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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Cancer; Cervical Intraepithelial Neoplasia; Condylomata Acuminata
• Intervention / Treatment: Biological: Nonavalent HPV vaccine; Biological: Bivalent HPV vaccine

• Study Type: Interventional
• Enrollment (Actual): 9327
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Jiangsu Provincial Centre for Disease Control and Prevention
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Sichuan Provincial Centre for Disease Control and Prevention

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Female aged between 18 and 45 years at the first vaccination;
2. 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;
3. 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;
4. The number of sexual partners so far less than four;
5. Have intact cervix and have no history of physical or surgical treatment;
6. No previous history of sexually transmitted diseases (including syphilis, gonorrhea, chancroid, venereal lymphogranuloma, groin granuloma, etc.);
7. No previous history of abnormal cervical screening results or cervical intraepithelial neoplasia (CIN), and no abnormality in gynecological examination;
8. Sexual intercourse has occurred.

Exclusion Criteria:

1. Participants with acute cervicitis and acute lower genital tract infection, or with obvious condyloma;
2. 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.
3. Axillary temperature > 37.0℃;
4. Participants who have positive urine pregnancy test, or are pregnant or breastfeeding;
5. 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;
6. 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.
7. Administration of immunoglobulin and/or blood products 3 months prior to vaccination or intending to use them during the study.
8. Administration of inactivated vaccine within 14 days before vaccination or live vaccine within 21 days;
9. 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.
10. Have received other HPV vaccines or participated in clinical research related to HPV or cervical cancer previously;
11. 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).
12. 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.
13. Asthma, which has been unstable for the past two years and requires emergency treatment, hospitalization, oral or intravenous corticosteroids;
14. Suffered from a serious medical illness;
15. Self-report past coagulation disorders or abnormal coagulation function;
16. 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;
17. According to the judgement of investigator, various medical, psychological, social, vocational or other factors that are not suitable for participating in the clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of CIN2 + and/or VIN2 + and/or VaIN2 + lesions related to HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 68 (Combined analysis of the high risk 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
Incidence of CIN1 + and/or VIN1 + and/or VaIN1 + lesions related to HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 68 (Combined analysis of the high risk 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
Incidence of Persistent infection of HPV35, 39,51,56,59 and 68 (total infection and 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

Collaborators and Investigators

• Sponsor: Xiamen University
• Collaborators: Xiamen Innovax Biotech Co., Ltd; Beijing Wantai Biological Pharmacy Enterprise Co., Ltd.
• Investigators: Principal Investigator: Feng-cai Zhu, master, Jiangsu Provincial Centre for Disease Control and Prevention; Study Chair: Jun Zhang, master, Xiamen University

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2020
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: August 28, 2020
• First Posted (Actual): September 3, 2020

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: cervical intraepithelial neoplasia; condylomata acuminata; cervical cancer; human papillomavirus vaccine
• Additional Relevant MeSH Terms: Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Precancerous Conditions; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Neoplasms; Uterine Cervical Neoplasms; Uterine Cervical Dysplasia; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: HPV-PRO-009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No