Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: (HPV-002 [Mi-CP-044]) Title: A Phase I Study of the Safety and Immunogenicity of, a Vaccine Against Human Papillomavirus Types 16 and 18, in Healthy Adult Female Volunteers. Rationale: The current study involved the first administration to humans of vaccine. This study was designed to provide initial safety data after administration of the individual components of (i.e., and ), followed by an assessment of safety and immunogenicity of vaccine. Immune responses to the and component vaccines were compared to those seen with the combination vaccine,. : HPV type 16 VLP vaccine. : HPV type 18 VLP vaccine. : virus-like particle (VLP) vaccine against human papillomavirus-16 (HPV-16) combined with HPV-18. Phase: I Study Period: 08 February 1999 to 05 August 2003 Study Design: Open-label, randomised* (1:1:2 ratio) study with 3 study groups. *Subjects were randomized (1:1) to the first 2 treatment groups of the study; the remaining subjects were then sequentially entered in the 3 rd treatment group of the study. Centres: Single centre study conducted in the USA. Indication: Prophylaxis against HPV-16 and HPV-18 disease/cancer. Treatment: The study groups were as follows: : all subjects received primary immunisation at Day 0 and booster immunisation at Day 28 with. Subjects showing no adverse events after this 2-dose immunisation received a third dose of at Day 112; an extended follow-up for that sub-group began approximately 1.5 years after the first dose and continued every 6 months for 3 years. : all subjects received primary immunisation at Day 0 and booster immunisation at Day 28 with. : all subjects received primary immunisation at Day 0 and booster immunisation at Day 28 with the combination vaccine,. All vaccines were administered by intramuscular injection into the deltoid muscle. Each injection was administered into the arm opposite to that of the previous injection. Objectives: To assess the safety of (HPV-16/18 VLP vaccine) and its components (, HPV-16 VLP vaccine and, HPV-18 VLP vaccine) in healthy young adult females and to determine if there were limiting toxicities which would prevent the further evaluation of its current formulation. Safety was assessed by the occurrence of adverse events (AEs) and serious adverse events (SAEs). Primary Outcome/Efficacy Variable: Safety Solicited adverse events collected within 7 days of an injection - the total number of events and number and percentage of patients in each treatment arm experiencing pain, redness and swelling at the injection site, and fever, headache, gastrointestinal symptoms, fatigue, rash and pruritis summarized by intensity grade. Adverse events (AEs) and serious adverse events (SAEs) collected from Study Day 0 (day of first injection) through 28 days past the second scheduled injection - the total number of events and number and percentage of patients in each treatment arm experiencing any adverse event or serious adverse event (coded by COSTART preferred term) summarized by severity grade and relationship to study drug.

2 AEs and SAEs collected from Study Day 112 through Study Day 140 for those subjects receiving a third immunization with and summarized by severity grade and relationship to study drug. Secondary Outcome/Efficacy Variable(s): Immunogenicity ELISA serum antibody titres against HPV-16 and HPV-18; titres obtained and summarized for each treatment arm using the geometric mean titre. Neutralisation antibody titres against HPV-16 and HPV-18; titres obtained and summarized for each treatment arm using the geometric mean titre. Cell mediated immunity (CMI) was assessed by lymphoproliferative assays, interferon-gamma (IFN-γ) release and interleukin-5 (IL-5) release. Extended follow-up (in the post third immunisation extension only) ELISA titres against HPV-16 and HPV-18*; titres obtained and summarized using the geometric mean titre Inhibitory ELISA assays*; titres obtained and summarized using the geometric mean titre. CMI assessed by lymphoproliferative assays, IFN- release and IL-5 release. *ELISA binding and inhibiting evaluations against HPV-18 were not performed in subjects from the group who received a third vaccine dose for bio specimens collected beyond Day 112, as these subjects were administered a vaccine that did not contain HPV-18 VLP. Satistical Methods: Analysis of safety: The analysis was based on all 49 subjects who received at least one study vaccine dose and on the 8 subjects who received a third vaccination in group. The incidence of each solicited local and general symptom was calculated during the 7-day (Day 0-6) follow-up period after each vaccination. The same calculation was done for grade 3 solicited local and general symptoms and for the general symptoms that were considered by the investigator to be causally related to the study vaccination. The percentage of subjects with unsolicited AEs and SAEs occurring within 28 days after each vaccination was tabulated according to the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART). The same calculation was done for severe AEs and for the AEs that were considered by the investigator to be causally related to the study vaccination. Analysis of immunogenicity: The analysis of immunogenicity was performed with data from all 48 subjects who received first 2 vaccinations and from the 8 subjects who received a third vaccination in group. For each group, the geometric mean midpoint titres were calculated for HPV-16 and HPV-18 antibodies using ELISA. Midpoint titres were obtained by averaging the values from all dilutions that fell within the working range of the standard positive control titration curve (20-80% of the maximal response). For each group, the geometric mean endpoint titres were calculated for HPV-16 and HPV-18 antibodies, using neutralising assay, at applicable time points. Neutralization endpoint titre was defined as the highest serum dilution that inhibits the synthesis of the viral transcript. For each group, the geometric mean titres were calculated for HPV-16 and HPV-18 antibodies, using Cell Mediated Immunity assay (determined by lymphoproliferation assays and by IFN-γ and IL-5 release using peripheral blood lymphocytes), at applicable time points. For the extended follow-up: Immunogenicity analysis was performed on the 8 subjects who received a third vaccination in group. Binding ELISA and inhibiting ELISA anti-hpv-16 antibody GMTs were calculated at each time point. Study Population: Healthy female adults (18-30 years) who, within 3 weeks of study entry, were seronegative* for HPV-16 and HPV-18 antibodies, had a normal Pap smear, had pelvic examination showing no evidence of anogenital HPV lesions or other gynaecologic pathogens and had a cervical specimen negative for HPV. Unless previously surgically sterilized, they had agreed to use an

3 effective method of birth control beginning 30 days before the first study injection and continuing through 60 days after the final study injection. Written informed consent was obtained from each participant prior to conduct of any protocol specific activity or study entry. * Serum samples from sexually naïve adults and/or children were used to define a negative cut off point for HPV-16 and HPV-18 VLP antibody reactivity. Number of subjects Planned, N Randomised, N Completed, n (%) 12 (10 12 (10 23 (9 Total Number Subjects Withdrawn, n (%) 0 (0. 0 (0. 0 (0. Withdrawn due to Adverse Events, n (%) 0 (0. 0 (0. 0 (0. Withdrawn due to Lack of Efficacy, n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons, n (%) 0 (0. 0 (0. 0 (0. Demographics N Females: Males 12:0 12:0 25:0 Mean Age, years (SD) 24 (1. 23 (0.8) 24 (0.7) White/Non-Hispanic, n (%) 10 (83) 10 (83) 19 (76) Primary Efficacy Results: The incidence and intensity of the solicited local symptoms during the 7-day (Day 0-6) follow-up period after each vaccination. Sympto m Intensit y (N=1 (N=1 (N=25) n % n % n % Dose 1 Pain Any Grade Rednes Any s >50 mm Swellin Any g >50mm Dose 2 Pain Any Grade Rednes Any s >50 mm Swellin Any g >50mm Dose 3 (N=8) Pain Any Rednes Any s >50 mm Any >50mm Swellin g N = number of subjects having received the vaccine n (%) = number (percentage) of subjects reporting at least one symptom Any = any specified local solicited symptom, irrespective of the intensity Grade 3 pain = spontaneously painful.

4 Primary Efficacy Results: The incidence and intensity of the solicited general symptoms during the 7-day (Day 0-6) follow-up period after each vaccine dose. Sympto m Intensity / relationship (N=1 (N=1 (N=25) n % n % n % Dose 1 Fever 37.5 C >39.0 C Related Headach e Any Grade Related Any Related Fatigue Any Related Rash Any Related Pruritus (Itching) Any Related Dose 2 Fever 37.5 C >39.0 C Related Headach e Gastrointestinal Gastrointestinal Any Related Any Related Fatigue Any Grade Related Rash Any Related Pruritus (Itching) Any Related Dose 3 (N=8) n % Fever 37.5 C >39.0 C

5 Headach e Any Any Fatigue Any Rash Any Pruritus (Itching) Any N = number of subjects having received the vaccine n (%) = number (percentage) of subjects reporting at least one symptom Any = any specified general solicited symptom, irrespective of the intensity or relationship to vaccination Grade 3 symptom = symptom which prevented daily activities. Related = symptoms considered by the investigator to have a causal relationship to vaccination Anti-HPV-16 and anti-hpv-18 antibody (ELISA) GMTs Timing Anti-HPV-16 Anti-HPV-18 N GMT N GMT Gastrointestinal PRE PI(D7) PI(D28) PII(D35) PII(D56) ) PRE PI(D7) PI(D28) PII(D35) PII(D56) PRE PI(D7) PI(D28) PII(D35) PII(D56) PRE = pre-vaccination blood sample Px(Dy) = post dose x blood sampling at day y GMT = geometric mean midpoint titres. Note: Midpoint titres were obtained by averaging the values from all dilutions that fell within the working range of the standard positive control titration curve (20-80% of the maximal response).

6 HPV-16 and HPV-18 neutralising antibody titres in subjects who received both injections of study vaccine Timing Anti-HPV-16 Anti-HPV-18 N GMT* N GMT* PRE PI(D28) PII(D56) PRE PI(D28) PII(D56) PRE PI(D28) PII(D56) PRE = pre-vaccination blood sample Px(Dy) = post dose x blood sampling at day y GMT= geometric mean endpoint titres. Note: Endpoint titres were defined as the highest serum dilution that inhibits the synthesis of the viral transcript. *In computation of GMT, titres <1:100 were set to 1.0 Lymphoproliferative Response (Stimulation Index SI*) to HPV-16 and HPV-18 VLPs Timing Anti-HPV-16 Anti-HPV-18 N N* GMT N N* GMT 10 µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs

7 PRE PII(D56) PRE PII(D56) PRE PII(D56) *A stimulation index of 2.2 was considered to be positive. IFN-γ Secretion (picogram/ml (pg/ml)) in response to HPV-16 and HPV-18 VLPs Timing Anti-HPV-16 antibody Anti-HPV-18 antibody N N* GMT N N* GMT 10 µg/ml VLPs N* = number of subjects with qualified samples at that time point PRE= pre-vaccination blood sample Px(Dy)= post dose x blood sampling at day y PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) Media

8 PRE PII(D56) PRE PII(D56) PRE PII(D56) N* = number of subjects with qualified samples at that time point PRE = pre-vaccination blood sample Px(Dy) = post dose x blood sampling at day y IL-5 Secretion (pg/ml) in response to HPV-16 and HPV-18 VLPs Timing Anti-HPV-16 antibody Anti-HPV-18 antibody N N* GMT N N* GMT 10 µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) µg/ml VLPs PRE PII(D56) PRE PII(D56) PRE PII(D56) Media

9 PRE PII(D56) PRE PII(D56) PRE PII(D56) N* = number of subjects with qualified samples at that time point PRE = pre-vaccination blood sample Px(Dy) = post dose x blood sampling at day y Binding ELISA anti-hpv-16 antibody GMTs in the subjects who participated in the extension study Timing Anti-HPV-16 antibody N GMT (EL.U/mL) PIII(Y1.5) PIII(Y PIII(Y2.5) PIII(Y3) PIII(Y3.5)* - - PIII(Y4) PIII(Y4.5) PIII(Yy) = post Dose 3 blood sampling at Year y GMT = geometric mean midpoint titres. Note: Midpoint titres were obtained by averaging the values from all dilutions that fell within the working range of the standard positive control titration curve (20-80% of the maximal response). *Insufficient volume for testing Inhibitory ELISA anti-hpv-16 antibody GMTs in the subjects who participated in the extension study Timing Anti-HPV-16 antibody N GMT (EL.U/mL) PIII(Y1.5) PIII(Y PIII(Y2.5) PIII(Y3) PIII(Y3.5) PIII(Y4) PIII(Y4.5) PIII(Yy) = post Dose 3 blood sampling at Year y GMT= geometric mean endpoint titres. Note: Endpoint titres were defined as the highest serum dilution that inhibits the synthesis of the viral transcript. Cell mediated immunity assessed by lymphoproliferative assays, IFN- release and IL-5 release. Due to small number of subjects enrolled in the extension study, the variability in the length of the follow-up, and the non-uniformity in the antigen concentrations eliciting a cell media immunity response, the cell media immunity assay results were only presented as a subject listing. Safety Results: Number (%) of subjects with unsolicited adverse events after first two vaccinations

10 Most frequent adverse events - On- Therapy (occurring within Day 0-28 following vaccination) N = 25 Subjects with any AE(s), n (%) 10 (83.3) 11 (91.7) 18 (72. Subjects with any severe* AE(s), n (%) 0 (0. 0 (0. 0 (0. Subjects with any related** AE(s), n (%) 3 (25. 5 (41.7) 7 ( 28. Pharyngitis 4 (33.3) 5 (41.7) 7 (28. Injection site reaction 2 (16.7) 5 (41.7) 7 (28. Headache 3 (25. 1 (8.3) 6 (24. Dysmenorrhoea 2 (16.7) 3 (25. 4 (16. Allergic reaction 0 (0. 4 (33.3) 5 (20. Flu syndrome 1 (8.3) 1 (8.3) 1 (4. Nausea 0 (0. 0 (0. 2 (8. Back pain 1 (8.3) 0 (0. 1 (4. Dizziness 1 (8.3) 0 (0. 1 (4. Insomnia 1 (8.3) 0 (0. 1 (4. Pain 0 (0. 1 (8.3) 1 (4. Rhinitis 1 (8.3) 0 (0. 1 (4. Accidental injury 0 (0. 1 (8.3) 0 (0. Aphthous stomatitis 1 (8.3) 0 (0. 0 (0. Asthenia 0 (0. 1 (8.3) 0 (0. Bronchitis 0 (0. 1 (8.3) 0 (0. Contact dermatitis 0 (0. 1 (8.3) 0 (0. Cough increased 1 (8.3) 0 (0. 0 (0. Dysuria 0 (0. 1 (8.3) 0 (0. Ear pain 0 (0. 1 (8.3) 0 (0. Increased appetite 0 (0. 0 (0. 1 (4. Lymphadenopathy 0 (0. 0 (0. 1 (4. Metrorrhagia 0 (0. 0 (0. 1 (4. Pruritus 0 (0. 1 (8.3) 0 (0. Sweating 1 (8.3) 0 (0. 0 (0. Thirst 0 (0. 0 (0. 1 (4. Tremor 0 (0. 0 (0. 1 (4. Urinary tract infection 0 (0. 1 (8.3) 0 (0. Urine abnormality 0 (0. 0 (0. 1 (4. Vaginitis 0 (0. 1 (8.3) 0 (0. *A severe AE = an AE with significant degree of inconvenience, discomfort or concern; significantly interfering with activities of daily living. **Related = AEs considered by the investigator to have a causal relationship to vaccination Safety Results: Number (%) of subjects with unsolicited adverse events after the third vaccination ( subjects who participated in the extension study) Most frequent adverse events - On- Therapy (occurring within Day 0-28 following vaccination) N = 8 Subjects with any AE(s), n (%) 2 (25. Subjects with any severe* AE(s), n (%) 0 (0. Subjects with any related** AE(s), n (%) 0 (0. Diarrhoea 1 (12.5) Dysuria 1 (12.5)

11 *A severe AE = an AE with significant degree of inconvenience, discomfort or concern; significantly interfering with activities of daily living. **Related = AEs considered by the investigator to have a causal relationship to vaccination Safety Results: Number (%) of subjects with Serious Adverse Events (SAEs) after first two vaccinations Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs N = 25 Subjects with any SAE(s), n (%) [n related] 0 (0. [0] 0 (0. [0] 0 (0. [0] Fatal SAEs N = 25 Subjects with fatal SAE(s), n (%) [n related] 0 (0. [0] 0 (0. [0] 0 (0. [0] Safety Results: Number (%) of subjects with Serious Adverse Events (SAEs) after third vaccination (subjects who participated in the extension study) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs N = 8 Subjects with any SAE(s), n (%) [n related] 0 (0. [0] Fatal SAEs N = 8 Subjects with fatal SAE(s), n (%) [n related] 0 (0. [0] Conclusion: Across doses and groups, pain was the most frequently reported solicited local symptom. Across doses, the most frequently reported solicited general symptoms were fever, fatigue and headache for the, and group, respectively. Unsolicited AEs were reported by 11 (91.7%), 11 (91.7%) and 18 (72.0%) subjects from the, and group, respectively. No SAEs were reported throughout the entire study. Publications: None. Date Updated: 29-Oct-2008