A Study to Evaluate the Safety and Efficacy of Inactivated Varicella-zoster Vaccine (VZV) as a Preventative Treatment for Herpes Zoster (HZ) and HZ-related Complications in Participants Undergoing Hematopoietic Cell Transplants (HCTs) (V212-001)

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study to assess the safety and efficacy of inactivated VZV vaccine for the prevention of HZ and HZ-related complications in adult recipients of autologous hematopoietic cell transplants (HCTs). The primary hypothesis is that vaccination with V212 vaccine will reduce the incidence of herpes zoster (HZ) compared to placebo when administered to recipients of HCT. The statistical criterion for success requires that the lower bound of the 95% confidence interval for the estimated vaccine efficacy in the V212 recipients (excluding the high-antigen lot) compared with that in the placebo recipients is >25%.

Detailed Description
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Study participants were randomized to receive one of 3 consistency lots of V212, a high antigen lot of V212, or placebo. To comply with regulatory requests, results for all lots of V212 were combined for the primary and secondary efficacy and safety evaluations (Protocol Amendment 2); all planned comparisons between the V212 lots were exploratory and are not included in this disclosure. Further, by regulatory request, the V212 High Antigen Lot was not included in the efficacy analyses for concerns that its inclusion would inflate the efficacy estimates (Protocol Amendment 4).

Official Title
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A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Clinical Trial to Study the Safety, Tolerability, Efficacy, and Immunogenicity of V212 in Recipients of Autologous Hematopoietic Cell Transplants (HCTs)

Conditions
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Herpes Zoster

Intervention / Treatment
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* Biological: V212
* Biological: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has prior history of varicella, antibodies to VZV (documented prior to receipt of blood products), or residence in a country with endemic VZV infection for ≥30 years or if participant is <30 years old, attended primary or secondary school in a country with endemic VZV infection. Scheduled to undergo an autologous hematopoietic cell transplant within 60 days of enrollment Is highly unlikely to conceive during the time period starting 2 weeks prior to enrollment through 6 months from last vaccination dose Female participants of childbearing potential must have a negative serum or urine pregnancy test. Exclusion Criteria: History of hypersensitivity reaction to any vaccine component Prior history of herpes zoster within 1 year of enrollment Prior receipt of any varicella or zoster vaccine More than 2 relapses of the underlying cancer (participants with Hodgkin's lymphoma may have had more than 2 relapses) Expectation of tandem transplant procedure Is expected to receive >6 months (>180 days) of prophylactic antiviral therapy post-HCT. Is pregnant or breastfeeding or expecting to conceive within the period of 2 weeks prior to enrollment through 6 months from last vaccination dose. Has received a live virus vaccine or is scheduled to receive a live virus vaccine in the period from 4 weeks prior to Dose 1 through 28 days Postdose 4. Has received an inactivated vaccine or is scheduled to receive an inactivated vaccine in the period between 7 days prior to and 28 days following Doses 1 through 4.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V212 Consistency Lot 1<br>Participants randomized to receive V212 consistency Lot 1 given as a 0.5 mL subcutaneous injection at 30 days before and 30, 60, and 90 days after auto-HCT. | Biological: V212<br>* V212 viral antigen for HZ. Participants will receive consistency Lot 1, 2, or 3 or the High Antigen Lot.<br>* Other names: Inactivated Varicella-Zoster (VZV) vaccine;|
| Experimental: V212 Consistency Lot 2<br>Participants randomized to receive V212 consistency Lot 2 given as a 0.5 mL subcutaneous injection at 30 days before and 30, 60, and 90 days after auto-HCT. | Biological: V212<br>* V212 viral antigen for HZ. Participants will receive consistency Lot 1, 2, or 3 or the High Antigen Lot.<br>* Other names: Inactivated Varicella-Zoster (VZV) vaccine;|
| Experimental: V212 Consistency Lot 3<br>Participants randomized to receive V212 consistency Lot 3 given as a 0.5 mL subcutaneous injection at 30 days before and 30, 60, and 90 days after auto-HCT. | Biological: V212<br>* V212 viral antigen for HZ. Participants will receive consistency Lot 1, 2, or 3 or the High Antigen Lot.<br>* Other names: Inactivated Varicella-Zoster (VZV) vaccine;|
| Experimental: V212 High Antigen Lot<br>Participants randomized to receive V212 High Antigen Lot given as a 0.5 mL subcutaneous injection at 30 days before and 30, 60, and 90 days after auto-HCT. | Biological: V212<br>* V212 viral antigen for HZ. Participants will receive consistency Lot 1, 2, or 3 or the High Antigen Lot.<br>* Other names: Inactivated Varicella-Zoster (VZV) vaccine;|
| Placebo Comparator: Placebo<br>Participants randomized to receive matching placebo given as a 0.5 mL subcutaneous injection at 30 days before and 30, 60, and 90 days after auto-HCT. | Biological: Matching placebo<br>* Vaccine stabilizer for V212 with no virus antigen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Confirmed Herpes-Zoster | Clinical criteria for suspected Herpes-Zoster (HZ) cases were the development of a papular or vesicular rash with a dermatomal or generalized distribution, or in the absence of a rash, clinical suspicion of VZV infection with or without the detection of VZV in diagnostic specimens from blood, cerebrospinal fluid, lung, liver, or other organ. All suspected cases of HZ were subjected to adjudication by the Clinical Adjudication Committee (CAC). Case confirmation was based on skin lesion polymerase chain reaction, if available, or by adjudication of the clinical case description by the CAC, conducted according to the CAC Standard Operations Procedure. | Up to approximately 5 years | 
| Percentage of Participants With One or More Serious Adverse Events | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in a persistent or significant disability or incapacity, results in or prolongs an existing hospitalization, is a congenital anomaly or birth defect, is a cancer, is an overdose, or is another important medical event. | Up to 28 days after vaccination 4 (up to 118 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Moderate to Severe Herpes-Zoster-Associated Pain | Moderate to severe HZ-associated pain was defined as 2 or more occurrences of a score 3 or greater (0-to-10 scale, where 0 is no pain and 10 is pain as bad as you can imagine) on the Zoster Brief Pain Inventory (ZBPI) at any time from HZ onset through the end of the 6 month HZ-follow-up period. | Up to 6 months after onset of HZ (up to approximately 5 years) | 
| Incidence of Herpes-Zoster Complications | The composite efficacy endpoint of the incidence of HZ complications was defined as the occurrence of any of the following during the study: hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, or administration of intravenous acyclovir therapy for treatment of HZ. | Up to 6 months after onset of HZ (up to approximately 5 years) | 
| Incidence of Postherpetic Neuralgia | Postherpetic Neuralgia (PHN) was defined as pain in the area of the HZ rash with pain in the last 24 hours scored as 3 or greater (on a 0 to 10 scale, where 0 is no pain and 10 is pain as bad as you can imagine) on the ZBPI that persists or appears greater than or equal to 90 days after HZ rash onset. | Up to 6 months after the onset of HZ rash (up to approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Herpes zoster, vaccine, herpes zoster-related complications, immunocompromised, autologous hematopoietic cell transplants