Effectiveness of Cervical Screening in Unvaccinated, Herd Effect Protected Women (HPV400) (HPV400)

Effectiveness of Cervical Screening in Unvaccinated, Herd Effect Protected Women - a Randomized Trial

To identify: 1) Whether being informed infrequently results about screening is at least as a) safe and b) accurate as frequently obtaining all information from (the present combination of opportunistic/organized) cervical screening by comparing regimen results of two screening visits at the ages of 25 and 28 years (Arm A1) vs. results of one screening visit at the age of 28 years (Arm A2) in unvaccinated herd effect protected women. Unvaccinated, frequently screened women, who are not under herd effect protection will be controls (C).

Study Overview

• Status: Enrolling by invitation
• Conditions: Cervical Intraepithelial Neoplasia Grade 2/3; Adenocarcinoma in Situ
• Intervention / Treatment: Other: Frequent information of cytological/ HPV DNA screening results

Detailed Description

Altogether 14.000 1995-1997 born women resident in communities where herd effect against high-risk HPV infections was created with gender-neutral vaccination of birth cohorts 1992-1995 (A-communities) or not (control C-communities) in 2007-2010 with the bi-valent HPV16/18 vaccine will be invited to participate a randomized screening trial at the ages of 25 and 28 years.

Cervical samples will be analysed for HPV DNA with MGP (Modified General Primer) primer system followed by MALDITOF(matrix assisted laser desorption ionization-time of flight mass spectrometry) mass spectrometry on the SEQUENOM (translation of genomic science into solutions for molecular medicine and biomedical research) platform (HPV).

With assumed 65% and 90% participation and retain rates the trial has 80% power to show non-inferiority of the infrequent vs. the frequent screening information.

At the study-end testing the null hypotheses of no difference in the incidence of the CIN2/3 (cervical squamous intraepithelial neoplasia 2/3) end-points comparing the A1 vs. C and A2 vs. C intervention arms will be done using the Mantel-Haenszel one degree of freedom chi-square statistics.

Work Content Letters of invitation to visit cervical screening at the nearest FICAN (Comprehensive Cancer Center Finland)-Mid study site will be send to the approximately 14.000 unvaccinated women at the ages of 25 and 28 years Following informed consent cervical liquid-based cytology samples will be taken for HPV DNA and/or cytology screening at study visits.

All cytological screening results will be communicated to Arm A1 and Arm C study participants. Arm A2 participants will get the test results at the age of 28. However, results of the cytology testing indicative of colposcopy according to local standard of care and currently accepted EU (the European Union) -guidelines (Käypä Hoito 2010, Franceschi et al. 2011) will be immediately communicated to all study participants. HPV DNA results will be communicated to all study participants at the study end. Pertinent colposcopy referrals to organized health care will be made.

All study participants will be offered a possibility to give an oropharyngeal sputum sample after 30 seconds gargling of sterile physiological saline (5 ml) for HPV PCR (polymerase chain reaction) analysis.

• Study Type: Interventional
• Enrollment (Estimated): 14000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland
    • HUS
  • Hämeenlinna, Finland, 40100
    • HPV-tutkimukset
  • Iisalmi, Finland, 74100
    • HPV-tutkimukset
  • Joensuu, Finland, 80100
    • HPV-tutkimukset
  • Jyväskylä, Finland, 40100
    • HPV-tutkimukset
  • Kemi, Finland, 94100
    • Nuorisotutkimusasema, PSHP/ Tampereen yliopisto
  • Kotka, Finland, 48100
    • Nuorisotutkimusasema, PSHP/Tampereen yliopisto
  • Kouvola, Finland, 45100
    • HPV-tutkimukset
  • Kuopio, Finland, 70100
    • Nuorisotutkimusasema, PSHP; Tampereen yliopisto
  • Lahti, Finland, 15110
    • Nuorisotutkimusasema, PSHP/ Tampereen yliopisto
  • Oulu, Finland, 90100
    • HPV-tutkimukset
  • Pori, Finland, 28100
    • HPV-tutkimukset
  • Porvoo, Finland, 06100
    • HPV-tutkimukset
  • Rauma, Finland, 26100
    • Nuorisotutkimusasema, PSHP; Tampereen yliopisto
  • Sastamala, Finland, 38200
    • HPV-tutkimukset
  • Seinäjoki, Finland, 60100
    • HPV-tutkimukset
  • Tampere, Finland, 33100
    • Nuorisotutkimusasema; PSHP/ Tamereen yliopisto
  • Varkaus, Finland, 78300
    • HPV-tutkimukset

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 25 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Born 1995-1997. 25 years of age residence in one of the eight community-randomized trial A communities with documented herd effect from gender-neutral vaccination or C communities devoid of the herd effect.

Exclusion Criteria:

• Immune compromising disease status (e.g. transplant recipients). HPV vaccination

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A1; Frequent information of screening results for cytology and/or HPV DNA at the ages of 25 (cytology only) and 28 (cytology only) vs A2	Other: Frequent information of cytological/ HPV DNA screening results; All participants will be referred to pertinent diagnosis and treatment according to local standard of care (Käypä hoito 2010) should the cytological screening results (HSIL, ASC-H, AGC-FN) or three consecutive LSIL findings at repeated control visits within 3 years indicate it. The most common screening results (ASCUS, LSIL) are, however, not convened to arm A2 participants before age 28. All cytology and HPV DNA results results are being revealed to all trial participants at age 28 at the study end.
No Intervention: A2; infrequent information of cytological screening/ HPV DNA results, only at the age 28 years.
Active Comparator: C; The third arm with at 8000 participants devoid of herd effect protection and frequent screening at ages 25 and 28 is enrolled for comparative analyses between A1 vs. C and A2 vs. C.	Other: Frequent information of cytological/ HPV DNA screening results; All participants will be referred to pertinent diagnosis and treatment according to local standard of care (Käypä hoito 2010) should the cytological screening results (HSIL, ASC-H, AGC-FN) or three consecutive LSIL findings at repeated control visits within 3 years indicate it. The most common screening results (ASCUS, LSIL) are, however, not convened to arm A2 participants before age 28. All cytology and HPV DNA results results are being revealed to all trial participants at age 28 at the study end.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The difference between arm A1 vs. arm C	No significant difference in the incidence ratios of CIN2/3 between arms A1 (participants under herd protection and frequently informed of the cytological results) vs. C (participants not under herd protection and frequently informed of the cytological findings) at the age of 28	Three years of follow up within 2020 - 2025
The difference between arm A2 vs. arm C	No significant difference in the incidence ratios of CIN2/3 between arms A2 (participants under herd protection and frequently informed of the cytological results) vs. C (participants not under herd protection and frequently informed of the cytological findings) at the age of 28.	Three years of follow up within 2020 - 2025

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life in infrequently vs. frequently screened unvaccinated women (RAND 36)	The difference between infrequently and frequently screened unvaccinated women at the age of 28 is measured using RAND 36 to measure quality of life. It consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability.	Three years of follow up within 2021 - 2025
Quality of life in infrequently vs. frequently screened unvaccinated women (EQ-VAS)	The difference between infrequently and frequently screened unvaccinated women at the age of 28 is measured using EQ-VAS a vertical visual analogue scale on which patients provide a global assessment of their health. The scale takes values between 100 (best imaginable health) and 0 (worst imaginable health).	Three years of follow up within 2021 - 2025
Quality of life in infrequently vs. frequently screened unvaccinated women (CECA 10)	The difference between infrequently and frequently screened unvaccinated women at the age of 28 is measured using CECA 10, a Spanish acronym for the Specific Questionnaire for Condylomata Acuminata, summary scores of the emotional and sexual activity dimensions will be derived from CECA 10 scales. The CECA questionnaire includes 10 questions across 2 domains: emotional and sexual activity. CECA scores range from 0 (worst HRQL) to 100 (best HRQL)	Three years of follow up within 2021 - 2025

Collaborators and Investigators

• Sponsor: Tampere University Hospital
• Collaborators: Karolinska Institutet; Tampere University; European Union
• Investigators: Principal Investigator: Matti Lehtinen, MD, PhD, Tampere University

Publications and helpful links

General Publications

• Lehtinen M, Elfstrom M, Vanska S, Dillner J. Elimination of cervical cancer by refined vaccination and screening. Int J Cancer. 2025 Feb 15;156(4):886-888. doi: 10.1002/ijc.35228. Epub 2024 Oct 25. No abstract available.
• Lehtinen M, Bruni L, Elfstrom M, Gray P, Logel M, Mariz FC, Baussano I, Vanska S, Franco EL, Dillner J. Scientific approaches toward improving cervical cancer elimination strategies. Int J Cancer. 2024 May 1;154(9):1537-1548. doi: 10.1002/ijc.34839. Epub 2024 Jan 9.
• Lehtinen M, Gray P, Louvanto K, Vanska S. In 30 years, gender-neutral vaccination eradicates oncogenic human papillomavirus (HPV) types while screening eliminates HPV-associated cancers. Expert Rev Vaccines. 2022 Jun;21(6):735-738. doi: 10.1080/14760584.2022.2064279. Epub 2022 Apr 15. No abstract available.
• Gray P, Kann H, Pimenoff VN, Eriksson T, Luostarinen T, Vanska S, Surcel HM, Faust H, Dillner J, Lehtinen M. Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial. PLoS Med. 2021 Jun 7;18(6):e1003588. doi: 10.1371/journal.pmed.1003588. eCollection 2021 Jun.
• Vanska S, Luostarinen T, Baussano I, Apter D, Eriksson T, Natunen K, Nieminen P, Paavonen J, Pimenoff VN, Pukkala E, Soderlund-Strand A, Dubin G, Garnett G, Dillner J, Lehtinen M. Vaccination With Moderate Coverage Eradicates Oncogenic Human Papillomaviruses If a Gender-Neutral Strategy Is Applied. J Infect Dis. 2020 Aug 17;222(6):948-956. doi: 10.1093/infdis/jiaa099.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2020
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 4, 2021
• First Submitted That Met QC Criteria: February 12, 2021
• First Posted (Actual): February 16, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Carcinoma; Neoplasms; Cervical Intraepithelial Neoplasia; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma in Situ; Adenocarcinoma in situ
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Uterine Diseases; Genital Diseases, Female; Neoplasms, Glandular and Epithelial; Carcinoma; Precancerous Conditions; Uterine Cervical Diseases; Carcinoma in Situ; Neoplasms; Adenocarcinoma; Uterine Cervical Dysplasia; Adenocarcinoma in Situ
• Other Study ID Numbers: HPV400

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No