Product Monograph - Prehevbrio
RECENT MAJOR LABEL CHANGES
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TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES .......................................................................................... 2
TABLE OF CONTENTS ............................................................................................................ 2
PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4
1 INDICATIONS ............................................................................................................. 4
1.1 Pediatrics .................................................................................................................. 4
1.2 Geriatrics .................................................................................................................. 4
2 CONTRAINDICATIONS ................................................................................................ 4
4 DOSAGE AND ADMINISTRATION ................................................................................ 4
4.2 Recommended Dose and Dosage Adjustment ........................................................ 4
4.4 Administration ......................................................................................................... 5
4.5 Missed Dose ............................................................................................................. 5
5 OVERDOSAGE ............................................................................................................ 5
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 5
7 WARNINGS AND PRECAUTIONS ................................................................................. 6
7.1 Special Populations .................................................................................................. 7
7.1.1 Pregnant Women ............................................................................................... 7
7.1.2 Breast-feeding .................................................................................................... 7
7.1.3 Pediatrics ............................................................................................................ 7
7.1.4 Geriatrics (≥ 65 years of age) ............................................................................. 7
8 ADVERSE REACTIONS................................................................................................. 8
8.1 Adverse Reaction Overview ..................................................................................... 8
8.2 Clinical Trial Adverse Reactions ............................................................................... 8
8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 12
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................. 12
8.5 Post-Market Adverse Reactions ............................................................................. 12
9 DRUG INTERACTIONS .............................................................................................. 12
9.2 Drug Interactions Overview ................................................................................... 12
9.4 Drug-Drug Interactions .......................................................................................... 12
9.5 Drug-Food Interactions .......................................................................................... 12
9.6 Drug-Herb Interactions .......................................................................................... 12
9.7 Drug-Laboratory Test Interactions......................................................................... 12
10 CLINICAL PHARMACOLOGY ...................................................................................... 13
10.1 Mechanism of Action ....................................................................................... 13
11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 13
PART II: SCIENTIFIC INFORMATION ..................................................................................... 13
13 PHARMACEUTICAL INFORMATION .......................................................................... 13
14 CLINICAL TRIALS ...................................................................................................... 13
14.1 Trial Design and Study Demographics ............................................................. 13
14.2 Study Results .................................................................................................... 15
15 MICROBIOLOGY ...................................................................................................... 16
16 NON-CLINICAL TOXICOLOGY .................................................................................... 16
PATIENT MEDICATION INFORMATION ................................................................................ 18
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
PREHEVBRIO (3-antigen, recombinant Hepatitis B vaccine) is indicated for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.
It can be expected that hepatitis D will also be prevented by immunization with PREHEVBRIO as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.
The National Advisory Committee of Immunization (NACI) provides additional guidance on the use of hepatitis B vaccines in Canada, including a list of recommended individuals for vaccination against hepatitis B. Please refer to the Canadian Immunization Guide.
1.1 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
1.2 Geriatrics
Geriatrics (>65 years of age): PREHEVBRIO has been studied in the geriatric population (see 7.1 Special Populations, 14 CLINICAL TRIALS).
2 CONTRAINDICATIONS
PREHEVBRIO is contraindicated in patients who are hypersensitive to this vaccine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container, and who have experienced the following:
- Hypersensitivity to the active substance or to any of the excipients listed in 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
- History of severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B antigen-containing vaccine.
4 DOSAGE AND ADMINISTRATION
4.2 Recommended Dose and Dosage Adjustment
The vaccination regimen of PREHEVBRIO consists of 3 doses (1.0 mL each) given according to the following schedule: first dose at an elected date; second dose 1 month after the first dose; third dose 6 months after the first dose.
Booster dose
The need for a booster dose has not been established. No data are available.
Geriatric population
No dose adjustments are required in persons aged 65 years and older.
4.4 Administration
For intramuscular use only.
PREHEVBRIO should be injected intramuscularly (IM) into the deltoid region using a sterile needle of appropriate length to ensure IM administration. Injection into the gluteal (buttocks) region should be avoided.
The vaccine should be used under aseptic conditions.
The suspension should be shaken well prior to administration.
The suspension is slightly white opaque when mixed. Upon settling, the solution is clear and colorless with a white deposit.
The suspension should be visually inspected prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, discard the vaccine.
4.5 Missed Dose
If a planned dose of PREHEVBRIO is missed, it should be administered as soon as possible. The schedule of administration should be adjusted to maintain the prescribed dosing interval.
5 OVERDOSAGE
No cases of overdose have been reported with PREHEVBRIO.
| For management of a suspected drug overdose, contact your regional poison control centre. |
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6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.
PREHEVBRIO is an injectable suspension, for intramuscular use supplied as a single-dose vial. A single dose of PREHEVBRIO is 1.0 mL.
Table 1: Dosage Forms, Strengths, Composition and Packaging
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Intramuscular injection | One dose (1.0 mL) of sterile suspension for injection contains Hepatitis B surface antigens (S [83%], pre-S2 [11%] and pre-S1 [6%])1, 2 10 micrograms. Packaged in 10 x 1.0 mL single-dose vials | Aluminum hydroxide, disodium phosphate dodecahydrate, hydrochloric acid, potassium chloride, potassium di-hydrogen phosphate, sodium chloride, sodium hydroxide, water for injection |
1 Adsorbed on 500 micrograms of Al3+ as aluminum hydroxide, hydrated
2 Produced in Chinese Hamster Ovary cells by recombinant DNA technology
Excipients with known effect
Sodium: This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e. is essentially 'sodium-free’.
Potassium: This medicinal product contains less than 1 mmol of potassium (39 mg) per dose, i.e. is essentially potassium-free’.
7 WARNINGS AND PRECAUTIONS
General
Vaccination should be postponed in subjects suffering from acute severe febrile illness or acute infection. The presence of a minor infection and/or low-grade fever should not delay vaccination.
Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paresthesia, and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury.
Hepatitis B has a long incubation period. PREHEVBRIO may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccine administration.
Acute Allergic Reactions
As with all injectable vaccines, appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.
Driving and Operating Machinery
PREHEVBRIO has no or negligible influence on the ability to drive and use machinery. However, some of the effects mentioned in 8 ADVERSE REACTIONS (e.g. fatigue, headache, dizziness) may temporarily affect the ability to drive or operate machinery.
Hematologic
As with other intramuscular injections, the vaccine should be given with caution in subjects receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as hemophilia) because bleeding or bruising may occur following an intramuscular administration in these vaccinees.
Immune
Immunocompromised persons may have a diminished immune response to PREHEVBRIO. There are limited data available among immunocompromised population. Attention should be given to ensure that a protective antibody level is maintained as defined by national recommendations and guidelines.
Patients with chronic liver disease or with HIV infection or hepatitis C carriers should not be precluded from vaccination against hepatitis B. The vaccine could be advised since hepatitis B infection can be severe in these patients: the PREHEVBRIO vaccination should thus be considered on a case-by-case basis by the physician.
Renal Impairment
Pre-hemodialysis and hemodialysis patients are at risk of exposure to hepatitis B virus and have a higher risk of becoming chronically infected. Attention should be given to ensure that a protective antibody level is achieved and maintained as defined by national recommendations and guidelines.
Reproductive Health: Female and Male Potential
- Fertility
There are no data on fertility in humans from the use of PREHEVBRIO (see 7.1.1 Pregnant Women).
- Teratogenic Risk
There are no data on teratogenic risk in humans from the use of PREHEVBRIO.
Animal studies do not indicate direct or indirect harmful effects with respect to embryolethality, fetotoxicity, or teratogenicity (see 16 NON-CLINICAL TOXICOLOGY).
7.1 Special Populations
7.1.1 Pregnant Women
There are no data from the use of the vaccine in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see 16 NON-CLINICAL TOXICOLOGY).
Vaccination during pregnancy should only be performed if the risk-benefit ratio at the individual level outweighs possible risks for the fetus.
7.1.2 Breast-feeding
It is unknown whether PREHEVBRIO is excreted in human milk.
A risk to the breastfed newborn/infant cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to abstain from PREHEVBRIO vaccination taking into account the benefit of breast-feeding for the child and the benefit of vaccination for the woman.
7.1.3 Pediatrics
Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of PREHEVBRIO in pediatric patients has not been established in Canada; therefore, Health Canada has not authorized an indication for pediatric use.
7.1.4 Geriatrics (≥ 65 years of age)
Immunogenicity of PREHEVBRIO has been studied in clinical trials in population 65 years of age and older. Seroprotection Rate (95% Confidence Interval) was 83.6% (78.6, 87.8) in a group of 268 individuals who received PREHEVBRIO compared to 64.7% (58.6, 70.4) in a group of 266 individuals who received Engerix-B with a difference in SPR of 18.9% (11.6, 26.1) between PREHEVBRIO and Engerix-B. Safety data were consistent with other age groups (See 8.2 Clinical Trial Adverse Reactions and 14 CLINICAL TRIALS).
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
The clinical trial safety profile of PREHEVBRIO is based on two Phase 3 controlled clinical trials (Sci-B-Vac-001 and Sci-B-Vac-002) in which 2920 adults received at least one dose of PREHEVBRIO.
Local and systemic post-injection reactions were monitored using diary cards for a 7-day period starting on the day of each vaccination. The most common solicited local reactions after three injections were injection-site pain (72.2%), tenderness (71.2%) and local pruritus/itching (12.2%). Most common solicited systemic reactions were myalgia (41.7%), fatigue (37.5%), and headache (36.3%).
The frequency and severity of solicited adverse events generally declined or remained similar with successive vaccinations.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
A total of 2920 individuals age ≥18 years received at least one dose of PREHEVBRIO in two phase 3 clinical trials conducted in the United States, Canada, Belgium, Finland, Germany, and United Kingdom. Enrolled subjects had no history of hepatitis B vaccination or infection. Vaccinations were administered at 0, 1 and 6 months.
Study Sci-B-Vac-001 in adults age ≥18 years
Study Sci-B-Vac-001 was a randomized, double-blind, active-controlled, multicenter study in which 796 subjects received at least 1 dose of PREHEVBRIO and 811 subjects received at least 1 dose of Engerix-B [Hepatitis B Vaccine (Recombinant)]. In the total study population at baseline the mean age was 57 years, 81% were age ≥45 years; 37.2% were age ≥65 years, 62% women, 90% White, 8% Black, 1% Asian, and 10% Hispanic/Latino; 37% obese (BMI >30 kg/m2), 14% current smokers and 8% had Type 2 diabetes mellitus. Demographic and baseline characteristics were similar in both vaccine groups. Completion rate of 3-dose vaccination was 95.2% for PREHEVBRIO 96.8% for Engerix-B.
Study Sci-B-Vac-002 in adults age 18-45 years
Study Sci-B-Vac-002 was a randomized, double-blind, active-controlled, multicenter study in which 2124 subjects received at least 1 dose of PREHEVBRIO and 712 subjects received at least 1 dose of Engerix-B. In the total study population at baseline, the mean age was 34 years; 58% women, 92% White, 6% Black, 2% Asian, and 10% Hispanic/Latino; 18% obese (BMI >30 kg/m2) and 19% current smokers. Demographic and baseline characteristics were similar in both vaccine groups. Completion rate of 3-dose vaccination was 92.6% for PREHEVBRIO and 94.2% for Engerix-B.
Solicited Local and Systemic Adverse Reactions
Subjects were monitored for local and systemic adverse reactions using diary cards for a 7-day period starting on the day of vaccination. The percentages of subjects who reported local and systemic reactions in both studies are shown in Table 2 to Table 5.
Table 2: Solicited Local and Systemic Adverse Events after Any Vaccination by Treatment Group – Age Group 18-44 Years (Study 001)
| Engerix-B (N=154) % | PREHEVBRIO (N=145) % | |||
|---|---|---|---|---|
| Local (Injection Site) | ||||
| Pain | 51.9 | 74.5 | ||
| Tenderness | 50.0 | 70.3 | ||
| Itching | 13.0 | 9.0 | ||
| Redness* | 1.9 | 2.1 | ||
| Swelling* | 2.6 | 3.4 | ||
| Systemic | ||||
| Headache | 40.9 | 51.0 | ||
| Fatigue | 41.6 | 43.4 | ||
| Myalgia | 29.2 | 43.4 | ||
| Diarrhea | 14.9 | 14.5 | ||
| Nausea/ vomiting | 15.6 | 12.4 | ||
| Fever | 1.9 | 1.4 | ||
* Redness and swelling ≥ 2.5 cm
Table 3: Solicited Local and Systemic Adverse Events after Any Vaccination by Treatment Group – Age Group 45-64 Years (Study 001)
| Engerix-B (N=361) % | PREHEVBRIO (N=355) % | |||
|---|---|---|---|---|
| Local (Injection Site) | ||||
| Pain | 36.8 | 67.0 | ||
| Tenderness | 37.1 | 63.4 | ||
| Itching | 7.8 | 8.5 | ||
| Redness* | 2.5 | 2.5 | ||
| Swelling* | 0.8 | 2.3 | ||
| Engerix-B (N=361) % | PREHEVBRIO (N=355) % | |||
|---|---|---|---|---|
| Systemic | ||||
| Headache | 32.4 | 34.6 | ||
| Fatigue | 30.2 | 30.1 | ||
| Myalgia | 25.8 | 37.2 | ||
| Diarrhea | 11.9 | 9.0 | ||
| Nausea/ vomiting | 10.2 | 7.0 | ||
| Fever | 1.1 | 0.6 | ||
* Redness and swelling ≥ 2.5 cm
Table 4: Solicited Local and Systemic Adverse Events after Any Vaccination by Treatment Group – Age Group ≥ 65 Years (Study 001)
| Engerix-B (N=296) % | PREHEVBRIO (N=296) % | |||
|---|---|---|---|---|
| Local (Injection Site) | ||||
| Pain | 27.4 | 53.0 | ||
| Tenderness | 24.0 | 53.0 | ||
| Itching | 6.1 | 11.1 | ||
| Redness* | 1.0 | 2.0 | ||
| Swelling* | 1.7 | 1.7 | ||
| Systemic | ||||
| Headache | 19.6 | 17.6 | ||
| Fatigue | 25.7 | 24.3 | ||
| Myalgia | 19.9 | 27.4 | ||
| Diarrhea | 10.1 | 9.8 | ||
| Nausea/ vomiting | 4.1 | 4.4 | ||
| Fever | 0.7 | 0.7 | ||
* Redness and swelling ≥ 2.5 cm
Table 5: Solicited Local and Systemic Adverse Events after Any Vaccination by Treatment Group – Age Group 18-45 Years (Study 002)
| Engerix-B (N=712) % | PREHEVBRIO (N=2124) % | |||
|---|---|---|---|---|
| Local (Injection Site) | ||||
| Pain | 53.9 | 75.6 | ||
| Tenderness | 54.9 | 75.1 | ||
| Itching | 12.4 | 13.2 | ||
| Redness* | 1.7 | 2.9 | ||
| Swelling* | 0.8 | 2.6 | ||
| Systemic | ||||
| Headache | 37.6 | 38.2 | ||
| Fatigue | 39.9 | 40.1 | ||
| Myalgia | 32.4 | 44.4 | ||
| Diarrhea | 14.7 | 13.0 | ||
| Nausea/ vomiting | 12.1 | 11.8 | ||
| Fever | 1.1 | 1.1 | ||
* Redness and swelling ≥ 2.5 cm
The majority of subjects who experienced local solicited AEs within 7 days of any vaccination reported the maximum severity as mild (50.2% and 44.2%) or moderate (28.3% and 10.0%) for PREHEVBRIO and Engerix-B, respectively. Similarly, the maximum severity of systemic solicited AEs was mild (40.7% and 32.6%) or moderate (21.1% and 18.9%) for PREHEVBRIO and Engerix-B, respectively. The frequency and severity of solicited AEs generally declined or remained similar with successive vaccinations.
Unsolicited Adverse Events (AEs)
In both studies, unsolicited adverse events, including serious and non-serious events, that occurred within 28 days following each vaccination were recorded on a diary card by all subjects.
In both studies combined, unsolicited AEs that occurred within 28 days of any vaccination were reported by 48.3% and 48.4% of subjects who received PREHEVBRIO or Engerix-B, respectively. The most common (≥ 1%) unsolicited AEs in subjects who received PREHEVBRIO for which available information suggests a causal relationship to vaccination include injection site bruising (1.4%), dizziness/vertigo (1.1%), abdominal pain (0.7%), and rash (0.3%).
8.3 Less Common Clinical Trial Adverse Reactions
The following adverse reactions have been reported in less than 1% of the patients in Study 001 and Study 002.
Gastrointestinal Disorders: Abdominal pain
General Disorders and Administration Site Conditions: General pruritus/itchiness
Immune system disorders: Lymphadenopathy/lymph node pain
Musculoskeletal and Connective Tissue Disorders: Arthralgia
Skin and Subcutaneous Tissue Disorders: Rash, urticaria/hives
Vascular Disorders: Flushing/hot flushes
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
There were no clinically significant changes in laboratory findings related to PREHEVBRIO identified during clinical trials or post-marketing of PREHEVBRIO.
8.5 Post-Market Adverse Reactions
The safety profile observed post-marketing with PREHEVBRIO is consistent with that observed during clinical studies.
9 DRUG INTERACTIONS
9.2 Drug Interactions Overview
No interaction studies have been performed.
There are no data to assess the concomitant use of PREHEVBRIO with immune globulin. When concomitant administration of PREHEVBRIO and immune globulin is required, they should be given with different syringes at different injection sites. If concomitant administration of other vaccines is required, these should be given with different syringes at separate injection sites.
9.4 Drug-Drug Interactions
Interactions with other drugs have not been established.
9.5 Drug-Food Interactions
Interactions with food have not been established.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Hepatitis B surface antigen (HBsAg) derived from hepatitis B vaccines has been transiently detected in blood samples following vaccination. Serum HBsAg detection may not have diagnostic value within 28 days after receipt of PREHEVBRIO.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
PREHEVBRIO confers seroprotection against hepatitis B virus infection through the stimulation of a specific immune response, as measured by the induction of anti-HBs antibodies at a level ≥10 mIU/mL.
11 STORAGE, STABILITY AND DISPOSAL
Store in a refrigerator at 2°C to 8°C. Store in original package in order to protect from light.
Do not freeze; discard if the vaccine has been frozen.
Do not use the vaccine after the expiration date shown on the vial label.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Hepatitis B surface antigens (S [83%], pre-S2 [11%] and pre-S1 [6%])
Product Characteristics
PREHEVBRIO is manufactured by recombinant DNA technology in CHO (Chinese Hamster Ovary) mammalian cells, and contains the full antigenic structure of the HBV surface antigen, including the small (S), middle (pre-S2) and large (pre-S1) hepatitis B surface antigens.
14 CLINICAL TRIALS
14.1 Trial Design and Study Demographics
The immunogenicity of PREHEVBRIO was evaluated in comparison with a licensed hepatitis B vaccine (Engerix-B) in 2 randomized, active controlled, double-blinded, multi-center Phase 3 clinical trials in adults 18 years of age and older. PREHEVBRIO and Engerix-B were given as a 3-dose regimen at 0, 1, and 6 months.
A total of 2920 individuals age ≥18 years received at least one dose of PREHEVBRIO in two phase 3 clinical trials (Sci-B-Vac-001 and Sci-B-Vac-002) conducted in the United States, Canada, Belgium, Finland, Germany, and United Kingdom. Enrolled subjects had no history of hepatitis B vaccination or infection. Vaccinations were administered at 0, 1 and 6 months. Summary of patient demographics is provided in Table 6.
Table 6: Summary of patient demographics for clinical trials
| Study # | Study design | Dosage, route of administration and duration | Study subjects (n) | Mean age (Range) | Sex |
| Sci-B-Vac-001 | Phase III Comparative Randomized, Two arm Double-blind Multi-center | PREHEVBRIO (Al(OH)3 without thimerosal); single dose IM, 10 μg (n=796) Comparator: Engerix B: 20 μg (n=811) | 1607 | 56.6 | Male = 38.5% (n=618) Female = 61.5% (n=989) |
| Sci-B-Vac-002 | Phase III Comparative Randomized, Four arm Double-blind Multi-center | PREHEVBRIO(Al(OH)3 without thimerosal) Single dose IM, 10 μg Lot A (n=711) Lot B (n=709), Lot C (n= 706) Comparator: Engerix B: 20 μg (n=712) | 2838 | 33.5 | Male = 42.2% (n=1198 Female = 57.8% (n=1638) |
Sci-B-Vac-001
A total of 2472 subjects were screened for the study with 1607 subjects randomized, including 796 subjects to the PREHEVBRIO treatment arm and 811 subjects to the Engerix-B® treatment arm. All randomized subjects received their assigned treatment.
Most subjects in both treatment arms completed study treatment as planned, including 758 (95.2%) in the PREHEVBRIO arm and 785 (96.8%) subjects in the Engerix-B® arm. Early discontinuation from treatment was reported for 38 (4.8%) in the PREHEVBRIO arm and 26 (3.2%) subjects in the Engerix-B® arm. The most common reason for treatment discontinuation was lost to follow-up (1.1% PREHEVBRIO and 1.2% Engerix-B®) followed by withdrawal of consent by the subject (1.0% PREHEVBRIO and 0.6% Engerix-B®). Treatment discontinuation due to non-serious AEs or SAE was uncommon, reported in 5 (0.6%) subjects in each treatment arm.
Overall, 756 (95.0%) in the PREHEVBRIO arm and 769 (94.8%) subjects in the Engerix-B® arm completed the study. The number of subjects who discontinued from the study was low and well balanced across the 2 treatment arms. Early discontinuation from the study was reported for 40 (5.0%) in the PREHEVBRIO arm and 42 (5.2%) subjects in the Engerix-B® arm. The most common reasons for early discontinuation from the study were lost to follow-up and withdrawal of consent. Study discontinuation due to non-serious AEs or SAE was uncommon, reported in 1 (0.1%) subject in the PREHEVBRIO arm and 3 (0.4%) subjects in the Engerix-B® arm.
Sci-B-Vac-002
A total of 4452 subjects were screened for the study with 2838 subjects randomized, including 712 subjects to the Engerix-B® group, and 2126 to the 3 PREHEVBRIO groups (711 to Lot A group, 709 to Lot B group, and 706 to Lot C group). Of the 2838 subjects, 2836 (99.9%) subjects received their assigned treatment. Two subjects were randomized to receive PREHEVBRIO but did not receive vaccination: One subject withdrew consent before receiving any vaccination and the other subject was discontinued due to non-compliance with the study procedures.
Most subjects (93%) completed study treatment as planned. Early discontinuation from treatment was reported in 159 (7.5%) subjects who received PREHEVBRIO and in 41 (5.8%) subjects who received Engerix-B®. The most common reason for treatment discontinuation was lost to follow-up or withdrawal of consent by subject.
14.2 Study Results
Immunogenicity
Study Sci-B-Vac-001 in adults age ≥18 years
The primary immunogenicity endpoint of the study was the seroprotection rate (SPR), defined as the percentage of subjects with anti-HBs levels of ≥10 mIU/mL. The two co-primary analyses, tested hierarchically, were: (1) non-inferiority of PREHEVBRIO compared to Engerix-B at Day 196, 4 weeks after receiving the third dose in all adults age ≥18 years and (2) superiority of PREHEVBRIO compared to Engerix-B in subjects ≥45 years old at Day 196.
The study met both co-primary endpoints. The estimated difference in SPR was 14.9% (95% CI: 11.2, 18.6) meeting the non-inferiority margin of -5%. The estimated difference in SPR in subjects ≥45 years of age was 16.4% (95% CI: 12.2, 20.7%) meeting the superiority criteria. These results are shown in Table 7, as well as SPR per age group.
Table 7: Seroprotection Rate (SPR) 4 Weeks After Receiving the Third Dose of PREHEVBRIO or Engerix-B
| Study Population | PREHEVBRIO N | PREHEVBRIO SPR (95% CI) | Engerix-B N | Engerix-B SPR (95% CI) | Difference in SPR; PREHEVBRIO – Engerix-B (95% CI) |
|---|---|---|---|---|---|
| All Adults (Age 18+) a | 718 | 91.4 (89.1, 93.3) | 723 | 76.5 (73.2, 79.5) | 14.9 (11.2, 18.6) c |
| Age 45+ b | 625 | 89.4 (86.8, 91.7) | 627 | 73.1 (69.4, 76.5) | 16.4 (12.2, 20.7) d |
| Age 18-44 | 125 | 99.2 (95.6, 100.0) | 135 | 91.1 (85.0. 95.3) |
|
| Age 45-64 | 325 | 94.8 (91.8, 96.6) | 322 | 80.1 (75.3, 84.3) |
|
| Age 65 + | 268 | 83.6 (78.6, 87.8) | 266 | 64.7 (58.6, 70.4) |
|
N=number of subjects in the Per-Protocol Set; SPR= Seroprotection Rate defined as % of subjects with anti-HBs titers ≥10 mIU/mL in serum
a Per-protocol set (PPS). PPS included all subjects in the full analysis set who received all 3 vaccinations, had an evaluable serum immunogenicity sample at baseline and at the time point of interest, were seronegative at baseline, and had no major protocol violations leading to exclusion.
b Full analysis set (FAS). FAS included all subjects who received at least 1 vaccination and provided at least 1 evaluable serum immunogenicity sample both at baseline and after baseline. Subjects were seronegative at baseline.
c Non-inferiority was met because the lower bound of the 95% CI of the difference in SPR (PREHEVBRIO - Engerix-B) was > -5%.
d Superiority was met if the lower bound of the 95% CI of the difference in SPR (PREHEVBRIO minus Engerix-B) was greater than 0%.
e Exploratory analysis
SPR (95% Confidence Interval) at 4 weeks after receiving the third dose was higher for PREHEVBRIO compared with Engerix-B in subjects with diabetes (83.3% vs. 58.3%) and in subjects with BMI over 30 (89.22% vs. 68.11%).
Study Sci-B-Vac-002 in adults aged 18-45 years
In the secondary analysis, the data from the three lots were combined (pooled) to demonstrate non-inferiority of PREHEVBRIO compared to Engerix-B based on SPR.
The non-inferiority of PREHEVBRIO compared to Engerix-B based on SPR was met, the estimated difference in SPR at day 196 was 4.49% (95% CI: 2.90, 6.63%). The results are shown in Table 8.
Table 89: Seroprotection Rate (SPR) 4 Weeks After Receiving the Third Dose of PREHEVBRIO or Engerix-B
| PREHEVBRIO Pooled | Engerix-B | Difference in SPR (PREHEVBRIO– Engerix-B) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study Population | N | SPR (95% CI) | N | SPR (95% CI) | Difference (95% CI)* | |||||||
| Age 18-45 years | 1753 | 99.26% (98.74. 99.60) | 592 | 94.76% (92.65, 96.41) | 4.49 (2.90, 6.63) | |||||||
N=number of subjects in the Per-Protocol Set 2 (received all 3 doses at months 0, 1 and 6); SPR= Seroprotection Rate defined as % of subjects with anti-HBs titers ≥10 mIU/mL in serum; Pooled PREHEVBRIO includes the PREHEVBRIO Lots A, B, and C
*Non-inferiority was met because the lower bound of the 95% CI of the difference in SPR (PREHEVBRIO - Engerix-B) was > -5%.
15 MICROBIOLOGY
No microbiological information is required for this drug product.
16 NON-CLINICAL TOXICOLOGY
PREHEVBRIO has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.
Vaccination of female rats with a vaccine formulation containing 10 micrograms/dose had no effect on fertility and no evidence of embryolethality, fetotoxicity or teratogenicity.