HPV Test-and-Treat-Strategy Versus Cytology-based Strateg... | NCT01315353

ID	Type	Description	Link
1U01AI068636	U.S. NIH Grant/Contract		View source

HPV Test-and-Treat-Strategy Versus Cytology-based Strateg... | NCT01315353 | Trialant

Sponsor/Collaborators Module

Name	Class
National Institute of Allergy and Infectious Diseases (NIAID)	NIH

Description Module

Detailed Description

The study had two components:

a randomized open-label comparison between immediate cryotherapy (test-and-treat strategy; Arm A) and cytology-based strategy (Arm B) in participants detected with high-risk HPV (hr-HPV), and
a brief cohort follow-up for participants for whom cryotherapy was inappropriate (Arm C).

The study's primary objective was to evaluate the effectiveness of immediate cryotherapy (Arm A) compared to the cytology-based strategy (Arm B).

The total target sample size was up to 450 (280 for Arms A and B, approximately 170 for Arm C). Randomization to Arms A and B was stratified by use of antiretroviral therapy (ART) at screening (taking any ART or not taking any ART) with institutional balancing.

All study participants were screened with the Abbott RealTime hr-HPV test (aHPV) to detect hr-HPV infection.

At screening, the examiner also performed a visual inspection and colposcopy without biopsies to determine whether the candidate's cervix was suitable for cryotherapy (see inclusion criteria for definition).

Participants with cervical lesions inappropriate for cryotherapy were not eligible for randomization (to Arms A or B) but were eligible to register to Arm C. Participants without hr-HPV (by aHPV) were also eligible to register to Arm C if lesions were seen on the screening colposcopy or if the screening cytology showed high-grade squamous intraepithelial lesions (HSIL). Arm C provided a larger number of participants for assessments of HPV genotypes found in CIN2+ (cervical intraepithelial neoplasia grade 2, 3, or invasive cancer) biopsy specimens and of the effect of LEEP on prevalent hr-HPV infections. In addition, Arm C provided important data for implementation of the HPV test-and-treat strategy including the role of HPV testing in the management of women with extensive cervical lesions inappropriate for cervical cryotherapy, hr-HPV negative women with cervical lesions or HSIL cytology.

Participants in Arm A undergo one or two cervical biopsies followed by immediate cervical cryotherapy at entry. Up to two visible lesions were biopsied. If no lesions were seen, then one normal-appearing area of the cervix was biopsied. Participants in Arm A received the results of the biopsy, but participants received cryotherapy treatment regardless of the results.

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

Participants in Arms A and B were seen at weeks 26, 52, 78, 104 and 130 post entry for evaluation using aHPV, HPV DNA PCR, cervical cytology, and cervical colposcopy and directed biopsies for a total follow-up length of 130 weeks. Biopsies were expected for participants with abnormal cytology and with visible cervical lesions on colposcopy.

Participants in Arm C undergo colposcopy and directed biopsies. If CIN2+ was detected by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for evaluation using aHPV, HPV DNA PCR, Xpert HPV, cervical cytology, and cervical colposcopy and directed biopsies. After the week 26 visit, Arm C participants went off study.

All participants who had cryotherapy or LEEP were seen 4 weeks post-procedure to evaluate potential adverse events (AEs) from the procedure.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm A: Immediate cryotherapy (HPV test-and-treat)	Experimental	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.	Procedure: Cervical Cryotherapy Procedure: Loop Electrosurgical Excision Procedure (LEEP)
Arm B: cytology-based strategy	Experimental	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed).	Procedure: Loop Electrosurgical Excision Procedure (LEEP)
Arm C : Ineligible for randomization to Arm A or B	Experimental	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+ was 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.	Procedure: Loop Electrosurgical Excision Procedure (LEEP)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Cervical Cryotherapy	Procedure	Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130	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.	Weeks 26, 52, 78, 104 and 130 post randomization

Secondary Outcomes

Measure	Description	Time Frame
Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory.	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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

HIV-1 infection.
Certain laboratory values obtained within 45 days prior to study entry (more information can be found in the protocol).
For candidates suitable for cervical cryotherapy, hr-HPV detected by aHPV within 45 days prior to study entry.
For women without hr-HPV detected by the aHPV assay, presence of lesions on visual inspection or HSIL cervical cytology. These participants are not eligible for randomization to Arms A or B and were followed in Arm C.
Suitable candidate for cervical cryotherapy (as defined in the protocol): No visible cervical lesions, OR (a) any visible lesions were located entirely on the ectocervix and were no more than 2 to 3 mm. into the endocervical canal, AND (b) visible lesions covered less than 75% of the cervix, AND (c) all visible lesions were deemed appropriate for cryotherapy by the treating local health care provider.

NOTE: Participants with cervical lesions inappropriate for cryotherapy are not eligible for randomization to Arms A or B and were followed in Arm C.

For participants of reproductive potential, negative pregnancy test within 48 hours prior to study entry.
Must agree not to participate in a conception process (e.g. active attempt to get pregnant or in vitro fertilization), or use at least one reliable contraceptive if participating in sexual activity, from time of study entry until 12 weeks after study entry.
If recently gave birth, must be at least 12 weeks postpartum.
Ability and willingness of participant or legal guardian/representative to provide written informed consent.

Exclusion Criteria:

Current or prior history of cervical, vaginal, or vulvar cancer.
Prior cervical cryotherapy, LEEP, cervical conization, or total or partial hysterectomy.
Cervical, vaginal, or vulvar lesions that are suspicious on clinical exam for cancer.
Visual evidence of bacterial STIs (sexually transmitted infections) or suspicion of pelvic inflammatory disease.
Prior vaccination with an HPV vaccine.
Hemophilia.
Currently on anticoagulation therapy other than acetylsalicylic acid.
Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to study entry.
Active drug or alcohol use or dependence or any other condition that, in the opinion of the site investigator, would interfere with the participant's ability to adhere to study requirements.

Contacts/Locations Module

Name	Affiliation	Role
Timothy J Wilkin, MD, MPH	Cornell Clinical Research Site	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Gaborone Prevention/Treatment Trials CRS (12701)		Gaborone			Botswana
Molepolole Prevention/Treatment Trials CRS (12702)

References Module

Label	URL
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009.	View source
Addendum 1 Female Genital Grading Table for Use in Microbicide Studies	View source

ID	Title	Description
FG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Jul 13, 2017	Jan 31, 2018

ID	Title	Description
BG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
BG001	Arm B: Cytology-based Strategy	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.
BG002	Arm C : Ineligible for Randomization to Arm A or B	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.
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG000145 BG001143 BG002177 BG003465

Categories

Title	Measurements
	OG00024.9(16.9 to 32.9) OG00126.5(18.3 to 34.7)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.					Cumulative rate difference	1.7			1-Sided	95	-7.9				The lower bound of the (lower) one-sided 95% confidence interval was provided.		Superiority	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.

Secondary

Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory.

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.

Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).

Posted

Number

95% Confidence Interval

weeks

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy

Secondary

Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130.

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.

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).

Posted

Number

95% Confidence Interval

Cumulative rate of events/100 persons

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001

Secondary

Number of Participants Who Discontinued Study Early.

The number of participants who did not complete the study.

Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).

Posted

Count of Participants

Participants

0 to 130 weeks post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Secondary

Number of Participants With Abnormal Cytology Results at Study Visits.

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.

Included participants with available cytology results.

Posted

Count of Participants

Participants

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Secondary

Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits.

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.

Includes participants with results for Abbott Real Time high-risk HPV assay

Posted

Count of Participants

Participants

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Secondary

Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits.

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.

Includes participants with results for Xpert HPV assay

Posted

Count of Participants

Participants

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Secondary

Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits.

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.

Includes participants with results for the Roche Linear Array HPV Genotyping test.

Posted

Count of Participants

Participants

Weeks 26, 52, 78, 104 and 130 post randomization

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Secondary

Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A.

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.

Included Arm A participants who had cryotherapy.

Posted

Number

percentage of participants

4 weeks post cryotherapy

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.

Units	Counts
Participants

Secondary

Percentage of Participants With Targeted AEs Reported Post LEEP.

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.

Participants in each arm who had LEEP were included in the analysis.

Posted

Number

percentage of participants

4 weeks post LEEP

ID	Title	Description
OG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.
OG001	Arm B: Cytology-based Strategy	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	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.	2	145	5	145	60	145
EG001	Arm B: Cytology-based Strategy	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.	1	143	2	143	49	143
EG002	Arm C: Ineligible for Randomization to Arm A or B	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.	0	177	5	177	38	177

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Localised infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected145 at risk EG0010 affected143 at risk EG0020 affected177 at risk
Cervix carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0001 affected145 at risk EG0011 affected143 at risk EG0020 affected177 at risk
Cervix carcinoma stage 0	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0001 affected145 at risk EG0010 affected143 at risk EG0020 affected177 at risk
Squamous cell carcinoma of the cervix	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0000 affected145 at risk EG0010 affected143 at risk EG0021 affected177 at risk
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA 20.0	Systematic Assessment	EG0001 affected145 at risk EG0010 affected143 at risk EG0020 affected177 at risk
Foetal death	Pregnancy, puerperium and perinatal conditions	MedDRA 20.0	Systematic Assessment	EG0000 affected145 at risk EG0011 affected143 at risk EG0020 affected177 at risk
Cervical dysplasia	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected145 at risk EG0010 affected143 at risk EG0021 affected177 at risk
Cervix haemorrhage uterine	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected145 at risk EG0010 affected143 at risk EG0021 affected177 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected145 at risk EG0010 affected143 at risk EG0022 affected177 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain lower	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG00014 affected145 at risk EG0013 affected143 at risk EG0023 affected177 at risk
Bacterial vaginosis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG00025 affected145 at risk EG00127 affected143 at risk EG0029 affected177 at risk
Cervicitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG00029 affected145 at risk EG00120 affected143 at risk EG00227 affected177 at risk
Cervicitis trichomonal	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0009 affected145 at risk EG0015 affected143 at risk EG0022 affected177 at risk
Vulvovaginal candidiasis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0009 affected145 at risk EG00110 affected143 at risk EG0023 affected177 at risk
Pregnancy	Pregnancy, puerperium and perinatal conditions	MedDRA 20.0	Systematic Assessment	EG0009 affected145 at risk EG0018 affected143 at risk EG0023 affected177 at risk
Cervical dysplasia	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG00012 affected145 at risk EG00113 affected143 at risk EG00218 affected177 at risk
Vaginal discharge	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG00039 affected145 at risk EG00115 affected143 at risk EG00215 affected177 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG00010 affected145 at risk EG0013 affected143 at risk EG0025 affected177 at risk

Title	Measurements
<=50 cells/mm^3	BG00016 BG00115 BG00213 BG00344
51-100 cells/mm^3	BG00012 BG00119 BG00217 BG00348
101-200 cells/mm^3	BG00033 BG00134 BG00234 BG003101
201-500 cells/mm^3	BG00061 BG00157 BG00270 BG003188
>500 cells/mm^3	BG00012 BG00110 BG00233 BG00355

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Null Hypothesis: There is no difference between Arm A and Arm B with respect to time to CIN2+.	Log Rank	Log-rank test was stratified by ART use at screening.	0.94	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.													Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.					Cumulative rate difference	4.4			2-Sided	95	-4.8	13.6			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.		Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Null hypothesis: There is no difference between Arm A and Arm B with respect to rate of premature study discontinuation.	Fisher Exact		0.445	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.													Other

Title

Denominators

Categories

Week 26: With Abnormal Cytology

- ParticipantsOG000123
- ParticipantsOG001116

Title	Measurements
	OG00080 OG00175

Week 52: With Abnormal Cytology

- ParticipantsOG000118
- ParticipantsOG001119

Title	Measurements
	OG00080 OG001

Week 78: With Abnormal Cytology

- ParticipantsOG000107
- ParticipantsOG001105

Title	Measurements
	OG00063 OG001

Week 104: With Abnormal Cytology

- ParticipantsOG00097
- ParticipantsOG00195

Title	Measurements
	OG00057 OG001

Week 130: With Abnormal Cytology

- ParticipantsOG00076
- ParticipantsOG00193

Title	Measurements
	OG00033 OG001

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Non-Inferiority Type
OG000 OG001	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.	Fisher Exact	1.000	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.	Other
OG000 OG001	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.	Fisher Exact	0.279	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.	Other
OG000 OG001	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.	Fisher Exact	0.781	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.	Other
OG000 OG001	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.	Fisher Exact	0.375	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.	Other
OG000 OG001	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.	Fisher Exact	0.444	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.	Other

Title

Denominators

Categories

Week 26: With hr-HPV Detected

- ParticipantsOG000122
- ParticipantsOG001111

Title	Measurements
	OG00074 OG00178

Week 52: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 78: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 104: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 130: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Fisher Exact		0.132	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.													Other

Title

Denominators

Categories

Week 26: With hr-HPV Detected

- ParticipantsOG000119
- ParticipantsOG001109

Title	Measurements
	OG00064 OG00168

Week 52: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 78: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 104: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 130: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Fisher Exact		0.227	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.													Other

Title

Denominators

Categories

Week 26: With hr-HPV Detected

- ParticipantsOG00092
- ParticipantsOG00191

Title	Measurements
	OG00074 OG00173

Week 52: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 78: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 104: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Week 130: With hr-HPV Detected

- ParticipantsOG0000
- ParticipantsOG0010

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Fisher Exact		1.000	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.													Other

Title

Denominators

Categories

Profuse watery vaginal discharge

Title	Measurements
	OG00020

Mild cervical bleeding

Title	Measurements
	OG00015

Heavy odorous discharge

Title	Measurements
	OG00013

Cervical infection

Title	Measurements
	OG0005

Mild watery vaginal discharge

Title	Measurements
	OG0004

Lower Abdominal Pain

Title	Measurements
	OG0003

Severe cramps or abdominal pain requiring parenter

Title	Measurements
	OG0003

Moderate Watery Vaginal Discharge

Title	Measurements
	OG0002

Pelvic inflammatory disease

Title	Measurements
	OG0001

Abdominal Pain, Mild, No Medicine Taken

Title	Measurements
	OG0001

Had Intermittent Blood Spotting Per Vagina

Title	Measurements
	OG0001

Heavy cervical bleeding

Title	Measurements
	OG0001

Light Watery Vaginal Discharge

Title	Measurements
	OG0001

Mild Odour

Title	Measurements
	OG0001

Mild P.V. Spotting

Title	Measurements
	OG0001

Mild Vaginal Bleeding

Title	Measurements
	OG0001

Mild Vaginal Bleeding Moderate Watery Vaginal Disc

Title	Measurements
	OG0001

Minimal Watery Discharge

Title	Measurements
	OG0001

Mod Watery Non Offensive Vag Discharge & Mod Yello

Title	Measurements
	OG0001

Moderate Offensive Vaginal Watery Discharge

Title	Measurements
	OG0001

Moderate Vaginal Discharge

Title	Measurements
	OG0001

Moderate Vaginal Watery Discharge And Minimal Yell

Title	Measurements
	OG0001

Moderate Vaginal Discharge & Minimal Yellowi

Title	Measurements
	OG0001

Post Coital Bleeding

Title	Measurements
	OG0001

Moderate Vaginal Watery & Brown Smelly Discharge

Title	Measurements
	OG0001

Slight Pv Discharge

Title	Measurements
	OG0001

Trichomonas Vaginitis

Title	Measurements
	OG0001

Title

Denominators

Categories

Cervical bleeding

Title	Measurements
	OG00050 OG00121 OG00222

Vaginal discharge

Title	Measurements
	OG00012 OG00115 OG00231

Cramps or abdominal pain requiring parenteral meds

Title	Measurements
	OG00012 OG0016 OG00213

Vaginal Bleeding

Title	Measurements
	OG0004 OG0013 OG00213

Cervical infection

Title	Measurements
	OG0000 OG0013 OG0022

Metrorrhagia

Title	Measurements
	OG0004 OG0010 OG0020

Pelvic inflammatory disease

Title	Measurements
	OG0000 OG0013 OG0020