Synopsis. Smallpox vaccine, LISTER strain, produced on chick embryo cells (VV LISTER/CEP) Live vaccinia virus (LISTER strain)

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1 Synopsis Title of the trial: Coordinating Investigator: Trial centers: Publications: Trial period: Development phase: Primary objective: Take Evaluation and Safety of Smallpox Vaccine (LISTER Strain) in Naive Healthy Adults Not disclosed Six centers. None at the time of report writing. 17 October 2005 (first visit first subject) to 01 December 2006 (last visit last subject) II To estimate the smallpox vaccination take rate in naive healthy adults. Primary endpoints: To evaluate the take for each subject on Day (D) 9, D14, D21, and D28. Secondary objectives: Secondary endpoints: The take is defined as the occurrence of a post-vaccination pock at the vaccination site (a pock is a typical major cutaneous lesion [erythematous papule, vesicle, or pustule]). The lesions at the vaccination site were reported by the investigators at each study visit. The presence of the take was evaluated on D9, based on the cutaneous lesions observed since D0. All analyses were performed for each batch and for the pooled batches. 1) To describe local signs and symptoms of the take for each batch and for the pooled batches; 2) To describe the safety of the vaccine in naive healthy adults for each batch and for the pooled batches; 3) To describe the antibody response to vaccination on D0 and D28 for each batch and for the pooled batches; 4) To evaluate the take for each subject on D9, D14, D21 and D28 for each batch. 1) Local signs and symptoms of the take Presence/absence of local signs and symptoms (macule, papule, vesicle, pustule, crust, erythema, induration, local satellite lesions, and axillary lymphadenopathy) on D4, D7, D9, D11, D14, D21, D28 and D42, and D90 (in case of persistent crust). Dates of first and last sign and symptom observed, size (in cm for macule, papule, vesicle, pustule, crust, erythema and induration), number of lesions (for local satellite lesions), and maximum intensity (for axillary lymphadenopathy). Date of occurrence of scar (i.e. when the crust separates).

2 2) Safety Clinical safety Occurrence, time to onset, number of days of occurrence and severity of solicited (prelisted in the subject diary and Case Report Form [CRF]) vaccination site reactions and systemic reactions occurring up to 14 days after vaccination. Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term), time to onset, duration, severity and relationship (for systemic events only) to vaccination of unsolicited (spontaneously reported) adverse events up to 28 days after vaccination. Serious Adverse Events (SAEs) throughout the trial (starting from screening). Biological safety Measures of the biological safety parameters: hematology (red blood cells [RBC] count, hemoglobin, hematocrit, mean corpuscular volume [MCV], platelets count, white blood cells [WBC] count and quantitative differential count [neutrophils / lymphocytes / monocytes / eosinophils / basophils]) and biochemistry (cardiac enzyme [Troponin-I]) at screening visit, D0, D9, and D28. Deviation/abnormality in biological safety parameters. 3) Immunogenicity Neutralizing antibody titers on D0 and D28. Titers ratio (D28/D0), seroconversion on D28 (detectable i.e. 10 (1/dil) antibodies). Four-fold increase between D28 and D0. Methodology: Sample size: Double-blind, randomized, three-arm (i.e., three-batch), multicenter, Phase II trial with a six-month duration/subject. Planned: 260 subjects. Included: 230 (in agreement with Competent Authority [Agence Française de Sécurité Sanitaire des Produists de Santé, AFSSAPS] and Ethics Committee). Vaccinated: 230 subjects.

3 Inclusion criteria Exclusion criteria Inclusion criteria 1 to 7 were checked at the Screening Visit (SC). Inclusion criteria 4, 7 and 8 were checked on D0 (V01): 1) Aged 18 to 25 years on the day of screening. 2) Informed consent form signed. 3) Able to attend all scheduled visits and to comply with all trial procedures. 4) For a woman, inability to bear a child or negative serum pregnancy test performed at screening (checked at V01). 5) Subject entitled to national social security. 6) Subject registered in the French file of healthy volunteers in clinical trials. 7) For a woman of child-bearing potential: use of an effective method of contraception (hormonal or barrier method) from at least three months prior to screening to three months following trial vaccination. 8) For a woman, inability to bear a child or negative urine pregnancy test. Exclusion criteria 1 to 27 were checked at SC and on D0 (V01): 1) Previous smallpox vaccination confirmed by vaccination record or typical scar. 2) Participation in another clinical trial in the three months preceding the trial vaccination. 3) Planned participation in another clinical trial during the present trial period. 4) Chronic illness at a stage likely to interfere with trial conduct or completion. 5) Breast-feeding. 6) Allergy to any known components of vaccinia immune globulin or previous allergic reaction to immunoglobulins. 7) Systemic hypersensitivity to eggs or to any of the vaccine components or history of a life-threatening reaction to a vaccine containing the same substances as the trial vaccine. 8) Congenital or acquired immunodeficiency, immunosuppressive therapy such as anticancer chemotherapy or radiation therapy within the preceding six months, or any treatment including corticosteroids (systemic, topical, ophthalmic). 9) Treatment with antiviral drugs (interferon, vidarabine, acyclovir, etc.) within one month before vaccination. 10) History of organ or bone marrow transplant. 11) History of skin disorders or atopy (such as progressive eczema, eczema, atopic dermatitis, Darier s disease, severe acnea, etc.).

4 12) History of autoimmune disease (multiple sclerosis, lupus, etc.) in the subject s parents, siblings or children. 13) History or current cardiac disease: Electrocardiogram (ECG) abnormalities, pericarditis, myopericarditis, myocardial infarction/heart attack, angina pectoris, congestive heart failure, cardiomyopathy, arrhythmia, stroke or transient ischemic attacks, or chest pain or shortness of breath with activity (such as walking up stairs), or other coronary artery disease and heart conditions under the care of a physician and associated with a heart condition, or family history of sudden death before the age of 50 years. 14) History or current central nervous system disease: neurodegenerative, infectious, or progressive tumoral disease, or epilepsy. 15) Subject having three or more major risk factors, including: current tobacco use, hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus, or family history of heart disease (a heart condition before age 50 in a parent, brother, or sister). 16) Ongoing acute infectious disease. 17) Blood or blood-derived products received in the past six months. 18) Any vaccination with a live-attenuated vaccine within the 60 days preceding the trial vaccination. 19) Any vaccination (other than a live-attenuated vaccine) in the four weeks preceding the trial vaccination. 20) Vaccination planned in the eight weeks following the trial vaccination. 21) Current abuse of alcohol or drug addiction that may interfere with the subject s ability to comply with trial procedures. 22) Planned or foreseeable close contact* after vaccination with infants of less than 12 months of age, or with immunosuppressed persons, pregnant and/or lactating woman, or with persons known to have chronic eczema, or severe skin disorders until the crust separates, leaving a permanent scar at the vaccination site. 23) Planned practice of contact sports or water sports after vaccination until the crust separates, leaving a permanent scar at the vaccination site. 24) Cutaneous lesion near the vaccination site. 25) Apparent lack of personal hygiene. 26) Lack of understanding of the questionnaire. 27) Subject deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized without his/her consent.

5 Investigational product: Form: Dose: Route: Batch number: Duration of treatment (Vaccination schedule) Duration of follow-up Control product Statistical methods Exclusion criteria 28 to 33 were checked on D0 (V01) only: 28) Human Immunodeficiency Virus (HIV), hepatitis B (Ag HBs) or hepatitis C seropositivity (screening tests). 29) Abnormal laboratory values for hematological parameters or cardiac enzyme (screening tests). 30) Any medical disease/condition (severe skin problems or immune system problems of subject or their close contacts*) according to the questionnaire given at the screening visit. 31) Febrile illness (oral temperature 37.5 C, rectal equivalent temperature 38.0 C) on the day of vaccination. ** 32) Acute intercurrent illness. ** 33) Absence of or unreturned completed questionnaire. ** *A close contact is any person who is living with the subject; **Vaccination will be deferred within the enrolment period until the subject is fully eligible. Smallpox vaccine LISTER strain,. Liquid suspension in multidose vials (0.25 ml per vial). Each dose is a drop of approximately 1 μl of vaccine containing approximately 10 5 CCID 50/mL. Percutaneous by multiple punctures in the deltoid area. Not disclosed A single vaccination: administration of one dose of the investigational vaccine on D0 (V01). Five blood samples were drawn: at the screening visit (D-14 max), before vaccination on D0 (V01), on D9 (V04), on D14 (V06), and on D28 (V08). One urine sample was taken on D0 (V01) for female subjects (pregnancy test). Eleven visits were performed: screening visit, then on D0 (V01), D4 (V02), D7 (V03), D9 (V04), D11 (V05), D14 (V06), D21 (V07), D28 (V08), D42 (V09), and D90 (V10). In case of crust (scab) persistence on D28 (V08), extra visits were performed every 3-4 days between D28 (V08) and D90 (V10) for bandage changes until the crust separation. A phone call (or visit) was arranged at 6 months post-immunization to record any SAE that could appear after V10 (or after the last visit performed by a subject in case of premature end of trial). The total duration of follow-up for each subject was 6 months. None. Statistical analyses were descriptive. The point estimate and the 95% Confidence Interval (CI) were used. Satistical analyses were performed for each batch and for the pooled batches.

6 SUMMARY - CONCLUSIONS was a double-blind, randomized, three-arm (i.e., three-batch), multicenter, Phase-II study of 6-month duration per subject, involving 230 subjects aged 18 to 25 years. A population of 102 females (44.3%) and 128 males (55.7 %) were vaccinated and completed the study up to D180. The mean age of the subjects was 22.2 ± 2.1 years. All the subjects completed the study. The primary objective of this trial was to describe the smallpox vaccination take rate of secondgeneration smallpox vaccine in this population. The secondary objectives were to describe the local signs and symptoms of the take, the safety of the investigational vaccine, the antibody response to vaccination on D0 and D28, and the take rate for each subject and per batch. TAKE RATE Take rates for pooled batches were analyzed as a primary endpoint. Overall, 100% of subjects had a take. The take rate was evaluated by the Investigators in 229/230 subjects on D9 since one subject missed his visit. The take rate on D9 was 99.6%, which is in agreement with the EMEA requirement to have a take rate of at least 95%. The profile of the evolution of the lesions at the site of vaccination of a Subject shows that he presented lesions suggestive of a take before D9: he had a vesicle (0.50 cm) on D4, a pustule that increased in size between D7 and D11 (0.80 to 1.00 cm), and erythema that increased between D4 and D7 (0.70 to 0.90 cm). On the next visit (D14), the Investigator was able to confirm that this subject had a take, as observed during postvaccination examination; the take rate reached 100% [95% CI: 98.4; 100.0]. TAKE LESIONS The time course of the pock observed in the 230 subjects showed that, from D4 to D28: All subjects had pustules, mainly from D7 to D14 ( %), with a peak between D9 and D11 ( %). Overall, from D4 to D28, a crust was observed in 229 out of 230 subjects (99.6%), with a maximum incidence on D21 (90.0%). For one subject, the Investigator did not report the presence of a crust between D0 and D28, which does not mean that there was none during the evolution of the lesions at the site of vaccination. Erythema was also observed in 228 out of 230 subjects (99.1%), from D4 to D14 ( %), and mainly from D7 to D11 ( ); intensity was mainly mild to moderate in 53.0% and 42.6%, respectively, and maximum (diameter > 5 cm) in 82 subjects (35.8%) on D9. Erythema was not observed by the investigators in two subjects ( and ) but this may be the consequence of a non-daily assessment and the observation may have been missed. Vesicles were observed in 212 out of 230 subjects (92.2%), mainly on D4 (84.8%). Only six subjects still had vesicles on D11 and none on D14. Induration was observed in 208 out of 230 subjects (90.4%), mainly from D9 to D11; intensity was maximum between D9 and D11 (diameter > cm). Macules and papules were observed in 20 and 44 subjects, respectively, mainly on D4 (range: 0.3 to 8.0 cm). Local satellite lesions at the application site were observed in 15 subjects (6.5%) in the D4-D28 period. Between D4 and D28, axillary lymphadenopathy was reported in 154 subjects (67.0%). Among these, axillary lymphadenopathy was mild in 126 subjects (54.8%) and moderate in 28 subjects (12.2%) from D7 to D14, the maximum incidence being reported on D9 (10.0%) for pooled batches. There were no severe cases of axillary lymphadenopathy.

7 Similar patterns were observed for each individual batch. SCAB SEPARATION All batches combined, scab separation occurred mostly between D42 and D56 or later. This was observed for each individual batch. The mean time between vaccination and scab separation was 51.1 days, ranging from 15.0 to days. The scab separated, at the latest, on D163 with batch Z5140, on D171 with batch Z5143, and on D117 with batch Z5146. SAFETY A total of 19 SAEs were reported in 18 subjects (7.8%) during the study period; 11 of these 19 SAEs were considered by the Investigator to be related to the vaccine. These related SAEs included one myopericarditis, four chest pains, two dry coughs, two abnormalities, one vasovagal syncope, and one macular rash After the end of the study, an SAE, first reported by the investigator as related, was finally re-assessed as unrelated (pneumoniae and chest pain). Overall, 224 subjects (97.4%) experienced at least one adverse event (AE). The most commonly reported AEs were observed in the following System Organ Class (SOCs): general disorders and administration site conditions (221 subjects [96.1%]), nervous system disorders (151 subjects [65.7%]), and musculoskeletal and connective tissue disorders (144 subjects [62.6%]). Consistently, AEs with the highest incidence were asthenia (75.7% of subjects), application site pain (74.8%), headache (65.7%), injection site pruritus (56.5%), myalgia (52.2%), back pain (38.3%), malaise (33.9%), rigors (33.0%), pyrexia (24.8%), axillary pain (21.7%), nausea (17.4%), rash maculo-papular (11.7%), and rhinitis (10.9%). In terms of intensity, severe vaccination site reactions were reported in 16 subjects (7.0 %). In addition, 22 subjects (9.6 %) experienced severe systemic reactions within 14 days post-vaccination. The incidence of adverse events and reactions was quite similar between the three batches. No inadvertent inoculation or close-contact contamination was observed. Biological Safety Hematology All batches combined, the overall number of subjects with at least one abnormal hematological value appeared to be similar on D0 (63 subjects) and D28 (58 subjects) but was higher on D9 (99 subjects). None of the individual values observed outside the reference range on D0, D9, or D28 was considered to be clinically relevant by the Investigator. Cardiac Assessment - Troponin-I Results were similar in all three batches. Abnormal values were found in four subjects but were not considered clinically relevant except for one Subject who presented with a myopericarditis (related SAE). Cardiac Monitoring Cardiac monitoring included ECG recordings, echocardiograms, and chest X-rays. Based on the cardiac assessments performed during the study, the majority of ECG recordings were normal. All abnormalities observed during cardiac assessments were reported as unsolicited systemic AEs (in 7 subjects) or SAEs (in 2 subjects) in the CRF. In addition to the subject who experienced myopericarditis, the following cardiac abnormalities were considered as SAEs related to the vaccine in the following subjects: One Subject: ECG showed repolarization trouble on D28,

8 One Subject: ECG showed a mild T-wave inversion on D28, One Subject: ECG showed repolarization trouble on D28. In addition, two subjects had abnormal cardiac assessments reported in the context of a related SAE: One Subject: abnormal ECG results (related SAE: chest pain), One Subject: abnormal echocardiogram results (related SAE: chest pain). IMMUNOGENICITY Two of the 230 subjects (0.9%) had pre-existing vaccinia neutralizing antibody titers on D0: Subject (number not disclosed) (15.1 1/dil) and Subject (number not disclosed) (24.8 1/dil). The sera from the remaining 228 subjects were found negative before vaccination (anti-vaccinia antibody titers <10 1/dil). One month after vaccination, 229 of the 230 subjects (99.6%) had anti-vaccinia antibody levels 10 1/dil. The titer of the negative subject (number not disclosed) was close to the cut-off value (9.6 1/dil). The profile of this subject in terms of nature and size of cutaneous lesions was comparable to the profile of the global study population. The geometric mean titer of the global study population was /dil [95% CI: 73.35; 88.75]. In the 228 subjects with seronegative status at baseline, the GM of titers was [95% CI: 37.27;45.42]. Seroconversion (antibody titer <10 1/dil on D0 and 10 1/dil on D28) was observed for 227 of the 228 subjects with seronegative status at baseline (seroconversion rate: 99.6%). CONCLUSION Not disclosed