Efficacy, Immunogenicity and Safty Study of Recombinant Human Papillomavirus Vaccine(6,11,16,18,31,33,45,52,58 Type)(E.Coli)

Study Overview
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Brief Summary
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This phase III clinical study was designed to evaluate the efficacy,immunogenicity and safety of Recombinant Human Papillomavirus Vaccine (6,11,16,18,31,33,45,52,58 Type)(E.Coli) manufactured by Xiamen Innovax Biotech CO., LTD., in healthy women aged 18-45 years old.

Official Title
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A Multicenter, Randomized, Double-Blind, Controlled (Bivalent Human Papillomavirus Vaccine (16,18 Type)(E. Coli)) Phase III Clinical Trial to Estimate Efficacy, Immunogenicity and Safty of the Recombinant Human Papillomavirus Vaccine (6,11,16,18,31,33,45,52,58 Type) (E.Coli) in Healthy Women Aged 18 to 45 Years

Conditions
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Condylomata Acuminata, Cervical Intraepithelial Neoplasia, Cervical Cancer

Intervention / Treatment
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* Biological: Nonavalent HPV vaccine
* Biological: Bivalent HPV vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged between 18 and 45 years at the first vaccination; Be able to understand and comply with the request of the protocol(e.g. biological specimen collection, diary card entry and attend regular follow-up), and sign written informed consent; Women who agree to use effective contraception within 8 months after the first vaccination, or women who have undergone tubal ligation, benign subtotal hysterectomy, benign ovarian tumor removal, or postmenopausal women; The number of sexual partners so far less than four; Have intact cervix and have no history of physical or surgical treatment; No previous history of sexually transmitted diseases (including syphilis, gonorrhea, chancroid, venereal lymphogranuloma, groin granuloma, etc.); No previous history of abnormal cervical screening results or cervical intraepithelial neoplasia (CIN), and no abnormality in gynecological examination; Sexual intercourse has occurred. Exclusion Criteria: Participants with acute cervicitis and acute lower genital tract infection, or with obvious condyloma; Participants during menstruation, or have vaginal medication, sexual behavior (including anal, vaginal or external genital contact, regardless of the sex of parterner) within two days (48 hours) before the visit, which may affect gynecological examinations and specimens collection. Axillary temperature > 37.0℃; Participants who have positive urine pregnancy test, or are pregnant or breastfeeding; Have used other investigational or unregistered products (drugs or vaccines) within 30 days before receiving the research vaccine or have participated in another clinical research in the past two years, or plan to use other research or unregistered products or participate in other research during the research period; Long-term use (more than 14 continuous days) of immunosuppressors and other Immunoregulatory agents or systemic corticosteroids (Except intranasal steroid, the use of low dose topical, ophthalmic and inhaled steroid preparations will be permitted.) 6 months prior to vaccination. Administration of immunoglobulin and/or blood products 3 months prior to vaccination or intending to use them during the study. Administration of inactivated vaccine within 14 days before vaccination or live vaccine within 21 days; Fever (Axillary temperature >38.0℃) 3 days prior to vaccination or system administration of antibiotics or antiviral agents (Anti-flu agents include but are not limited to Tamiflu, Tamiflu, Symmetrel and Flumadine) 5 days prior to vaccination. Have received other HPV vaccines or participated in clinical research related to HPV or cervical cancer previously; Immunodeficiency disease, primary disease of important viscera, cancer and autoimmune disease (including systemic lupus erythematosus, rheumatoid arthritis, asplenia or splenectomy due to any condition, and other autoimmune diseases that investigators believe may influence the immune response). History of severe allergy (e.g., anaphylaxis, generalized urticaria, dyspnea, angioedema, and other significant reaction) to any previous vaccines, or allergy to any of the components of investigational vaccine. Asthma, which has been unstable for the past two years and requires emergency treatment, hospitalization, oral or intravenous corticosteroids; Suffered from a serious medical illness; Self-report past coagulation disorders or abnormal coagulation function; Epilepsy, excluding febrile epilepsy under 2 years of age, alcoholic epilepsy 3 years prior to abstinence or simple epilepsy that did not require treatment in the past 3 years; According to the judgement of investigator, various medical, psychological, social, vocational or other factors that are not suitable for participating in the clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HPV vaccine (6,11,16,18,31,33,45,52,58 Types)<br>Participants in this arm would receive 270μg/0.5ml HPV vaccines (6,11,16,18,31,33,45,52,58 Types). | Biological: Nonavalent HPV vaccine<br>* Nonavalent HPV vaccine (270μg/0.5ml) administered intramuscularly according to a 0, 1, 6 month vaccination schedule.<br>|
| Active Comparator: HPV vaccine (16,18 Types)<br>Participants in this arm would receive 60μg/0.5ml HPV vaccines (16,18 Types). | Biological: Bivalent HPV vaccine<br>* Bivalent HPV vaccine (60μg/0.5ml) administered intramuscularly according to a 0, 1, 6 month vaccination schedule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority of anti-HPV 16 and 18 seroconversion rates and geometric mean concentrations at Months 7 (type specific neutralizing antibody) in the PPS-I set | Detect the level of anti-HPV 16 and 18 specific neutralizing antibodies at one month after the third dose to determine whether nine-valent HPV vaccine is non-inferior to the control bivalent HPV vaccine | Specific neutralizing antibodies at 7 months after first dose | 
| Persistent infection of HPV31, 33, 45, 52 and 58 (over 12 months) (Combined analysis of the 5 types) in the mITT-PI set | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Incidence of CIN2 + and/or VIN2 + and/or VaIN2 + lesions related to HPV 31, 33, 45, 52 or 58 (Combined analysis of the 5 types) in the mITT-E when the first two endpoints are satisfied | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy1: Incidence of CIN2 + and/or VIN2 + and/or VaIN2 + lesions related to HPV 31, 33, 45, 52 or 58(Combined analysis of the 5 types) and genital warts related to HPV 6, 11 (Combined analysis of each type) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy2: Incidence of CIN1 + and/or VIN1 + and/or VaIN1 + lesions related to HPV 31, 33, 45, 52 or 58(Combined analysis of the 5 types) and genital warts related to HPV 6, 11 (Combined analysis of each type) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy3: Incidence of Persistent infection of HPV31, 33, 45, 52 and 58 (transient infection and over 6 months) (Combined analysis of the 5 types) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy4: Incidence of CIN1 + and/or VIN1 + and/or VaIN1 + lesions related to HPV 31, 33, 45, 52 or 58(Combined analysis of the 5 types) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy5: Incidence of Persistent infection of HPV31, 33, 45, 52 and 58 (over 6 months) and/or incidence of CIN1 + and/or VIN1 + and/or VaIN1 + lesions related to HPV 31, 33, 45, 52 or 58(Combined analysis of the 5 types) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy6: Incidence of genital warts related to HPV 6, 11 | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy7: Incidence of Persistent infection of HPV31, 33, 45, 52, 58, 6 and 11 (transient infection and over 6 months and over 12 months) (Combined analysis of the 7 types) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Efficacy8: Incidence of Persistent infection of HPV31, 33, 45, 52, 58, 6 and 11 (over 6 months and over 12 months) (Independent analysis of each type) | To evaluate the efficacy of the nine-valent vaccine against this outcome compared with the control vaccine | Cumulative incidence of this endpoint events in 78 months after the first dose | 
| Immunogenicity1: Anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 seroconversion rates and geometric mean concentrations at Months 7 | Analysis the seroconversion and geometric mean concertration of the type specific antibodies of the 7 types. | Month 7 after first vaccination | 
| Immunogenicity2: Anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 seroconversion rates and geometric mean concentrations at Months 18 and 30 | Analysis the seroconversion and geometric mean concertration of the type specific antibodies of the 7 types. | Month 18 and 30 after first vaccination | 
| Immunogenicity3: Anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 seroconversion rates and geometric mean concentrations at Months 42, 54, 66 and 78 | Analysis the seroconversion and geometric mean concertration of the type specific antibodies of the 7 types. | Month 42, 54, 66 and 78 after first vaccination | 
| Safety1: Local and systematic adverse events/reactions occurred within 7 days after each vaccination | safety analysis | During the 7-day (Day 0-6) period following each vaccination | 
| Safety2: Adverse events/reactions occurred within 30 days after each vaccination | safety analysis | Within 30 days (Day 0-30) after any vaccination | 
| Safety3: Serious adverse events occurred throughout the study | safety analysis. To evaluate number of SAEs compared with the control vaccine. | Up to 78 month | 
| Safety4: Pregnancy and pregnancy outcome | safety analysis. To evaluate number of births and terminations compared with the control vaccine. | Up to 78 month | 
| Safety5: Emerging chronic diseases | safety analysis.To evaluate number of emerging chronic diseases compared with the control vaccine. | Up to 78 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human papillomavirus vaccine, cervical cancer, cervical intraepithelial neoplasia, condylomata acuminata