{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:40:05Z","timestamp":1772163605953,"version":"3.50.1"},"reference-count":33,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shanghai Yahong MediTech Co., Ltd, Pudong, Shanghai, China.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,5,13]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>High-risk human papilloma virus (HPV)-associated cervical cancer is the fourth most common cancer in women worldwide. Current treatments of high-grade squamous intraepithelial lesion (HSIL) of the cervix are based on invasive surgical interventions, compromising cervical competence and functionality. APRICITY is a multicentre, prospective, double-blind, randomised controlled phase 3 study further evaluating the efficacy and safety of Cevira, an integrated drug-delivery and light-delivery device for hexaminolevulinate photodynamic therapy, which shows promise as a novel, non-invasive outpatient therapy for women with HSIL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>Patients with biopsy-confirmed HSIL histology are invited to participate in the study planned to be conducted at 47 sites in China and 25 sites in Ukraine, Russia and the European Union. The aim is to include at least 384 patients, which will be randomised to either Cevira or placebo group (2:1). All patients will be assessed 3 months after first treatment and a second treatment will be administered in patients who are HPV positive or have at least low-grade squamous intraepithelial lesion. Primary endpoint is the proportion of the responders 6 months after first treatment. Secondary efficacy and safety endpoints will be assessed at 6 months, and data for secondary performance endpoints of the Cevira device will be collected at 3 months and 6 months, in case second treatment was administered. All patients in the Cevira group will be enrolled in an open, long-term extension study for 6 months to collect additional efficacy and safety data (study extension endpoints).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study was approved by the ethics committee of the Peking Union Medical College Hospital and Hannover Medical University, Germany. Findings will be disseminated through peer review publications and conference presentations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04484415\">NCT04484415<\/jats:ext-link>\n                      ; clinicaltrials.gov.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-061740","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T11:31:21Z","timestamp":1654515081000},"page":"e061740","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Multicentre, prospective, randomised controlled trial to evaluate hexaminolevulinate photodynamic therapy (Cevira) as a novel treatment in patients with high-grade squamous intraepithelial lesion: APRICITY phase 3 study protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04484415","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04484415","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Fei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zolt\u00e1n","family":"Nov\u00e1k","sequence":"additional","affiliation":[{"name":"Aranyklinika Gynecology, Budapest, Hungary"},{"name":"Department of Gynaecology, National Institute of Oncology, Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Dannecker","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University Hospital Augsburg, Augsburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ctirad","family":"Mokr\u00e1\u0161","sequence":"additional","affiliation":[{"name":"MCM GYNPED, s.r.o, Dubnica nad Vahom, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Sui","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youzhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixue","family":"You","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Han","sequence":"additional","affiliation":[{"name":"Asieris Pharmaceuticals (Shanghai) Co., Ltd, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghe","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9829-3531","authenticated-orcid":false,"given":"Peter","family":"Hillemanns","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany"},{"name":"Comprehensive Cancer Center Niedersachsen, Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"key":"2025121515321743000_12.6.e061740.1","unstructured":"Cervical cancer. Available: https:\/\/www.who.int\/health-topics\/cervical-cancer"},{"key":"2025121515321743000_12.6.e061740.2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2025121515321743000_12.6.e061740.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(07)01183-8"},{"key":"2025121515321743000_12.6.e061740.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2010.02.002"},{"key":"2025121515321743000_12.6.e061740.5","unstructured":"Human papillomavirus (HPV) and cervical cancer. Available: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/human-papillomavirus-(hpv)-and-cervical-cancer"},{"key":"2025121515321743000_12.6.e061740.6","doi-asserted-by":"crossref","DOI":"10.3390\/v9100267","article-title":"Natural history of HPV infection across the lifespan: role of viral latency","volume":"9","author":"Gravitt","year":"2017","journal-title":"Viruses"},{"key":"2025121515321743000_12.6.e061740.7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008376","article-title":"Cervicovaginal microbiome and natural history of HPV in a longitudinal study","volume":"16","author":"Usyk","year":"2020","journal-title":"PLoS Pathog"},{"key":"2025121515321743000_12.6.e061740.8","unstructured":"Khieu M , Butler SL . High grade squamous intraepithelial Lesion. [Updated 2021 Jan 11]. In: StatPearls [online]. Treasure Island, FL: StatPearls Publishing, 2021. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430728\/"},{"key":"2025121515321743000_12.6.e061740.9","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-12-1406"},{"key":"2025121515321743000_12.6.e061740.10","unstructured":"WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. Available: https:\/\/www.who.int\/publications\/i\/item\/9789240030824"},{"key":"2025121515321743000_12.6.e061740.11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k499"},{"key":"2025121515321743000_12.6.e061740.12","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/1471-0528.16081","article-title":"Conservative management of women with cervical intraepithelial neoplasia grade 2 in Denmark: a cohort study","volume":"127","author":"Skorstengaard","year":"2020","journal-title":"BJOG: Int J Obstet Gy"},{"key":"2025121515321743000_12.6.e061740.13","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000525"},{"key":"2025121515321743000_12.6.e061740.14","article-title":"Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease","volume":"11","author":"Kyrgiou","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121515321743000_12.6.e061740.15","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-012-2493-1"},{"key":"2025121515321743000_12.6.e061740.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30700-3"},{"key":"2025121515321743000_12.6.e061740.17","doi-asserted-by":"crossref","DOI":"10.3802\/jgo.2016.27.e3","article-title":"Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis","volume":"27","author":"Onuki","year":"2016","journal-title":"J Gynecol Oncol"},{"key":"2025121515321743000_12.6.e061740.18","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000023155","article-title":"Clearance of human papillomavirus infection in patients with cervical intraepithelial neoplasia: a systemic review and meta-analysis","volume":"99","author":"Xiong","year":"2020","journal-title":"Medicine"},{"key":"2025121515321743000_12.6.e061740.19","doi-asserted-by":"crossref","DOI":"10.1016\/j.gore.2020.100608","article-title":"Topical therapies for the treatment of cervical intraepithelial neoplasia (CIN) 2-3: a narrative review","volume":"33","author":"Desravines","year":"2020","journal-title":"Gynecol Oncol Rep"},{"key":"2025121515321743000_12.6.e061740.20","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02478","article-title":"Advances in designing and developing vaccines, drugs and therapeutic approaches to counter human papilloma virus","volume":"9","author":"Dadar","year":"2018","journal-title":"Front Immunol"},{"key":"2025121515321743000_12.6.e061740.21","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2303.2008.00636.x"},{"key":"2025121515321743000_12.6.e061740.22","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/lsm.20095","article-title":"Time-dependent hexaminolaevulinate induced protoporphyrin IX distribution after topical application in patients with cervical intraepithelial neoplasia: a fluorescence microscopy study","volume":"35","author":"Andrejevic-Blant","year":"2004","journal-title":"Lasers Surg Med"},{"key":"2025121515321743000_12.6.e061740.23","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1517\/13543784.2015.990150","article-title":"Topical hexaminolevulinate photodynamic therapy for the treatment of persistent human papilloma virus infections and cervical intraepithelial neoplasia","volume":"24","author":"Hillemanns","year":"2015","journal-title":"Expert Opin Investig Drugs"},{"key":"2025121515321743000_12.6.e061740.24","doi-asserted-by":"crossref","first-page":"300.e1","DOI":"10.1016\/j.ajog.2007.07.045","article-title":"Pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate in patients with cervical intraepithelial neoplasia","volume":"198","author":"Hillemanns","year":"2008","journal-title":"Am J Obstet Gynecol"},{"key":"2025121515321743000_12.6.e061740.25","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/lsm.22255","article-title":"Efficacy and safety of hexaminolevulinate photodynamic therapy in patients with low-grade cervical intraepithelial neoplasia","volume":"46","author":"Hillemanns","year":"2014","journal-title":"Lasers Surg Med"},{"key":"2025121515321743000_12.6.e061740.26","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/lsm.22041","article-title":"Photodynamic therapy of cervical intraepithelial neoplasia 1-3 and human papilloma virus (HMV) infection with methylaminolevulinate and hexaminolevulinate-a double-blind, dose-finding study","volume":"44","author":"Soergel","year":"2012","journal-title":"Lasers Surg Med"},{"key":"2025121515321743000_12.6.e061740.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.10.1107"},{"key":"2025121515321743000_12.6.e061740.28","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/lsm.20979","article-title":"Effects of photodynamic therapy using topical applied hexylaminolevulinate and methylaminolevulinate upon the integrity of cervical epithelium","volume":"42","author":"Soergel","year":"2010","journal-title":"Lasers Surg Med"},{"key":"2025121515321743000_12.6.e061740.29","doi-asserted-by":"crossref","DOI":"10.3389\/fpubh.2020.552028","article-title":"Epidemiology and burden of human papillomavirus and related diseases, molecular pathogenesis, and vaccine evaluation","volume":"8","author":"Kombe Kombe","year":"2020","journal-title":"Front Public Health"},{"key":"2025121515321743000_12.6.e061740.30","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.2095-3941.2012.01.002"},{"key":"2025121515321743000_12.6.e061740.31","doi-asserted-by":"crossref","DOI":"10.3390\/cancers9020019","article-title":"Oncologic photodynamic therapy: basic principles, current clinical status and future directions","volume":"9","author":"van Straten","year":"2017","journal-title":"Cancers"},{"key":"2025121515321743000_12.6.e061740.32","doi-asserted-by":"crossref","DOI":"10.3389\/fchem.2021.686303","article-title":"Photodynamic therapy for the treatment and diagnosis of cancer-a review of the current clinical status","volume":"9","author":"Gunaydin","year":"2021","journal-title":"Front Chem"},{"key":"2025121515321743000_12.6.e061740.33","unstructured":"Einstein M , Sordal T , Lunde T . Safety of hexaminolevulinate photodynamic therapy - a non-extirpative treatment for cervical neoplasia (CIN). San Francisco: ASCCP, 2012."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-061740","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T23:32:29Z","timestamp":1765841549000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-061740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":33,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6,6]]},"published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1136\/bmjopen-2022-061740"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-061740","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.02.21266991","asserted-by":"object"}]},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6]]}}}