| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Women infected by HPV 16 and/or HPV 18 with normal cytology or ASCUS/LSIL |
|
| E.1.1.1 | Medical condition in easily understood language |
| Human Papillomavirus infection before precancerous cervical smear. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064328 |
| E.1.2 | Term | Human papilloma virus test positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
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| 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 |
To evaluate the efficacy of ProCervix adjuvanted with imiquimod, in comparison with placebo adjuvanted with imiquimod, to induce HPV 16 and 18 viral clearance at 12 months in HPV 16 and/or 18 infected women using a type specific, sensitive and quantitative HPV polymerase chain reaction (PCR) assay.
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|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of ProCervix adjuvanted with imiquimod, in comparison with placebo to induce HPV 16 and 18 sustained viral clearance.
2. To evaluate the efficacy of ProCervix adjuvanted with imiquimod, in comparison with placebo , to induce HPV 16 and/or 18 viral clearance at 6, 12, 15, 18 and 24 months.
3. To evaluate the safety and tolerability of ProCervix adjuvanted with imiquimod.
Exploratory (in brief):
1. To assess HPV 16 and/or HPV 18 viral clearance at one or more timepoints up to 12, 18 and 24 months in HPV 16 and/or 18 infected woman.
2. To evaluate the cellular and humoral immunogenicity of ProCervix adjuvanted with imiquimod.
3. To assess regression of cytological abnormalities and histological lesions at 12, 18 and 24 months in subjects with HPV 16 and/or HPV 18-associated ASCUS/LSIL at enrolment.
4. To assess the prevention of progression to CIN2+ in HPV 16 and/or 18 infected women 18 and 24 months after first immunisation.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study if the following criteria apply:
1. Subject is female between the ages of 25 and 50 years (inclusive).
2. Subject is pre-menopausal (referring to the time period preceding menopause, excluding perimenopause) and not on hormone replacement therapy (HRT).
3. Subject must have cervical HPV 16 and/or 18 infection confirmed by Riatol realtime polymerase chain reaction (RT-PCR) assay at baseline. Subject can be co-infected with other HPV serotypes.
4. Subject has a cervical cytological evaluation with a normal, ASCUS or LSIL result at baseline.
5. Subject has employed highly effective contraception the month prior to the first vaccination and will agree to employ highly effective contraception for at least 12 months after the first vaccination. Highly effective methods of birth control include those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectable, combined oral contraceptives, levonorgestrel-releasing intrauterine system, intra-uterine devices (IUDs), vasectomised partner and true sexual abstinence.
6. Subject is in general good health based on medical history and physical examination.
7. Subject is able to communicate effectively with study personnel and is considered reliable, willing, and cooperative in terms of compliance with the protocol requirements.
8. Subject voluntarily gives written informed consent to participate in the study. |
|
| E.4 | Principal exclusion criteria |
A subject who meets any of the following exclusion criteria must not be enrolled:
1. Subject has a current acute or chronic disease, other than infection with HPV, which would be expected to interfere with the planned evaluations of response to ProCervix, in the judgment of the Investigator.
2. Subject has vaginal atrophy with or without topical hormonal therapies or systemic selective estrogen receptor modulators (SERMs).
3. Subject has prior exposure to HPV prophylactic vaccine or subject has participated in the past in another vaccination clinical trial related to infection with HPV including vaccination with ProCervix.
4. Current high grade lesions or history of untreated high grade cervical lesion (either CIN2 or CIN3).
5. Subject has current or a history of cancer of the cervix.
6. Subject has clinically significant (CS) gynaecological abnormalities that could interfere with study evaluation, in the judgment of the Investigator (e.g. prolapse, myoma, fibroid, hysterectomy).
7. Subject has a laboratory abnormality Grade ≥ 2, as defined using the Toxicity
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in
Preventative Vaccine Clinical Trials for the following parameters:
- haemoglobin (Hb)
- haematocrit (Hct)
- white blood cell count (WBC)
- lymphocytes
- neutrophils
- eosinophils
- platelet count (plt)
- urea nitrogen (BUN)
- creatinine
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)
- alkaline phosphatase (ALP)
- total bilirubin (Tbili)
- prothrombin time (PT)
8. Subject has received any live viral vaccine within 3 months or any other non-live vaccine within 2 weeks prior to screening.
9. Subject has primary or secondary systemic immunosuppression (defined as prolonged [≥ 7 days] use of corticosteroids that is greater than or equal to 20 mg of prednisone-equivalent per day or any other immunosuppressive drug).
10. Subject has a history of severe allergy (requiring hospital care) or history of severe asthma requiring oral or parenteral drug management in the last year (treatments with inhaled corticosteroids, short-acting beta agonists [SABA], long-acting beta agonists [LABA] or theophylline are allowed).
11. Subject has a history malignancy, except the following adequately treated cancers: basal cell carcinoma, or dermatological squamous cell carcinoma.
12. Subject was administered with another investigational drug or vaccine within 30days prior to the screening visit or is participating in any other study.
13. Subject has a known hypersensitivity to imiquimod.
14. Subject has a history of severe reaction to any drug, include kamamycin or vaccination.
15. Subject has a medical condition with clinical and/or biological consequences judged by the Investigator incompatible with vaccination(s).
16. Subject has positive results for human immunodeficiency virus (HIV), hepatitis B virus (HBV) surface antigen (HBsAg), or hepatitis C virus (HCV).
17. Subject has a symptomatic vaginal or genital infection (for example, symptomatic candida infection). If appropriate in the judgment of the Investigator, subjects with symptomatic infection may be treated and reconsidered for enrolment after resolution of the symptomatic infection.
18. Subject has a history of or currently active genital herpes disease.
19. Subject is pregnant or is breastfeeding.
20. Subject has a positive serum human chorionic gonadotrophin (HCG) result at enrolment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The clearance (non detection of HPV 16 and or HPV18 DNA by RT-PCR at one specific visit) at Month 12 of HPV 16 and HPV 18 infection using a type specific, sensitive and quantitative HPV PCR assay. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At month 12 clearance of HPV 16 and 18 infection. |
|
| E.5.2 | Secondary end point(s) |
Secondary virology endpoints:
1. Clearance at Month 6, 15, 18 and 24 of HPV 16 and HPV 18 infection.
2. Confirmed clearance of HPV 16 and HPV 18 infection at two consecutive visits at least 6 months apart.
3. Sustained clearance of HPV 16 and HPV 18 infection. Of note: Unless otherwise specified, missing data will not be replaced. However, some imputation of missing data might be performed for some efficacy analyses as detailed in the Statistical Analysis Plan.
4. Time to the first clearance of HPV 16 and HPV 18 infection.
5. Duration of the first clearance of HPV 16 and/or HPV 18 infection.
6. Proportion of incident HPV 16 or HPV 18 infections when absent at baseline.
Safety:
1. Occurrence, intensity, duration and relationship of any solicited local and general reactions during a 14-day follow-up period after each ProCervix or placebo dose.
2. Occurrence, intensity, duration and relationship of unsolicited adverse events occurring during the 14-day period following each vaccination and throughout the study.
3. Occurrence and relationship of all SAEs occurring throughout the study period.
4. Haematologic and biochemical levels outside the normal laboratory ranges at each specified visit.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Months 6, 15, 18 and 24 of infection.
2. Measured on Month 12, 18 and 24 of trial period.
3. Measured on Month 24 of trial period.
4/5/6. Measured on Month 6, 12, 15, 18 and 24 of trial period.
Safety:
1. 14-day follow up period (i.e. day of administration and 13 subsequent days).
2. 14-day period following each vaccination and throughout the study
3/4. Study period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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