Safety, Tolerability and Immunogenicity of a Nine-valent Human Papillomavirus (HPV) Vaccine in HIV and Transplant Patients

Human Immunodeficiency Virus Clinical Trial

Official title:

An Open-label Phase III Study to Investigate the Safety, Tolerability and Immunogenicity of a Nine-valent Human Papillomavirus (HPV) Vaccine (Gardasil®9) in Solid Organ Transplant Recipients and HIV-infected Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03482739
• Other study ID #: V503-IC
• Secondary ID: 2017-004322-15
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 9, 2018
• Est. completion date: August 2019

Study information

• Verified date: February 2019
• Source: Universitaire Ziekenhuizen Leuven
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-center, open-label study on safety, tolerability and immunogenicity of Gardasil®9 in 18 to 45 year-old HIV patients, in 18 to 55 year-old solid-organ transplant (SOT) patients.

This study will enrol 100 HIV patients with CD4+ count of >200cells/mm² and 170 SOT patients, all of whom have not yet received a prophylactic HPV vaccine. The 170 SOT patients will be equally divided over 3 different SOT patient groups, namely heart, lung and kidney transplant patients. Therefore the target is to include approximately 57 heart transplant patients, 57 lung transplant patients and 57 kidney transplant patients. Enrolment in a SOT subgroup will be stopped when 57 patients have been included unless recruitment cannot be achieved within one of the other SOT-patient population.

All enrolled subjects will receive a 3-dose regimen (Day 1, Month 2, and Month 6) of GARDASIL®9. Serum samples will be collected on Day 1 and Month 7 for anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antibody determination. The time point for comparison of immune responses will be Month 7, or approximately 4 weeks after the administration of the third dose. The safety/tolerability profile of the vaccine will be evaluated in all subjects in the study. Safety information will be collected on Day 1 through 1 month following the third vaccination or for a total of approximately 7 months for each subject.

The immunogenicity and the safety data will be analyzed per group of patients. More specifically a separate analysis of HIV and SOT patients is planned, since it is expected that the immunosuppressive therapy of SOT patients might have a more profound effect on immunogenicity following vaccination.

This study will provide a comparison of immunogenicity of Gardasil ®9 in immunocompromised patients, with historical controls. The number of subjects to be enrolled in the study was determined based on the primary immunogenicity objective.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 270
• Est. completion date: August 2019
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

1. Independent Ethics Committee (IEC)-approved written informed consent form (ICF) must be obtained from the subject prior to any study-related procedure (including discontinuation of prohibited medication, if applicable) as required by local law.

2. Subject (man or woman) is between the age of 18 years and 0 days and 45 years and 365 days for HIV patients, between 18 years and 0 days and 55 years and 365 days for transplant patients at time of signing the ICF.

3. Subject is able to understand and adhere to the study procedures (e.g., is not planning to relocate far from the investigational centre during the study period); is able to read, understand, and complete the vaccination diary; is able to understand the risks involved with the study; and voluntarily agrees to participate in the study by giving written informed consent.

4. * Since the first day of their last menstrual period through Day 1, female subjects have not had sex with males or has had sex with males and used effective contraception with no failures (an example of a failure is a male condom that ruptures during sexual intercourse). Effective contraception is defined as a marketed, approved contraceptive product that the subject has used per the manufacturer's instructions with every act of sexual intercourse. The subject understands and agrees that during the Day 1 through Month 7 period, she should not have sexual intercourse with males without effective contraception. The use of the rhythm method alone, withdrawal alone, and emergency contraception, are not acceptable methods per the protocol. Subjects who have reached menopause, undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation are eligible without the use of contraceptives. Postmenopausal status is defined as: (1) No menses for >1 year but <3 years and confirmed by follicle stimulating hormone (FSH) levels elevated into the postmenopausal range, or (2) no menses for at least 3 years.

5. * Subject has had no temperature =37.8°C within 24 hours prior to the first injection.

6. Patient considerations

• HIV patients: have CD4+ T cell count of >200 cells/mm² at the last control (less than 16 months ago).

• SOT patients received their organ transplantation =12 months prior to vaccination and has been stable in the past 6 months (i.e. no acute rejection or other immunological reactions).

7. Apart from having HIV or received a solid organ transplant, the subject is in stable condition (i.e. no graft-versus-host disease or other immunological reactions) and is judged to be in good physical health on the basis of medical history, physical examination (if deemed necessary), and laboratory testing

8. Subject agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes.

Exclusion Criteria:

1. Subject has a history of an abnormal Pap test or abnormal cervical biopsy results (showing cervical intraepithelial neoplasia or worse) or cervical disease (i.e., surgical treatment for cervical lesions).

2. Patient medical history regarding HPV lesions:

1. Exclusion criterion for HIV patients: Subject has history of high grade Anal Intraepithelial Neoplasia, high grade Vulvar Intraepithelial Neoplasia or high grade Vaginal Intraepithelial Neoplasia.

• history of anal or peri-anal condyloma is allowed

2. Exclusion criterion for SOT patients: Subject has history genital warts, Anal Intraepithelial Neoplasia, Vulvar Intraepithelial Neoplasia or Vaginal Intraepithelial Neoplasia.

3. Subject has a history of known prior vaccination with an HPV vaccine, i.e., received a marketed HPV vaccine, or has participated in an HPV vaccine clinical study and has received either active agent or placebo.

4. Subject is pregnant (as determined by serum or urine pregnancy test).

5. Subject is, at the time of signing ICF, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence. Alcohol abusers are defined as those who drink despite recurrent social, interpersonal, and/or legal problems as a result of alcohol use.

6. Subject has a history of severe allergic reaction, including known allergy to any vaccine component, including aluminum, yeast, or BENZONASE® (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]) (e.g., swelling of the mouth and throat, difficulty breathing, hypotension or shock) that met the criteria for serious adverse experiences defined in this protocol.

7. Patient's condition

1. Exclusion criterion only for HIV patients: Subject has had a splenectomy, or has been diagnosed as having a congenital immunodeficiency, lymphoma, leukaemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, or other autoimmune or immunosuppressive condition, or has a history of any disease, which, in the investigator's opinion, may confound the results of the study or pose an additional risk to the subject.

2. Exclusion criterion only for SOT patients: Subject has had a splenectomy, or has been diagnosed as having a congenital or acquired immunodeficiency, HIV infection, lymphoma, leukaemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, or other autoimmune or immunosuppressive condition, or has a history of any disease, which, in the investigator's opinion, may confound the results of the study or pose an additional risk to the subject.

8. Patient's medication

1. Exclusion criterion only for HIV patients: Subject is receiving or has received in the year prior to enrolment the following immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine, methotrexate, any chemotherapy, cyclosporin, leflunomide (tumour necrosis factor-a antagonists, monoclonal antibody therapies (including rituximab [Rituxan]), intravenous gamma globulin, antilymphocyte sera, or other therapy known to interfere with the immune response. With regard to systemic corticosteroids, a subject will be excluded if she is currently receiving steroid therapy, has recently (defined as within 2 weeks of enrolment) received such therapy, or has received 2 or more courses of high dose corticosteroids (=20mg/day of prednisone [or equivalent] orally or parenterally) lasting at least 1 week in duration in the year prior to enrolment. Subjects using inhaled, nasal, or topical corticosteroids are considered eligible for the study

2. Exclusion criterion only for SOT patients: Subject is receiving or has received in the year prior to enrolment the following immunosuppressive therapies: radiation therapy, cyclophosphamide, methotrexate, any chemotherapy, leflunomide (tumour necrosis factor-a antagonists, monoclonal antibody therapies (including rituximab [Rituxan]) ,intravenous gamma globulin or antilymphocyte sera.

9. Subject has received any immune globulin or blood-derived product within the 3 months prior to the Day 1 vaccination, or plans to receive any such product during Day 1 through Month 7 of the study.

10. Subject has thrombocytopenia or other coagulation disorder that would contraindicate intramuscular injections.

11. * Subject has received inactivated vaccines within 14 days prior to the Day 1 vaccination or has received replicating (live) vaccines within 28 days prior to the Day 1 vaccination. The administration of the inactivated influenza vaccine is allowed 7 days prior to or after each study vaccine.

12. Subject is concurrently enrolled in a clinical study of investigational agent.

13. Subject has a history or current condition of which the investigator believes that it might interfere with the study vaccines.

14. Subject has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the subject's participation for the full duration of the study, such that it is not in the best interest of the subject to participate.

15. Subject is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus
• Human Papilloma Virus
• Immunologic Deficiency Syndromes
• Papilloma
• Solid Organ Transplant

Intervention

Biological:
• nine-valent HPV vaccine
HPV vaccination

Locations

Country	Name	City	State
Belgium	University Hospitals Leuven	Leuven

Sponsors (1)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen Leuven

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Anti-HPV seroconversion	The seroconversion percentages to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 at 4 weeks after the third dose of the vaccine as measured by a competitive Luminex immunoassay. The percentage of participants who were seronegative on Day 1 and have anti-HPV titer greater or equal to the type-specific serostatus cutoff at 4 weeks postdose 3 will be assessed.	4 weeks postdose 3 (Month 7)
Secondary	Anti-HPV geometric mean titers	The geometric mean titers to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 at 4 weeks after the third dose of the vaccine as measured by a competitive Luminex immunoassay.	4 weeks postdose 3 (Month 7)
Secondary	Adverse Events	The percentage of participants with one or more adverse events will be assessed.	Up to 1 month after Dose 3 (up to 7 months)
Secondary	Elevated Temperature (Fever)	The subjects will be asked to record oral body temperature in a vaccination diary. The percentage of participants with elevated temperature (=37.8°C) will be assessed.	Up to 5 days after any vaccination
Secondary	Injection-site Adverse Events	The subjects will be asked to record any injection-site reactions in a vaccination diary, i.e., injection-site tenderness, swelling, or redness, occurring after each study vaccination (solicited injection-site reactions). The percentage of participants with one or more injection-site adverse events will be assessed.	Up to 5 days after any vaccination