normal activity with effort; some  signs or symptoms of disease.   | 1                                                                                                   |                                                                                                                        |
| Requires occasional assistance, but |                                                                    |                                                                                                     |                                                                                                                        |
| 60                                  | is able to care for most of his/her  needs.                        | 2                                                                                                   | In bed <50% of the time.  Ambulatory and capable of all selfcare, but unable to carry out any                                                                                                                        |
| Requires considerable assistance    | work activities. Up and about more                                 |                                                                                                     |                                                                                                                        |
| 50                                  | than 50% of waking hours.                                          |                                                                                                     |                                                                                                                        |
| and frequent medical care.          |                                                                    |                                                                                                     |                                                                                                                        |
| 40                                  | Disabled, requires special care and  assistance.                   | 3                                                                                                   | In bed >50% of the time. Capable of  only limited self-care, confined to  bed or chair more than 50% of  waking hours. |
| 30                                  | Severely disabled, hospitalization  indicated. Death not imminent. |                                                                                                     |                                                                                                                        |
| 20                                  | Very sick, hospitalization  indicated. Death not imminent.         | 4                                                                                                   | 100% bedridden. Completely  disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                        |
| 10                                  | Moribund, fatal processes  progressing rapidly.                    |                                                                                                     |                                                                                                                        |
| 0                                   | Dead.                                                              | 5                                                                                                   | Dead.                                                                                                                  |
appendix ii performance status scales
all anal cytology specimens will

The participant should undress so that buttocks are exposed, and either bend over the exam table or lay on their side in left lateral decubitus. The examiner should use one hand to spread the buttocks and expose the anal verge.
appendix ii performance status scales
procedure for obtaining anal swab

For anal cytology and correlative science studies: A non-scored polyester swab moistened in tap water will then be inserted as far as is comfortable into the anus, a minimum of 1-2 inches. If there is difficulty inserting the swab, the participant should also retract their buttocks and the swab reoriented in the canal. With pressure on the swab rotate it firmly in a circular fashion for approximately 20 seconds and slowly remove from the canal. Do not retract the buttocks when the swab is close to the verge to ensure that it is sampled as well. Immediately immerse the swab in a liquid-cytology vial agitating vigorously over 20 to 45 seconds to disperse the cells. The liquid cytology vial will be sent the local cytopathology lab for processing. The first slide will be used for the study. The leftover material from anal swab cytology suspension will be shipped to the ANCHOR Biorepository, processed according to the ANCHOR Biorepository's procedures, and stored for future correlative studies. For additional correlative science studies: Two additional moistened polyester swabs should be obtained. The second swab will be used for DNA studies, and the third for RNA/protein studies. These two swabs will be processed for storage in the ANCHOR Biorepository according to the instructions in the ANCHOR Study Manual of Procedures (MOP). All three swabs will be collected in this order at each visit where required. If a local cytology result exists to satisfy protocol requirements at the time of the visit, the first anal swab will be recollected with the second and third swabs, and the first swab sent to the ANCHOR Biorepository without local processing for the cytology result. Procedures and schedules for shipping monolayer slides, Thinprep solution, and swabs to the ANCHOR Biorepository are outlined in the ANCHOR Study MOP. Guidance regarding inconclusive cytology results: Any insufficient or inconclusive cytology at screening must be repeated. Valid results must be available within 12 weeks before randomization. If a cytology specimen collected after randomization is interpreted as insufficient or inconclusive for any 6-month visit, repeat cytology is required. If an interim visit is planned, the repeat specimen can be collected at that visit, otherwise the participant should be asked to return specifically for sample collection within 3 months. The two additional swabs for correlative science studies will be recollected if the local cytology specimen requires recollection. The residual media from both cytology specimens should be submitted to the ANCHOR Biorepository for correlative studies, denoting which specimen was found to be insufficient or inconclusive. Guidance regarding discrepant cytology and histology results: During screening, if the local cytology result is ASC-H or HSIL and no lesions were observed or no biopsy result showed HSIL, the participant will return for a repeat HRA within 3 months.
appendix ii performance status scales
appendix iv high resolution anoscopy

High resolution anoscopy should only be done **after** the specimens for anal cytology and HPV
testing are collected. The patient will already be positioned for anal evaluation. A mixture of an anesthetic cream (e.g., 4% lidocaine cream) and water-soluble lubricating jelly should be used as a lubricant. A digital anal rectal exam should then be performed palpating the entire anal canal, distal colon and perianus, noting any masses or areas of induration. The procedure for HRA is as follows: 1. Insert the anoscope, remove obturator, and place a cotton swab wrapped in gauze soaked in 5% acetic acid into anus.  
2. Remove the anoscope over the swab and leave swab in place for 1 to 2 minutes.  
3. Remove the swab and re-insert the anoscope. Carefully examine the anal canal with a colposcope.  
4. Re-apply acetic acid frequently to ensure adequate detection of lesions and verify that all aspects of the Anal Transformation Zone (AnTZ) have been visualized.  
5. If acetowhitening is noted, note vascular characteristics, if present. 6. Lugol's solution (iodine) may be used as desired to aid in identifying areas of possible LSIL
and HSIL near the squamocolumnar junction.  
7. At each visit the clinician will carefully map the location of each lesion and where they did their biopsies, if any. Sites are requested to photograph each lesion at every visit using Second Opinion or other software that allows for easy sharing of images between study sites, for the purposes of training and quality control.  
8. Biopsy abnormal appearing areas according to the protocol requirements for the assigned study arm. Local anesthetic (e.g., 1% lidocaine with or without epinephrine or .5% bupivacaine) may be used at the provider's discretion prior to biopsy. Biopsies from different quadrants must go in separate formalin containers and get separate pathologic interpretations.  
9. Attain hemostasis with pressure prior to removal of the anoscope or by removing the anoscope.  
Monsel's solution or silver nitrate should be used **judiciously and only** after all biopsies have been obtained because it can interfere with histologic interpretation. Electrocautery or infrared coagulation should be used judiciously to stop significant bleeding that does not respond to the above measures. It must be documented if used for hemostasis.
10. Apply acetic acid for one minute to perianal area and examine carefully with colposcope. 11. Biopsy any external (perianal) areas per the assigned study arm using a local anesthetic (e.g.,
1% lidocaine with or without epinephrine or 0.5% bupivacaine) prior to biopsy.  
12. Participants with signs or symptoms consistent with proctitis or sexually transmitted infections other than HPV should be referred for appropriate diagnosis and treatment.
appendix ii performance status scales
procedures for biopsy review

All pathology specimens will be reviewed by the designated pathologist on site. p16 IHC staining is not required on all biopsies diagnosed as HSIL by the local laboratories for the ANCHOR Study. If performed, the immunostained slides are also requested to be sent for Central Pathology review. p16 IHC is useful to adjudicate differential diagnoses on H&E particularly for the following indications:
- To differentiate between the H &E morphologic diagnosis of HSIL (–IN 2 or –IN 3) and a mimic of precancer (e.g., processes known to be unrelated to neoplastic risk such as immature squamous metaplasia, reparative epithelial changes, tangential cutting). Strong and diffuse block-positive p16 results support a categorization of HSIL. Negative or non– block-positive staining strongly supports a non–HPV-associated pathology.  
- To *clarify a diagnosis of –IN2* when the lesion is clearly HPV-associated, but on H&E
morphologic interpretation the diagnosis of –IN 2 (under the old terminology) is considered. –IN2 is a biologically equivocal lesion falling between the morphologic changes of a productive HPV infection (LSIL) and precancer (HSIL). Strong and diffuse block-positive p16 results support a categorization of HSIL. Negative or non–blockpositive staining strongly favors an interpretation of LSIL.  
A p16 stain must be obtained if the only area of HSIL among all biopsies taken is AIN 2. At any visit, if other lesions show AIN2-3 or more severe histology, p16 staining is highly recommended for AIN2 biopsies to adjudicate the diagnosis, but is not mandatory. If, after evaluation of screening biopsies, the only remaining focus of HSIL at randomization is AIN2, p16 staining is required for that lesion. The local pathology lab relied upon for this trial must be willing to send slides and tissue blocks as requested by this study. Stained H&E slides from all biopsies with a result of AIN2 or greater will be sent from participants who are biopsied as part of the screening process and randomized at the baseline visit. If p16 IHC staining is performed, the immunostained slides are also requested to be sent for Central Pathology review. Participants who fail screening due to suspected cancer diagnoses or cancer diagnoses will undergo central pathology review to confirm the diagnosis, if biopsies are available from screening procedures performed by the site. The protocol team may request additional slides undergo central pathology review. Slides will be submitted in real time for any cancer diagnoses, as well as all biopsies collected prior to progression to cancer, and any cases that are suspicious for progression to cancer during local pathology review. Tissue blocks may be requested for correlative studies, for participants who develop cancer, and for matched controls. Blocks will not be exhausted and will be returned to the local pathology lab. The baseline pathology review will serve to identify the discrepancy in HSIL vs. no HSIL readings, and HSIL vs. LSIL readings between the local pathologist's finding and the central pathology result. If a significant discrepancy is identified at a study site, 100% of the slides will be reviewed from the site from all subsequent biopsies, and additional slides will be required from all other participating sites. Slides will be batched for shipment for central pathology review at least every six months according to the instructions in the ANCHOR Study Manual of Procedures. The pathology slides will be reviewed later at UCSF, and results of the central pathology review will not be available in real time. Guidance regarding repeat biopsy and inconclusive biopsy results/discordant cytology results:
- After the screening visit, if all biopsies do not show HSIL and the local cytology result shows high grade disease (ASC-H or HSIL), the investigator should bring the participant back for repeat HRA. If the biopsies at screening do not show HSIL and the local cytology result is inconclusive, repeat HRA with biopsy should only be performed if the investigator's clinical impression of the participant's disease is strongly suggestive of HSIL. If the repeat biopsies do not show HSIL, the participant should discontinue screening.  
- After randomization, if all biopsies at a 6-month visit do not show HSIL or are inconclusive, and the local cytology result shows high grade disease (ASC-H or HSIL), the investigator should bring the participant back for repeat HRA at 3 months (interim visit, window of ± 4 weeks). If a biopsy is performed at an even-numbered visit for a monitoring arm participant and the biopsy results are discordant, the participant will not be asked to return for repeat biopsy until the next 6-month visit unless there is suspicion for progression to cancer. If at least one biopsy shows HSIL, repeat biopsies of lesions with inconclusive histology may be deferred to the next 6-month visit so long as there is no suspicion of progression to cancer. If the visit window for the next 6-month visit is within 8 weeks of the last biopsy, repeat HRA and biopsies will occur as part of the next 6-month visit.  
- The investigator may request that a participant return for repeat biopsy at any time there is suspicion for cancer.
appendix v risk factor questionnaire
background

Thank you for agreeing to be part of the ANCHOR Study. Before starting the study, we are giving all volunteers this ANCHOR Visit 1 Questionnaire. This questionnaire is a survey that asks questions about your medical history, including medical conditions related to anal HSIL, your sexual history, and whether you smoke or have used drugs. This questionnaire will take about 25 minutes to complete. Please read the information below before you start the questionnaire.  
- Your completion of this questionnaire is voluntary. All of your responses will be confidential.  
- Some people may find some of the questions embarrassing. It is important that you answer all questions honestly.  
- No one will force you to answer any questions if it is too uncomfortable for you. If you do not feel comfortable answering a question, you may leave the question blank and move on to the next one.  
- If you feel that you do not have privacy to fill out this questionnaire, talk to a study team member immediately.  
- When you are finished completing the questionnaire, place the questionnaire in the envelope provided by the study staff. After you submit the questionnaire, the study team will not be able to see your answers.  
1) What was the month and year of your positive HIV test result? (IF MORE THAN 1 POSITIVE
TEST, RECORD THE EARLIEST TEST DATE. IF YOU RECALL THE YEAR BUT NOT THE MONTH, ENTER "06" (JUNE) FOR THE MONTH.)  
  
2) Have you ever had anal condyloma or warts, also known as venereal warts?  
Yes (1) No (2)
3) Have you ever had anal herpes?  
Yes (1) No (2)
4) Have you ever had anal gonorrhea?  
Yes (1) No (2)
5) Have you ever had syphilis?  
Yes (1) No (2)
6) Have you had chlamydia infection of the anus? Chlamydia infection of the anus is also known as chlamydia proctitis.  
Yes (1) No (2)
7) Have you ever had any of the following conditions?  
a. Inflamed hemorrhoids or piles?  
Yes (1) No (2)
b. Diarrhea, 2 or more loose stools per day for at least 2 weeks?  
Yes (1) No (2)
c. A draining or crack-like sore or hole in the anal wall, fissure or fistula?  
Yes (1) No (2)
d. An infection or abscess in your anal area?  
Yes (1) No (2)
e. Swollen or tender lumps around your crotch area?  
Yes (1) No (2)
f. Hardening or narrowing of the anal passage, or stenosis?  
Yes (1) No (2)
8) At what age was your first sexual experience with another person?  
  
  
9) Have you ever had receptive anal intercourse, that is, anal intercourse in which a man's penis was inserted into your anus?
Yes (1) No (2) If no, skip to question 12.  
10) Using the letter codes below, please tell me the letter that best describes the total number of sexual partners you have had receptive anal intercourse with over your lifetime. ________
Letter Codes for Question 10  
| 1 to 10…………….. B  11 to 50………… C  51 to 100………….. D  101 to 200………… E  201 to 500………… F  501 to 1000……….. G  over 1000…………. H   |
|---------------------------------------------------------------------------------------------------------------------------------|  
11) Using the letter codes below, please tell me the letter that best describes how often you had receptive anal intercourse during the past 12 months? ___________
Letter Codes for Question 11  
| Never……………………………. A  once/month or less ……………… B  about once a week ………………. C  about 3 or 4 times per week …….. D  about 5 to 10 times per week ……. E  about 11 to 20 times per week …... F  more than 20 times per week ……. G   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
12) During the past 5 years did you have any objects inserted into your anus, other than a penis, fingers, or a scope by a medical provider?  
Yes (1) No (2)
13) If you replied "yes" to question 12, which letter code below best describes how many times an object was inserted into your anus (other than by a medical provider) during the past 5 years? __________
Letter Codes for Question 13  
| Less than 10 times total……….. A  10 to 100 times ……………….. B  101 to 500 times ……………… C  more than 500 times ………….. D   |
|------------------------------------------------------------------------------------------------------------------------|  
14) Overall, does your sexual partner wear condoms when he inserts his penis into your anus/rectum?  
Letter codes for Question 14  
| Never………………………………………………………….A  Some of the time (<50% of the time)…………………………B  Most of the time ( >50% but less than 100% of the time)…….C  All of the time…………………………………………………D  Not applicable…………………………………………………E   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
15) For women: have you ever had an abnormal cervical Pap smear?  
Yes (1)  
 No (2)  
  
16) For women: have you ever been diagnosed with pre-cancer or high-grade dysplasia of the cervix, vulva, or vagina?  
  
  
17) Have you smoked more than 100 cigarettes in your lifetime?  
Yes (1) No (2) If no, skip to question 23 18) At what age did you first start smoking? 19) At that time, how many cigarettes did you smoke per day? 20) How many years did you smoke this amount of cigarettes?  
154
appendix v risk factor questionnaire
21) do you currently smoke?

22) Currently, how many cigarettes/day do you smoke? 23) Have you ever used any of the following substances in the past year? Please indicate how many times you have used the substance using the letter codes below.  
Letter Codes for Question 23  
| Never………………………………..A  Less than 10 times total……………..B  10 to 100 times ……………………..C  101 to 500 times ……………………D  more than 500 times ………………..E   |
|--------------------------------------------------------------------------------------------------------------------------------------------------|  
a. Marijuana or hashish _____ b. Cocaine, (blow, snow) or crack cocaine _____ c. Amyl or Butyl nitrite or poppers _____ d. LSD or Acid _____ e. Angel dust, PCP, Ketamine, Special K, or Super K _____ f. Speed, crank, crystal, or amphetamines _____ g. Ecstasy or MDMA _____ h. MDA or Adam _____ i. Ethylchloride _____ j. Molly_____ k. Heroin ______
appendix vi amc data and
introduction

The AIDS Malignancy Consortium (AMC) Data and Safety Monitoring Plan (DSMP) outlines the measures employed by the group to monitor the safety of participants and ensure the data validity and integrity for all clinical trials it conducts. This includes methods to: 1) monitor the progress of trials and the safety of participants; 2) comply with regulatory requirements for adverse event (AE) reporting; 3) processes for trial termination or temporary suspension and major modifications; and 4) plans for ensuring data accuracy and protocol compliance. As the AMC conducts protocols of varying research phase, region of conduct (which may include trials conducted in the U.S., international sites, or both), IND sponsor (AMC investigator, CTEP, or industry-sponsored) and clinical data entry system use, this plan addresses broad processes applying to the range of trial designs and requirements. Refer to the individual AMC protocol to identify the applicable study characteristics for the relevant requirements described in this plan.
appendix vi amc data and
monitoring the progress of trials

All AMC protocols that collect safety data adhere to the National Cancer Institute (NCI), Cancer Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements (https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm), as applicable to the clinical protocol. AEs are to be recorded in the source documents, assessed by a clinical investigator for the AE reporting criteria, and promptly reported in the clinical data entry system as required by each protocol. For AMC trials conducted under a CTEP IND and AMC trials conducted within the U.S., all AEs that meet the NCI's expedited reporting requirements are reported to the NCI via the CTEP Adverse Event Reporting System (CTEP-AERS) web application, either directly or through integration with Medidata Rave where this system is employed for AMC protocols. Use of this system ensures notification to the protocol chair and Investigational Drug Branch (IDB) at CTEP, as required for trials conducted under a CTEP IND, and a uniform expedited reporting and safety review process for AMC domestic trials. The system may also be programmed to include sponsor notification as required for trials with industry support. Alternate process for expedited AE reporting to the AMC protocol chairs and AMC Operations and Data Management Center (ODMC) within the clinical data entry system (AdvantageEDC or Advantage eClinical only) may be defined in the protocol for select trials (international studies and The ANCHOR Study). All serious adverse events (SAEs) received by the AMC ODMC will be reviewed by the AMC medical monitor at the AMC ODMC for consideration of individual participant safety, safe trial conduct, data reporting quality for AE term selection, and appropriate application of the regulatory criteria for seriousness, expectedness, and relatedness to the investigational therapy. If alternate procedures are followed for SAE review, the process for adequate medical monitoring will be defined in the AMC protocol and the Transfer of Regulatory Obligations (TORO) with the sponsor. AMC medical monitor review includes review of the CTEP-AERS report before CTEP submission for IDB review (if applicable), or review of the SAE report in the data entry system for trials not using CTEP-AERS for expedited reporting. The IND sponsor or its designee will issue the determination as to whether the AE requires IND safety reporting to FDA as a serious and unexpected suspected adverse drug reaction (SUSAR). For protocols not conducted under an IND, in the event of disagreement between the reporting physician and the AMC medical monitor regarding the relationship of the AE to the investigational agent(s) (i.e., determination of whether the attribution is unrelated or unlikely, or possible, probable, or definite), the AMC medical monitor will provide the final determination of the relationship. IND safety reporting to FDA is performed by CTEP for trials conducted under a CTEP IND; IND safety reporting is performed by the sponsor or sponsor's designee (AMC ODMC or other party defined in the study agreement or TORO) for IND studies sponsored by AMC investigators or industry sponsors.
appendix vi amc data and
expedited reporting to the institutional

The requirements for IRB review will be identified in the protocol section on ethical and regulatory obligations. All AMC trials initiated before September 1, 2020 and all international sites for all AMC studies are subject to local IRB review; only U.S. sites are subject to the NCI requirement to use a single IRB for protocols initiated on or after September 1, 2020. For trials subject to local IRB review, the site principal investigator is responsible for ensuring that expedited AE reports for its trial participants and any unanticipated problems that affect the local institution only are submitted to the local IRB of the reporting institution, per the local IRB's requirements for such reporting. For studies reviewed by the single IRB, the protocol chair will render a determination as to whether a SAE or other problem constitutes a trial-wide unanticipated problem that requires reporting to that IRB, in accordance with its standards of procedure. To comply with investigator notification requirements for IND studies under 21 CFR 312.32 and 312.55, IND safety reports from all trials the AMC conducts and reports from external sponsors investigating the same agents are made available to all investigators upon receipt from the sponsor or its designee, either via the password-protected section of the AMC Operations web site (AMC trials subject to local IRB review only) or the CTSU website (U.S. trials subject to single IRB review/CTEP IND agents). The site clinical investigator responsible for the applicable AMC protocol(s) is responsible for reviewing any IND safety reports received and documenting submission to the IRB of record (if required by local policy) within the timeline defined by the Clinical Trials Monitoring Branch (CTMB) audit guidelines.
appendix vi amc data and
procedures for monitoring trial progress

For trials using AdvantageEDC or Advantage eClinical for clinical data entry, the AMC ODMC provides on demand tabular listings of all reported AEs and SAEs on a participant level to the protocol chair and co-chair(s) for review via the password-protected section of the AMC Operations web site, www.AIDScancer.org. For trials using OPEN and Medidata Rave for clinical data collection, data listing will be made available using that system. Summary reports of AEs by frequency and relationship to the investigational agent(s) are provided to all AMC investigators and their staff It is the responsibility of each site to provide trial-specific AE listings to their respective IRB, if required by its policies. For blinded studies, the AE and SAE listings are reviewed and tabulated without treatment assignment. Accrual summaries for each AMC trial are updated nightly on the password-protected section of the AMC web site. The progress of each AMC trial is reviewed regularly by the protocol chair and also by the appropriate Scientific Working Group (SWG) during scheduled conference calls (monthly SWG calls and as required, protocol-specific monitoring conference calls). Summary accrual, summary AE, and individual SAE reports are provided to SWG leadership and protocol chairs to monitor participant safety during these monthly calls. The AMC medical monitor reviews listings of all reported AEs on a quarterly basis for assuring compliance with the protocol requirements for AE reporting and the identification of any safety concerns (individual AE or increased frequency/severity of expected AEs) for the agents under investigation. Findings from these reviews are communicated to the protocol chairs and all AMC investigators, and posted to the AMC Operations web site.
appendix vi amc data and
data and safety monitoring board

The AMC has formed an independent Data and Safety Monitoring Board (DSMB) for AMC trials and for the ANCHOR Study. As required by NCI policy, the AMC requires DSMB review for all phase III randomized trials. All other clinical trials that the AMC initiates will be reviewed by the AMC ODMC and AMC Statistical Center during protocol development to issue a recommendation as to whether the study requires DSMB oversight, which will require the approval of the AMC Executive Committee. This determination will be based on the phase of the study, experimental design, risk posed by the investigational approach, extent of data available on the safety of an investigational agent, risk posed by the natural course of the health condition under research, and the categories of vulnerable populations involved. The involvement of a DSMB in reviewing an AMC protocol will be identified in each clinical protocol as approved by CTEP and, as applicable, required by the IRB of record. Regarding the composition of the AMC DSMB, voting members usually include physicians, statisticians, an ethicist, and a patient advocate. All voting members have no other affiliation to the AMC and are appointed by the AMC Executive Committee with the approval of the OHAM Director. Nonvoting members are the AMC group statistician, the protocol statistician, an AMC ODMC staff member, two representatives (normally a clinician or statistician) from CTEP, and the grant program directors from the NCI Office of HIV and AIDS Malignancy (OHAM). The DSMB reviews all applicable AMC studies in accordance with the National Cancer Institute's Policy for Data and Safety Monitoring. Confidential reports of all trials under review are prepared by the AMC group statistician with support from the AMC ODMC. A written report containing the current status of each trial monitored, and when appropriate, any toxicity and outcome data, are sent to DSMB members by the AMC ODMC within the timelines specified by the DSMB charter. This report addresses specific toxicity issues and any other concerns about the conduct of the trial, as defined by the protocol plan for DSMB review. The report may contain information for the DSMB to render determinations for participant safety, early trial termination, results reporting, or continuing accrual or follow-up. The results of each DSMB meeting are summarized in a formal report sent by the DSMB chair to the AMC group chair and AMC ODMC. The DSMB report contains recommendations on whether to close each study reviewed, whether to report the results, and whether to continue accrual or follow-up. A primary recommendation (e.g., continue with no change; recommended or required modification; stop) must be included in the document. The group chair or designee is then responsible for notifying the protocol chair and relevant SWG chair before the recommendations of the DSMB are carried out. In the unlikely event that the protocol chair does not concur with the DSMB, then the OHAM program directors and the NCI division director or designee must be informed of the reason for the disagreement. The protocol chair, relevant SWG chair, group chair, DSMB chair, and NCI division director or designee will be responsible for reaching a mutually acceptable decision about the study. CTEP approval of a protocol amendment will be required prior to any implementation of a change to the study. Following a DSMB meeting, the DSMB's recommendations are provided to all AMC investigators and staff. It is each site principal investigator's responsibility for conveying this information to its local IRB as relevant for its protocol participation. For trials reviewed by a single IRB, the AMC ODMC will support notification to the IRB as required per its procedures. Cohort trial reviews not subject to DSMB review For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in the protocol and the protocol chair, AMC medical monitor, and protocol statistician determine whether these criteria have been met based on a review of all safety data for the protocol-defined evaluation period. If applicable for phase II trials, stopping the trial for toxicity or efficacy, or suspending enrollment pending observation of responses in a multi-stage phase II trial, is based on meeting criteria stated in the protocol, and the protocol chair, AMC medical monitor, and protocol statistician determine whether these criteria have been met.
appendix vi amc data and
plans for assuring compliance with

The protocol chair, AMC group chair, and the AMC ODMC share responsibility in assuring that participating investigators comply with applicable regulatory and protocol requirements for AE reporting. The AMC site principal investigator certifies compliance with NCI and FDA requirements for trial conduct by signing the site subaward agreement for the grant and the AMC Adherence Statement for site membership; clinical investigators also certify compliance in completing the protocol signature page for each protocol active at the site, and Form FDA-1572 for CTEP investigator registration, and also for AMC IND studies sponsored by AMC investigators or industry sponsors. Protocol compliance with AE identification, assessment and reporting requirements is assessed by the AMC ODMC using several methods: 1) programmed system checks and messages to instruct the site to complete routine and/or expedited reporting when certain criteria are reported in the clinical data entry system; 2) programmed data reports provided to the protocol chairs that identify reports requiring expedited AE reporting; 3) remote review of data entry or data reports to ensure compliance with protocol and NCI AE reporting requirements; 4) AMC medical monitor review described in the section above; and, 5) routine site audits by reviewing the site's source documentation. The clinical data entry systems used for AMC studies include the Oncology Patient Enrollment Network, OPEN for enrollment, and Medidata Rave for clinical data entry for enrolled participants; trials activated before September 1, 2020 or that involve only AMC international sites may be reported in AdvantageEDC/Advantage eClinical, a web-based data entry and enrollment system. These data entry systems are programmed to notify the site investigator, protocol chair, AMC medical monitor, and AMC ODMC via email in the event that a site reports an AE that meets expedited reporting criteria to NCI and/or FDA. Additional reporting conditions may be programmed depending on the sponsor reporting requirements of a given protocol (e.g., adverse events of special interest [AESI]). If the site does not follow with an expedited report, the AMC ODMC contacts sites to request compliance with reporting requirements. Additionally, the protocol chair, AMC ODMC, and the AMC medical monitor review reported AEs on a routine basis to identify AEs reported by sites that require expedited reporting. The protocol chair, AMC SWG chairs, AMC group chair, and IND sponsors have general oversight for assuring that routine and expedited adverse reporting requirements are met by the responsible parties. For studies monitored by CTEP using the Data Mapping Utility (DMU), cumulative protocol- and patient-specific data will be submitted weekly to CTEP electronically via the DMU. For trials monitored by the NCI's Clinical Data Update System (CDUS), AE information is transmitted electronically to NCI on a quarterly basis. For trials monitored by NCI's Clinical Trials Monitoring Service (CTMS), AE information is transmitted electronically to NCI every two weeks. Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible
appendix vi amc data and
for the grant

In the event that temporary or permanent suspension of a trial, or major modification to the protocol is under consideration, the protocol chair will convene the AMC ODMC, AMC Statistical Center, and SWG chair by conference call to discuss the options. Suspension actions will also be reviewed by the AMC Executive Committee for program oversight and direct communication of the action with the OHAM program directors. For phase III trials, closure decisions are typically rendered by the AMC DSMB; if the trial in question is under AMC DSMB oversight but rendered by the AMC investigators, the AMC DSMB will be notified of the suspension and the reason. For phase I and II trials, the protocol chair also has the option of asking the DSMB to review the study. The AMC ODMC will inform the CTEP Protocol Information Office (PIO), with copy to OHAM Directors, when studies are temporarily or permanently closed. In the event of major trial modification, CTEP must approve all protocol amendments prior to distributing to the AMC sites.
appendix vi amc data and
plans for assuring data accuracy

All study data for AMC clinical trials are entered directly by AMC clinical site staff into the applicable clinical data entry system for the trial. During data entry, the system performs validation checks on many fields and performs consistency checks between select fields. Range checks are placed on each field to eliminate entry of out-of-range values. Edit check programs are run on the database on a set schedule to identify and resolve inconsistencies between forms or data collected at different points in time. Submitted data entry forms are reviewed for compliance with the protocol and data entry instructions according to the AMC ODMC's standards for data quality processes. AMC ODMC staff routinely interacts with site staff to resolve any data submission problems. In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate compliance with regulatory issues, and to review data for specific cases by checking source documents. These reports are sent to the site principal investigator and to the NCI. In the event that major violations are identified, sites are asked to provide a written corrective and preventative action plan to correct deficiencies. If needed, a repeat site audit is conducted. In the event that a site does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee has the option to implement remedial action(s) for the site. Possible actions include, but are not limited to, suspending enrollment of new patients to AMC trials until deficiencies are corrected; recommending a decrease in funding to the site; and requiring specific training for site investigators or staff members.
appendix vi amc data and
appendix vii participant instructions for

You have been prescribed to receive topical imiquimod 5% cream three times a week at night for 8 weeks. You will receive imiquimod for up to 16 weeks if you are tolerating the treatment. Please follow the directions below for applying the cream you have been given. The imiquimod dose will be 750 mg of cream per week, administered as one single use sachet (250 mg) applied 3 times per week. You have been given at least 24 sachets with 250 mg of imiquimod for 8 weeks of treatment. If you have perianal HSIL, you will be given extra sachets. When applying the cream, a latex glove or other protective covering must be used on your hand. Apply the imiquimod cream at night before bed or before your longest period of rest once a day. You will place half of the contents of the packet onto your right index finger and insert the cream approximately one inch into the anus on the right side, rubbing from side to side as far along the right side as your finger can reach. Then place the remaining cream on the left index finger, and insert the cream one inch into the anus on the left side, rubbing from side to side as far along the left side as your finger can reach. You may find it is easier to lie on your side then turn over. Or, you may crouch, or place your right and left leg alternately on the toilet or chair. Use whatever position allows you to reach into the anus. If perianal HSIL is present, the study clinician will tell you to apply one additional packet of cream using a gloved finger to the perianus. When applying the cream to the perianus, you will place half of the contents of the packet onto your right finger and rub the cream on the right side of your perianus. You will place the remaining cream on the left index finger and rub the cream on the left side of your perianus. Please speak to the study clinician if you have any side effects that are more than mild. The study clinician will tell you if you should reduce the dose. If you miss a dose please apply the next dose as scheduled. Do not try to make up for it by adding the contents of more than one sachet at your next dose. Store the packets of imiquimod at room temperature, away from sunlight.
appendix vi amc data and
appendix viii participant instructions for

You have been randomized to receive topical 5-fluorouracil (5-FU) cream for 8 weeks. You will receive 5-FU for up to 16 weeks if you are tolerating the treatment. Please follow the directions below for applying the cream you have been given. You have been given a 40 gram tube of 5-FU cream. If you have also been given a syringe or applicator, you will join the syringe tip onto the end of the tube. You will squeeze out the cream to the marked line on the applicator (0.5mL of cream). Please continue to do this until you can confidently squeeze the correct volume of cream. If you do not have a syringe or applicator, you may also measure out one inch of cream to apply. Using gloves or a finger cot, squeeze one half the amount of cream (0.25mL) from the syringe (if using) onto your right index finger. You will then insert the cream approximately one inch into the anus on the right side, rubbing from side to side as far along the right side as your finger can reach. Then place the remaining cream (0.25mL) on the left finger, and insert the cream one inch into the anus on the left side, rubbing from side to side as far along the left side as your finger can reach. You may find it is easier to lie on your side then turn over. Or, you may crouch, or place your right and left leg alternately on the toilet or a chair. Use whatever position allows you to reach into the anus. Clean any excess cream from the outside of the anus unless you are treating the outside area. The study clinician will let you know if you should treat the outside. The 5-FU cream will be inserted twice a day (it does not need to be exactly 12 hours apart) for 5 days in a row. You will then stop for 9 days. Each cycle of 5-FU consists of 14 days. You will then repeat the cycle continually for 16 weeks, or 8 cycles. If you miss a dose please apply the next dose as scheduled. Do not try to make up for it by using extra 5-FU cream at your next dose. Please speak to the study clinician if you have any side effects that are more than mild. The study clinician will tell you if you should reduce the dose.
appendix vi amc data and
appendix ix regulatory status of

This appendix serves to outline the regulatory status of the topical drugs and medical devices that will be used in the treatment of anal high grade squamous intraepithelial lesions for the ANCHOR
Study: Anal Cancer/HSIL Outcomes Research Study. Questions pertaining to this justification for the regulatory status of these agents may be directed to the ANCHOR Study Chair, Dr. Joel Palefsky, and the ANCHOR Data Management Center via email at anchordmc@emmes.com.
appendix vi amc data and
ind exempt topical treatments

Topical imiquimod 5% and topical 5-fluorouracil 5% meet all of conditions of exemption from the requirement for an Investigational New Drug (IND) application at 21 CFR 312.2(b). This investigation will not be used to support a change in the labeling, marketing authorization, advertising, or the indications for use for any of the study agents. ANCHOR Study investigators will use a supply of these drugs that are sourced as legally marketed in the U.S. Participants will not be charged for any of the agents. The protocol will be conducted at participating U.S. AMC member sites in compliance with the requirements for informed consent and institutional review set forth in 21 CFR 50 and 56, respectively. The investigation will not involve an exception from informed consent (21 CFR 50.24). By review of an IND application for a related AMC trial of topical imiquimod and 5-fluorouracil creams, the Food and Drug Administration (FDA) determined that these agents are exempt from the requirement for an IND when used in the treatment of anal HSIL in persons with HIV infection. (Protocol AMC-088, PI: Dr. Timothy Wilkin, IND 122,224 for Efudex and Zyclara 2.5%). The sponsor-investigator believes that the exemption status of the agents used in protocol AMC-088 apply to the ANCHOR Study as the agents will be used for the same indication for use, patient population, and route. The use of the 5% imiquimod cream in this trial as compared to the 2.5% strength imiquimod cream used in AMC-088 is addressed by a less frequent dosing schedule in the ANCHOR Study and does not significantly increase the risks or decrease the acceptability of the risks associated with the use of imiquimod. The FDA has concurred with this determination of IND exemption for these agents in discussions related to this trial.
appendix vi amc data and
ide exempt study devices

By review of this investigation, FDA has confirmed that the classes of medical devices used in the ANCHOR Study, described in protocol Section 7.3.3, are exempt from the requirement for an Investigational Device Exemption (IDE). A copy of FDA's exemption letter is available upon request. As a Federally-funded cancer research initiative, the ANCHOR Study protocol chairs and the collaborating consortium, the AMC, have no intention to demonstrate safety and effectiveness of the study devices for clearance or approval in the prevention of cancer, nor will the results of this study be submitted to the FDA to support a change in the labeling or the marketing of the study devices. Redfield infrared coagulator FDA regulates the Redfield Infrared Coagulator as an endoscopic electrosurgical unit (21 CFR 876.4300) intended for use in electrosurgical procedures. It is a class II medical device (intermediate risk) that FDA has cleared for use in the treatment of hemorrhoids, tattoo removal, chronic rhinitis, genital condyloma (condyloma acuminata), and general warts. It is contraindicated in the use of invasive cancer, vulvar or vaginal intraepithelial neoplasia, and in patients with severe photosensitivity reactions.
appendix vi amc data and
hyfrecator and electrosurgical devices

Electrosurgical devices are class II medical devices that are regulated as electrosurgical cutting and coagulation devices intended to remove tissue and control bleeding by use of high-frequency electrical current (21 CFR 878.4400). Specific indications for use vary by device. These devices are cleared for use in general and plastic surgery, in applications including dermatology, gynecology, and proctology, including the removal of hemorrhoids, condyloma, Bowen's disease, basal cell carcinoma, and squamous cell carcinoma.
appendix vi amc data and
laser surgical devices

The generic type of medical devices regulated under 21 CFR 878.4810 includes laser surgical instruments for use in general and plastic surgery and in dermatology, which are regulated as class II medical devices. This classification includes devices intended to cut, destroy, or remove tissue by light energy emitted by carbon dioxide, or argon lasers intended to destroy or coagulate tissue in dermatology by light energy emitted by argon. Laser surgical devices in this classification are indicated for use to cut, destroy, remove, or coagulate tissue, generally soft tissue, for general surgical purposes in medical specialties such as general and plastic surgery, dermatology/aesthetic surgery, podiatry, otolaryngology, gynecology, neurosurgery, orthopedics (soft tissue), dental and oral surgery, and dentistry. Legally marketed carbon-dioxide lasers that are indicated for use in general surgical procedures, including the excision or ablation of tissue, are permitted for use on this trial.
appendix x anchor health-related symptom
laser surgical devices

Below is a list of statements that other people diagnosed with anal HSIL (pre-cancer lesion in the anus) and treated or actively monitored have said are important. Please check the box to select your answer based on your experiences in **the past 7 days**.  
| Very  much 4                                                                                                                                                                                                                                                                                                                                                                           |                |                 |             |               |              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-----------------|-------------|---------------|--------------|
| 1. I have anal pain                                                                                                                                                                                                                                                                                                                                                                    | Check if       |                 |             |               |              |
| PHYSICAL SYMPTOMS                                                                                                                                                                                                                                                                                                                                                                      | Not            |                 |             |               |              |
| Applicable                                                                                                                                                                                                                                                                                                                                                                             | Not at  all  0 | A little  bit 1 | Somewhat  2 | Quite a bit 3 |              |
| 2. I have pain other than anal pain 3. I have pain during bowel movements 4. I have constipation 5. I have bleeding from the anus 6. I have itching in or around the anus 7. I have discharge (wetness) in my anal area 8. I have burning sensations in the anal area 9. I have urgency for bowel movements                                                                            | Check if       |                 |             |               |              |
| PHYSICAL IMPACTS                                                                                                                                                                                                                                                                                                                                                                       | Not            |                 |             |               |              |
| Applicable                                                                                                                                                                                                                                                                                                                                                                             | Not at  all  0 | A little  bit 1 | Somewhat  2 | Quite a bit 3 | Very  much 4 |
| 10. I have problems with my physical ability to move around 11. I have problems with sitting 12. I have problems completing daily household chores (e.g.,  cleaning, cooking, laundry, house maintenance) 13. I have problems taking care of myself (e.g., bathing,  dressing, shaving) 14. I have problems participating in leisure activities (e.g.,  watching television, relaxing) |                |                 |             |               |              |  
141  
| 15. I have problems participating in social activities (e.g., going  out to eat, visiting friends) 16. I have problems with work productivity                                                                                                                                                                                                                                                                                                           | Very  much 4              |                |                 |             |               |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|----------------|-----------------|-------------|---------------|
| 17. I have difficulty concentrating PSYCHOLOGICAL SYMPTOMS                                                                                                                                                                                                                                                                                                                                                                                              | Check if  Not  Applicable | Not at  all  0 | A little  bit 1 | Somewhat  2 | Quite a bit 3 |
| 18. I have a decreased enjoyment of anal sexual activity 19. I have a decreased enjoyment of forms of sexual activity  other than anal sexual activity 20. I have a decreased desire for anal sexual activity 21. I have a decreased desire for forms of sexual activity other  than anal sexual activity 22. I am worried about my condition getting worse 23. I have anxiety 24. I have depression 25. I have problems with my intimate relationships |                           |                |                 |             |               |
appendix xi anchor health-related symptom
laser surgical devices

A continuación presentamos una lista de afirmaciones que otras personas diagnosticadas con HSIL (lesión precancerosa en el ano) y que han sido tratadas o monitoreadas activamente han dicho que son importantes. Por favor seleccione la casilla con su respuesta basándose en sus experiencias en **los últimos 7 días**.  
| Muchísimo 4                                                                                                                                                                                                                                                                                                                                                                                       |                                                              |                      |            |             |            |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|----------------------|------------|-------------|------------|
| 1.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo dolor anal                                             |                      |            |             |            |
| 2.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo dolor pero no en el área anal                          |                      |            |             |            |
| 3.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo dolor cuando entro al baño a defecar                   |                      |            |             |            |
| 4.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo estreñimiento                                          |                      |            |             |            |
| 5.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo sangrado del ano                                       |                      |            |             |            |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo picazón en el ano o alrededor del ano                  |                      |            |             |            |
| 7.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo una secreción (mojado) en el área anal                 |                      |            |             |            |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                | Tengo sensación de ardor en el área anal                     |                      |            |             |            |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                | Siento urgencia de entrar al baño a defecar IMPACTOS FÍSICOS | Escoja si  no aplica |            |             |            |
| SÍNTOMAS FÍSICOS                                                                                                                                                                                                                                                                                                                                                                                  | Escoja si  no aplica                                         | Nada 0               | Un poco 1  | Algo 2      | Bastante 3 |
| Nada 0                                                                                                                                                                                                                                                                                                                                                                                            | Un poco 1                                                    | Algo 2               | Bastante 3 | Muchísimo 4 |            |
| 10. Tengo problemas con mi capacidad física para  moverme  11. Tengo problemas para sentarme 12. Tengo problemas manteniendo la casa (por ej.,  limpiar, cocinar, preparar el café, administrar la casa) 13. Problemas con mi arreglo personal (por ej.,  bañándome, vistiéndome, afeitándome)  14. Tengo problemas participando en actividades de relajo  (por ej., mirar televisión, relajarme) |                                                              |                      |            |             |            |  
| 15. Tengo problemas participando en actividades sociales  (por ej., salir a comer, visitar amigos)  16. Tengo problemas siendo productivo en el trabajo  debido a mis síntomas  SÍNTOMAS PSICOLÓGICOS                                                                                                                                                                                                                                                                                                                | Escoja si  no aplica   | Nada 0   | Un poco 1   | Algo 2   | Bastante 3   | Muchísimo 4   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|----------|-------------|----------|--------------|---------------|
| 17. Tengo dificultad concentrándome  18. Me ha disminuido el disfrute de la actividad sexual  anal  19. Me ha disminuido el disfrute de cualquier forma de  actividad sexual diferente a la actividad sexual anal  20. Me ha disminuido el deseo por la actividad sexual anal  21. Me ha disminuido el deseo por formas de actividad  sexual diferentes a la actividad sexual anal  22. Me preocupa que mi enfermedad empeore 23. Tengo ansiedad  24. Tengo depresión 25. Tengo problemas con mis relaciones íntimas |                        |          |             |          |              |               |