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HPV Test-and-Treat-Strategy Versus Cytology-based Strategy for Prevention of CIN2+ in HIV-Infected Women

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ClinicalTrials.gov Identifier: NCT01315353
Recruitment Status : Completed
First Posted : March 15, 2011
Results First Posted : May 11, 2018
Last Update Posted : May 11, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV-1 Infection
Interventions Procedure: Cervical Cryotherapy
Procedure: Loop Electrosurgical Excision Procedure (LEEP)
Enrollment 467
Recruitment Details Participants were enrolled from April 2012 to June 2014 from 7 different countries.
Pre-assignment Details  
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C : Ineligible for Randomization to Arm A or B
Hide Arm/Group Description

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants were eligible for Arm C under the conditions noted in the inclusion criteria. Participants in Arm C had colposcopy and directed biopsies at entry. If CIN2+ is found by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. After the week 26 visit, Arm C participants went off study.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Period Title: Overall Study
Started 145 143 179
Completed 116 120 166
Not Completed 29 23 13
Reason Not Completed
Death             2             1             0
Withdrawal by Subject             2             6             1
Lost to Follow-up             13             6             6
Unwilling to adhere to requirements             5             5             4
Site closing             7             4             0
Taken off study by site in error             0             1             0
Inadvertent randomization/assignment             0             0             2
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C : Ineligible for Randomization to Arm A or B Total
Hide Arm/Group Description

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants were eligible for Arm C under the conditions noted in the inclusion criteria. Participants in Arm C had colposcopy and directed biopsies at entry. If CIN2+ is found by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. After the week 26 visit, Arm C participants went off study.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Total of all reporting groups
Overall Number of Baseline Participants 145 143 177 465
Hide Baseline Analysis Population Description
Intent to treat: All eligible participants were included in the analysis.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 143 participants 177 participants 465 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
145
 100.0%
143
 100.0%
175
  98.9%
463
  99.6%
>=65 years
0
   0.0%
0
   0.0%
2
   1.1%
2
   0.4%
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 145 participants 143 participants 177 participants 465 participants
38
(32 to 42)
34
(29 to 39)
36
(32 to 42)
36
(31 to 41)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 143 participants 177 participants 465 participants
Female
145
 100.0%
143
 100.0%
177
 100.0%
465
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 143 participants 177 participants 465 participants
Black Non-Hispanic
106
  73.1%
107
  74.8%
156
  88.1%
369
  79.4%
Hispanic (Regardless of Race)
11
   7.6%
9
   6.3%
6
   3.4%
26
   5.6%
Asian, Pacific Islander
28
  19.3%
27
  18.9%
15
   8.5%
70
  15.1%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Haiti Number Analyzed 145 participants 143 participants 177 participants 465 participants
3
   2.1%
3
   2.1%
16
   9.0%
22
   4.7%
Malawi Number Analyzed 145 participants 143 participants 177 participants 465 participants
35
  24.1%
37
  25.9%
23
  13.0%
95
  20.4%
Botswana Number Analyzed 145 participants 143 participants 177 participants 465 participants
8
   5.5%
7
   4.9%
45
  25.4%
60
  12.9%
South Africa Number Analyzed 145 participants 143 participants 177 participants 465 participants
40
  27.6%
41
  28.7%
55
  31.1%
136
  29.2%
Zimbabwe Number Analyzed 145 participants 143 participants 177 participants 465 participants
20
  13.8%
19
  13.3%
17
   9.6%
56
  12.0%
Peru Number Analyzed 145 participants 143 participants 177 participants 465 participants
11
   7.6%
9
   6.3%
6
   3.4%
26
   5.6%
India Number Analyzed 145 participants 143 participants 177 participants 465 participants
28
  19.3%
27
  18.9%
15
   8.5%
70
  15.1%
CD4+ T-cell Count   [1] [2] 
Median (Inter-Quartile Range)
Unit of measure:  Cells/mm^3
Number Analyzed 108 participants 106 participants 146 participants 360 participants
529
(386 to 687)
479
(330 to 649)
568
(391 to 728)
521
(381 to 699)
[1]
Measure Description: CD4+ T-cell count at entry.
[2]
Measure Analysis Population Description: Includes participants with non-missing entry CD4+ T-cell counts.
Nadir CD4+ T-Cell Count   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 134 participants 135 participants 167 participants 436 participants
<=50 cells/mm^3
16
  11.9%
15
  11.1%
13
   7.8%
44
  10.1%
51-100 cells/mm^3
12
   9.0%
19
  14.1%
17
  10.2%
48
  11.0%
101-200 cells/mm^3
33
  24.6%
34
  25.2%
34
  20.4%
101
  23.2%
201-500 cells/mm^3
61
  45.5%
57
  42.2%
70
  41.9%
188
  43.1%
>500 cells/mm^3
12
   9.0%
10
   7.4%
33
  19.8%
55
  12.6%
[1]
Measure Description: Nadir CD4+ T-cell count at screening.
[2]
Measure Analysis Population Description: Included participants with non-missing nadir CD4+ T-cell count.
HIV-1 RNA   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 143 participants 177 participants 465 participants
<LLQ
93
  64.1%
85
  59.4%
116
  65.5%
294
  63.2%
>=LLQ
52
  35.9%
58
  40.6%
61
  34.5%
171
  36.8%
[1]
Measure Description: Entry HIV-1 RNA value categorized as below the assay's corresponding lower limit of quantification (<LLQ) or otherwise (>=LLQ).
Antiretroviral Therapy (ART) Use   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 143 participants 177 participants 465 participants
Not taking any ART
25
  17.2%
22
  15.4%
35
  19.8%
82
  17.6%
Taking any ART
120
  82.8%
121
  84.6%
142
  80.2%
383
  82.4%
[1]
Measure Description: Participants status of ART use at screening.
1.Primary Outcome
Title Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130
Hide Description

The Kaplan-Meier estimate of the cumulative rate of CIN2+ (CIN2, CIN3 or invasive cancer) by week 130.

Time to CIN2+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN2+ was first detected. For those who did not develop CIN2+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. CIN2+ diagnosis by biopsy was determined by local review at a DAIDS-assessed laboratory.

Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat: All eligible participants were included in the analysis: participants were analyzed per original assigned randomized treatment. Analysis was limited to the two randomized study arms (Arms A and B).
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 145 143
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Events per 100 persons
24.9
(16.9 to 32.9)
26.5
(18.3 to 34.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Treatment comparison was made using the difference (arm B - arm A) in the stratified Kaplan-Meier estimate for the week 130 cumulative rate of CIN2+ with 95% one-sided confidence interval.
Type of Statistical Test Superiority
Comments Confidence interval estimation was stratified by ART use at screening using Greenwood's variance with the inverse of this variance used for the stratum weights.
Method of Estimation Estimation Parameter Cumulative rate difference
Estimated Value 1.7
Confidence Interval (1-Sided) 95%
-7.9
Estimation Comments The lower bound of the (lower) one-sided 95% confidence interval was provided.
2.Secondary Outcome
Title Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory.
Hide Description Time to CIN2+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN2+ was first detected. For those who did not develop CIN2+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. The 10th percentile of the time to CIN2+ (the number of weeks at which 10% of participants had had CIN2+ diagnosis) is presented in the data table below.
Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 145 143
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: weeks
31
(28 to 66)
30
(27 to 87)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to time to CIN2+.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.94
Comments The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
Method Log Rank
Comments Log-rank test was stratified by ART use at screening.
3.Secondary Outcome
Title Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130.
Hide Description

The Kaplan-Meier estimate of the cumulative rate of CIN3+ (CIN3 or invasive cancer) by week 130.

Time to CIN3+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN3+ was first detected. For those who did not develop CIN3+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. CIN3+ diagnosis by biopsy was determined by local review at a DAIDS-assessed laboratory.

Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat: All eligible participants were included in the analysis: participants were analyzed per original assigned randomized treatment. Analysis was limited to the two randomized study arms (Arms A and B).
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 145 143
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Cumulative rate of events/100 persons
12.7
(6.8 to 18.6)
17.1
(10.0 to 24.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Treatment comparison was made using the difference (arm B - arm A) in the stratified Kaplan-Meier estimate for the week 130 cumulative rate of CIN3+ with 95% two-sided confidence interval.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cumulative rate difference
Estimated Value 4.4
Confidence Interval (2-Sided) 95%
-4.8 to 13.6
Estimation Comments Confidence interval estimation was stratified by ART use at screening using Greenwood’s variance with the inverse of this variance used for the stratum weights.
4.Secondary Outcome
Title Number of Participants Who Discontinued Study Early.
Hide Description The number of participants who did not complete the study.
Time Frame 0 to 130 weeks post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 145 143
Measure Type: Count of Participants
Unit of Measure: Participants
29
  20.0%
23
  16.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null hypothesis: There is no difference between Arm A and Arm B with respect to rate of premature study discontinuation.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.445
Comments The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
Method Fisher Exact
Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Abnormal Cytology Results at Study Visits.
Hide Description Number of participants with abnormal (ASCUS: atypical squamous cells; undetermined significance, ASC-H: atypical squamous cells; favor high-grade squamous intra-epithelial lesion, LSIL: low-grade squamous intraepithelial lesion/mild dysplasia/HPV, HSIL: high-grade squamous intraepithelial lesion/moderate or severe dysplasia/carcinoma in situ/features of invasion; squamous cell carcinoma) cytology results.
Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Included participants with available cytology results.
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 145 143
Measure Type: Count of Participants
Unit of Measure: Participants
Week 26: With Abnormal Cytology Number Analyzed 123 participants 116 participants
80
  65.0%
75
  64.7%
Week 52: With Abnormal Cytology Number Analyzed 118 participants 119 participants
80
  67.8%
72
  60.5%
Week 78: With Abnormal Cytology Number Analyzed 107 participants 105 participants
63
  58.9%
64
  61.0%
Week 104: With Abnormal Cytology Number Analyzed 97 participants 95 participants
57
  58.8%
62
  65.3%
Week 130: With Abnormal Cytology Number Analyzed 76 participants 93 participants
33
  43.4%
46
  49.5%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 26.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments P-value for the week 26 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between the Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 52.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.279
Comments

P-value for the week 52 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 78.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.781
Comments

P-value for the week 78 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 104.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.375
Comments

P-value for the week 104 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 130.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.444
Comments

P-value for the week 130 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits.
Hide Description Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Abbott Real Time high-risk HPV assay. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding.
Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Includes participants with results for Abbott Real Time high-risk HPV assay
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 122 111
Measure Type: Count of Participants
Unit of Measure: Participants
Week 26: With hr-HPV Detected Number Analyzed 122 participants 111 participants
74
  60.7%
78
  70.3%
Week 52: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 78: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 104: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 130: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.132
Comments

P-value for the week 26 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits.
Hide Description Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Xpert HPV assay. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding.
Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Includes participants with results for Xpert HPV assay
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 119 109
Measure Type: Count of Participants
Unit of Measure: Participants
Week 26: With hr-HPV Detected Number Analyzed 119 participants 109 participants
64
  53.8%
68
  62.4%
Week 52: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 78: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 104: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 130: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.227
Comments

P-value for the week 26 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
8.Secondary Outcome
Title Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits.
Hide Description Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Roche Linear Array HPV Genotyping test. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding.
Time Frame Weeks 26, 52, 78, 104 and 130 post randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Includes participants with results for the Roche Linear Array HPV Genotyping test.
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 92 91
Measure Type: Count of Participants
Unit of Measure: Participants
Week 26: With hr-HPV Detected Number Analyzed 92 participants 91 participants
74
  80.4%
73
  80.2%
Week 52: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 78: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 104: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Week 130: With hr-HPV Detected Number Analyzed 0 participants 0 participants
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
Comments Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments

P-value for the week 26 comparison.

The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.

Method Fisher Exact
Comments [Not Specified]
9.Secondary Outcome
Title Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A.
Hide Description Cryotherapy was performed in Arm A within 7 days of study entry. Targeted AEs four weeks after cryotherapy is provided in the data table below. The AE categories are not mutually exclusive. A participant may have experienced AEs and may be counted in more than one category.
Time Frame 4 weeks post cryotherapy
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Included Arm A participants who had cryotherapy.
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat)
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 142
Measure Type: Number
Unit of Measure: percentage of participants
Profuse watery vaginal discharge 20
Mild cervical bleeding 15
Heavy odorous discharge 13
Cervical infection 5
Mild watery vaginal discharge 4
Lower Abdominal Pain 3
Severe cramps or abdominal pain requiring parenter 3
Moderate Watery Vaginal Discharge 2
Pelvic inflammatory disease 1
Abdominal Pain, Mild, No Medicine Taken 1
Had Intermittent Blood Spotting Per Vagina 1
Heavy cervical bleeding 1
Light Watery Vaginal Discharge 1
Mild Odour 1
Mild P.V. Spotting 1
Mild Vaginal Bleeding 1
Mild Vaginal Bleeding Moderate Watery Vaginal Disc 1
Minimal Watery Discharge 1
Mod Watery Non Offensive Vag Discharge & Mod Yello 1
Moderate Offensive Vaginal Watery Discharge 1
Moderate Vaginal Discharge 1
Moderate Vaginal Watery Discharge And Minimal Yell 1
Moderate Vaginal Discharge & Minimal Yellowi 1
Post Coital Bleeding 1
Moderate Vaginal Watery & Brown Smelly Discharge 1
Slight Pv Discharge 1
Trichomonas Vaginitis 1
10.Secondary Outcome
Title Percentage of Participants With Targeted AEs Reported Post LEEP.
Hide Description LEEP was performed on participants who had CIN2+. For Arm A participants, LEEP was available starting at week 26; for Arms B and C, LEEP was available starting at study entry. Targeted AEs four weeks after LEEP is provided in the data table below. The AE categories are not mutually exclusive. A participant may have experienced AEs and may be counted in more than one category.
Time Frame 4 weeks post LEEP
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in each arm who had LEEP were included in the analysis.
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C : Ineligible for Randomization to Arm A or B
Hide Arm/Group Description:

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants were eligible for Arm C under the conditions noted in the inclusion criteria. Participants in Arm C had colposcopy and directed biopsies at entry. If CIN2+ is found by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. After the week 26 visit, Arm C participants went off study.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Overall Number of Participants Analyzed 24 34 54
Measure Type: Number
Unit of Measure: percentage of participants
Cervical bleeding 50 21 22
Vaginal discharge 12 15 31
Cramps or abdominal pain requiring parenteral meds 12 6 13
Vaginal Bleeding 4 3 13
Cervical infection 0 3 2
Metrorrhagia 4 0 0
Pelvic inflammatory disease 0 3 0
Time Frame AEs reported from entry visit to off study visit (at week 130 or earlier).
Adverse Event Reporting Description At entry, all signs/symptoms (s/s) and lab values Grade >=3 that occurred within 45 days prior to entry were recorded; post entry, s/s and lab values Grade >=3 were recorded. Post entry, all grades of s/s related to cervical cryotherapy or LEEP treatments included in Addendum 1 were reported. SUSAR Reporting Category in DAIDS EAE Manual V2.0 was used. Grading was based on DAIDS AE Grading Table (V1.0) and Addendum 1.
 
Arm/Group Title Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C: Ineligible for Randomization to Arm A or B
Hide Arm/Group Description

Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP.

Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

Participants were eligible for Arm C under the conditions noted in the inclusion criteria. Participants in Arm C had colposcopy and directed biopsies at entry. If CIN2+ is found by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. After the week 26 visit, Arm C participants went off study.

Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.

All-Cause Mortality
Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C: Ineligible for Randomization to Arm A or B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/145 (1.38%)   1/143 (0.70%)   0/177 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C: Ineligible for Randomization to Arm A or B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/145 (3.45%)   2/143 (1.40%)   5/177 (2.82%) 
Infections and infestations       
Localised infection  1  1/145 (0.69%)  0/143 (0.00%)  0/177 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Cervix carcinoma  1  1/145 (0.69%)  1/143 (0.70%)  0/177 (0.00%) 
Cervix carcinoma stage 0  1  1/145 (0.69%)  0/143 (0.00%)  0/177 (0.00%) 
Squamous cell carcinoma of the cervix  1  0/145 (0.00%)  0/143 (0.00%)  1/177 (0.56%) 
Pregnancy, puerperium and perinatal conditions       
Abortion spontaneous  1  1/145 (0.69%)  0/143 (0.00%)  0/177 (0.00%) 
Foetal death  1  0/145 (0.00%)  1/143 (0.70%)  0/177 (0.00%) 
Reproductive system and breast disorders       
Cervical dysplasia  1  1/145 (0.69%)  0/143 (0.00%)  1/177 (0.56%) 
Cervix haemorrhage uterine  1  0/145 (0.00%)  0/143 (0.00%)  1/177 (0.56%) 
Vaginal haemorrhage  1  0/145 (0.00%)  0/143 (0.00%)  2/177 (1.13%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm A: Immediate Cryotherapy (HPV Test-and-treat) Arm B: Cytology-based Strategy Arm C: Ineligible for Randomization to Arm A or B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   60/145 (41.38%)   49/143 (34.27%)   38/177 (21.47%) 
Gastrointestinal disorders       
Abdominal pain lower  1  14/145 (9.66%)  3/143 (2.10%)  3/177 (1.69%) 
Infections and infestations       
Bacterial vaginosis  1  25/145 (17.24%)  27/143 (18.88%)  9/177 (5.08%) 
Cervicitis  1  29/145 (20.00%)  20/143 (13.99%)  27/177 (15.25%) 
Cervicitis trichomonal  1  9/145 (6.21%)  5/143 (3.50%)  2/177 (1.13%) 
Vulvovaginal candidiasis  1  9/145 (6.21%)  10/143 (6.99%)  3/177 (1.69%) 
Pregnancy, puerperium and perinatal conditions       
Pregnancy  1  9/145 (6.21%)  8/143 (5.59%)  3/177 (1.69%) 
Reproductive system and breast disorders       
Cervical dysplasia  1  12/145 (8.28%)  13/143 (9.09%)  18/177 (10.17%) 
Vaginal discharge  1  39/145 (26.90%)  15/143 (10.49%)  15/177 (8.47%) 
Vaginal haemorrhage  1  10/145 (6.90%)  3/143 (2.10%)  5/177 (2.82%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone: (301) 628-3313
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01315353     History of Changes
Other Study ID Numbers: ACTG A5282
1U01AI068636 ( U.S. NIH Grant/Contract )
First Submitted: March 14, 2011
First Posted: March 15, 2011
Results First Submitted: February 1, 2018
Results First Posted: May 11, 2018
Last Update Posted: May 11, 2018