E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cervical intra-epithelial neoplasia |
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E.1.1.1 | Medical condition in easily understood language |
cervical high-grade pre-invasive lesions |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the research is to show that the vaccine Gardasil 9™ can reduce HPV infection in women with high grade cervical intra-epithelial neoplasia (CIN). High grade CIN is a condition where there are abnormal cells on at least two-thirds of the surface of the cervix (the opening to the vagina from the womb). Gardasil 9™ will be given at the same time as localised cervical treatment, a procedure which uses a scalpel or laser to remove a cone-shaped piece of the cervix containing the area with abnormal cells.
HPV infection following localised cervical treatment will be grouped as follows, and compared between the two treatment arms:
1. Incident - an infection detected 2 years after first dose that was not detected at baseline 2. Recurrent - an infection detected 2 years after first dose that was detected at baseline but not 6 months after first dose 3. Prevalent - an infection detected 2 years after first dose that was detected at baseline, 6 months after first dose, |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of the research are as follows:
- To look at levels of incident, recurrent and prevalent HPV infections separately, and compare between the two treatment arms - To look at the level of HPV infections after localised cervical treatment that are oncogenic, which means able to cause development of cancer - To look at the number of patients who develop new abnormal cells on at least two-thirds of the surface of the cervix, and whether these cells are able to cause development of cancer - To examine the safety of Gardasil 9™ in terms of adverse events (side effects)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Female 18-55 years old, attending hospital for localised cervical treatment for biopsy confirmed cervical intra-epithelial neoplasia (CIN) 2/3 - Written informed consent - Free of other relevant health problems as established by medical history and clinical examination - Able to comply with protocol including completion of diary cards, follow up etc |
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E.4 | Principal exclusion criteria |
- Women treated for cervical glandular intra-epithelial neoplasia (cGIN) / adenocarcinoma in situ (AIS) - Use of other investigational/ non-registered product within 30 days prior to the 1st vaccine dose - Continuous administration of immunosuppressants prior to the 1st vaccine dose - Previous vaccination against HPV with Gardasil™ or Cervarix™ - Cancer or autoimmune disease under treatment - Any confirmed or suspected immunosuppressive condition, including HIV infection - History of allergic disease or any neurologic disorders likely to interact with study vaccination - Acute febrile disease at enrolment (oral > 37.5°C / axillary temperature > 37.5°C) (will be postponed) - Pregnant women or women intending to get pregnant in the next year (if pregnant during follow-up, remaining doses will be delayed until after delivery)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is a weighted composite of the following 3 endpoints concerning the efficacy of the Gardasil 9™ HPV-vaccine as compared to no vaccine, all of which will be evaluated at 24 months after the first dose (i.e. by Month 24) in female subjects aged 18-55 years at the baseline local treatment.
• Against persistent incident (I) (>6 months interval) cervical infections with vaccine HPV types 6/11/16/18/31/33/45/52/58. Incident infection is defined as an HPV type not detected at baseline. • Against persistent recurrent (R) (>6months interval) cervical infections with vaccine HPV types 6/11/16/18/31/33/45/52/58. Recurrent is infection with a type present at baseline, but not detected at 6 months. • Against persistent prevalent (P) (>6 months interval) cervical re-infections with vaccine HPV types 6/11/16/18/31/33/45/52/58. Prevalent infection is one present at baseline, 6 months and 12 months.
The hypothesised efficacy is 20% for prevalent, 80% for incident and 50% for recurrent infection (50). Additionally, we anticipate that the ratio of women with each of these outcomes (P:I:R) will be 3:2:1 in the controls. In order to maximise the power under these assumptions (see Section 9.1 for details), the composite endpoint will be a weighted sum: 6 x “incident” + 3 x “recurrent” + 1 x “prevalent infection”.
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E.5.2 | Secondary end point(s) |
To evaluate the three components of the composite endpoint separately • Against post-treatment cervical infections (incident, recurrent, prevalent) with any oncogenic HPV types. • Against new, post-treatment, CIN2+ lesions (high-grade squamous intra-epithelial lesions (HSIL)) associated with vaccine HPV types 6/11/16/18/31/33/45/52/58. • Against new, post-treatment, CIN2+ lesions (HSIL) associated with any oncogenic HPV types. • To monitor the safety of Gardasil 9™ with the first dose given at conization.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as the last data capture for the LVLS on study; this will be 24 months after vaccination or 30 months if there has been one positive HPV test at 24 months after vaccination whichever is sooner |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 31 |