The primary objective of the study is to evaluate the safety and efficacy of inactivated VZV vaccine for the prevention of HZ and HZ-related complications in adult recipients of autologous hemotopoietic cell transplants (HCTs).
ID
Source
Brief title
Condition
- Viral infectious disorders
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary goals of the study:
1. To assess the safety and tolerability of inactivated VZV vaccine in
recipients of autologous HCT.
2. To assess the impact of the inactivated VZV vaccine on the development of HZ
following autologous HCT.
Secondary outcome
Secundary goals of the study:
1. To asses the impact of inactivated VZV vaccine on the development of
moderate to severe HZ-associated pain at any time from HZ onset through the end
of the 6 month HZ follow-up period. Moderate to severe HZ-associated pain is
defined as 2 or more occurrences of a score of 3 or greater (0-to-10 scale) on
the Zoster Brief Pain Inventory (ZBPI) post-autologous HCT.
2. To assess the impact of inactivated VZV vaccine on the development of HZ
complications 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 post-autologous HCT.
3. To assess the impact of inactivated VZV vaccine on the development of PHN.
PHN is defined as pain in the area of the HZ rash with a "worst pain in the
last 24 hours" score of 3 or greater (on a 0-to-10 scale) on the ZBPI that
persists or appears greater than or equal to 90 days after the HZ rash onset
post-autologous HCT.
Background summary
Immunocompromised patients, such as recipients of autologous HCTs, have a
substantially higher incidence of HZ compared with the general population, and
are at increased risk for developing severe and life-threatening
complications. HZ is common after autologous HCT, occurring in more than 20%
of patients within 12 to 24 months of transplantation. In this population, HZ
is a cause of significant morbidity, including pain, postherpetic neuralgia
(PHN), secondary bacterial infection, disseminated VZV infection,
hospitalization, and occasional mortality. Merck Research Laboratories (MRL)
has developed ZOSTAVAX* for prevention of HZ and its complications, especially
HZ-related pain and PHN. ZOSTAVAX*, a live attenuated vaccine, is
contraindicated in immunocompromised patients. Therefore, autologous HCT
recipients, a most vulnerable population, will not be eligible for vaccination
with ZOSTAVAX*.
Proof-of-concept (POC) for a VZV vaccine inactivated by heat-treatment for use
in HCT recipients was demonstrated in two clinical trials conducted by Arvin,
et al. These trials utilized inactivated Oka/Merck varicella vaccine supplied
by Merck & Co., Inc. The results of these two studies demonstrated that
inactivated VZV vaccine given to recipients of HCT had significant impact on
the development of HZ. Protection appeared to correlate with the
reconstitution of T-cell immunity against VZV. A 4-dose regimen, with doses
given 30 days prior to HCT and 30, 60, and 90 days post-HCT, resulted in a
significant reduction in the risk of HZ.
More recently, two phase I clinical studies of V212 were conducted by the
sponsor. Protocol 002 was a randomized, double-blind, multicenter study to
evaluate the safety and immunogenicity of a VZV vaccine inactivated by
heat-treatment in 4 distinct immunocompromised populations, one of which
consists of autologous HCT patients. The study enrolled 341 patients of 18
years of age or older, who were randomized to receive either a 4-dose regimen
of inactivated VZV vaccine or placebo. Of the 50 patients included in the
autologous HCT population, 40 patients were vaccinated with V212 and 10
patients were vaccinated with placebo. The objective of the study was to
provide additional reassurance regarding the safety and immunogenicity of V212
in a broader group of immunocompromised individuals. No safety signals were
identified in any of the patient populations. The study demonstrated promising
immunogenicity results in the autologous-HCT population. Overall, the results
of this study indicate that the inactivated vaccine is immunogenic and has a
favorable safety profile when administered as a 4 dose regimen to patients
undergoing autologous HCT.
Protocol 004 was a randomized, double-blind, multicenter study to evaluate the
safety, tolerability, and immunogenicity of a gamma-irradiated VZV vaccine in
healthy adults 50 to 59 years old. The results from the study indicate that the
VZV vaccine inactivated by gamma-irradiation and the VZV inactivated by
heat-treatment are immunogenic when administered to healthy individuals and
have an acceptable safety profile.
Prevention of HZ disease in this population represents an area of significant
medical need, since these profoundly immunocompromised patients cannot receive
the live attenuated zoster vaccine. The current study will expand upon the
experience of the earlier studies and will provide confirmatory results on the
safety and efficacy of the inactivated VZV vaccine in a larger population of
patients undergoing autologous HCT. This study will be conducted using a 4-dose
regimen, since the available results suggest additional benefit from a pre-HCT
dose in addition to 3 post-HCT doses compared with a regimen consisting soley
of 3 post-HCT doses. The 4-dose regimen with doses given ~30 days prior to HCT
and ~30, ~60, and ~90 days post-HCT resulted in a significant reduction in the
risk of HZ. The addition of a fourth dose, pre-HCT, provided ~60% efficacy in
reducing the incidence of HZ compared with placebo.
Inactivation of the vaccine via the heat-treatment targets a reduction of VZV
infectious particles to <10 plaque-forming units (PFU) per dose. POC studies
of vaccine inactivated by heat-treatment in HCT/Bone Marrow Transplant (BMT)
recipients demonstrated that this level of residual infectivity content is not
required for vaccine efficacy and the results of P004 indicate that
immunogenicity is not affected by gamma irradiation treatment up to 25 kGy.
Therefore, the vaccine to be used for this study and future studies of V212
will be inactivated by gamma irradiation.
Study objective
The primary objective of the study is to evaluate the safety and efficacy of
inactivated VZV vaccine for the prevention of HZ and HZ-related complications
in adult recipients of autologous hemotopoietic cell transplants (HCTs).
Study design
This is a randomized, double-blind (with in-house blinding procedures),
placebo-controlled, multicenter study to evaluate the safety, tolerability,
efficacy, and immunogenicity of inactivated VZV vaccine for the prevention of
HZ in recipients of autologous HCTs. Approximately 1204 patients >=18 years of
age will be enrolled in this study and randomly allocated to receive either
inactivated VZV vaccine from one of three consistency lots (~552 patients) ),
inactivated VZV vaccine from a high antigen lot (~100 patients), or placebo
(~552 patients), administered in a 4-dose regimen.
This will be an event-driven study based on the occurrence of confirmed HZ
cases. Patients will remain in the study from the time of enrollment until
accrual of the target number (~252) of confirmed HZ cases among inactivated VZV
vaccine consistency lot and placebo recipients. A confirmed case of HZ is
defined primarily on the basis of detection of VZV DNA in a skin lesion
specimen by PCR. For those suspected cases that do not have a diagnostic skin
lesion PCR result, either because the result is indeterminate or missing, case
confirmation will be based on the result of adjudication of the clinical case
description by the Clinical Adjudication Committee (CAC), conducted according
to the CAC Standard Operations Procedure (SOP).
Patients will be evaluated for safety utilizing a vaccination report card (VRC)
following each vaccine dose. Completion of the VRC is required by all patients
up until 28 days Postdose 4. Each patient will be followed for at least 1-year
following their last vaccination dose. The planned study duration stated in
this protocol is estimated based on assumptions of patient enrollment and
follow-up times and HZ incidence. If these assumptions are met, patients will
be followed for approximately 3 years for the occurrence of suspected HZ, in
order to accrue approximately 252 confirmed HZ cases among inactivated VZV
vaccine consistency lot and placebo recipients. It should be noted that
patients may be followed in the study for less than or more than 3 years,
depending on the time that it takes to accrue approximately 252 confirmed cases
among inactivated VZV vaccine consistency lot and placebo recipients. In the
event that the necessary 252 confirmed cases of HZ among inactivated VZV
vaccine consistency lot and placebo recipients accrue sooner than 1 year after
the last vaccine dose is administered in this study, the study will continue to
allow all patients to complete the 1 year postvaccination follow-up.
Patients will be educated on the signs and symptoms of HZ and instructed to
call the study site if such symptoms develop, to arrange evaluation by a
physician. Monthly contact by telephone, via the internet, or during a
follow-up visit will be required for each patient to assess for the occurrence
of unreported symptoms of suspected HZ. A suspected HZ case is defined as 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, CSF,
lung, liver or other organ. In immunocompromised patients, HZ rashes may be
atypical, for example involving more than one dermatome, or it may not be
present. Monthly contact will be required until study completion to determine
if unreported HZ symptoms occurred. All patients with suspected HZ will
undergo serial assessment over 6 months for evolution of rash and/or acute HZ
symptom(s), and severity of pain (ZBPI), interference with activities of daily
living (ZBPI), development of HZ-associated complications, functional health
status and quality of life (QoL), and HZ-related healthcare utilization (HCU),
as well as work and productivity loss (WPQ). Serum samples will be collected
for all patients on Day 1 (prior to Dose 1), Visit 4 (21 to 35 days Postdose
3), Visit 5 (28 to 60 days Postdose 4), and annually Postdose 4 in order to
measure immune responses by glycoprotein enzyme-linked immunospot assay
(gpELISA). For this protocol, annually is defined as occurring every 12-months
(i.e., 12, 24, 36) Postdose 4, with the first annual sample collected 12-months
Postdose 4. Dependent upon the duration of the study, not all patients will
have samples drawn at all of these later time points. Furthermore, in a subset
of patients (N~416), immune responses will also be measured by interferon-gamma
enzyme-linked immunospot (IFN-γ ELISPOT) assay. Blood samples will be
collected from patients enrolled in the IFN-γ ELISPOT substudy on Day 1 (prior
to Dose 1), Visit 4 (21 to 35 days Postdose 3), Visit 5 (28 to 60 days Postdose
4), and annually Postdose 4. All patients in the Netherlands will participate
in this substudy.
Intervention
The V212 vaccination will take place in 4 doses. Dose 1 may be administered ~30
days (60 to 5 days) prior to HCT. Doses 2 through 4 will be administered 30,
60 and 90 days post-HCT. Dose 2 should be administered 21 to 35 days
post-HCT. The visit window between vaccine doses 2 to 3 and 3 to 4 is 21 to 35
days. Patients will be randomized in a 1:1:1 ratio to receive vaccine from one
of three vaccine consistency lots. In addition, 100 patients will be randomized
to receive inactivated VZV vaccine from a high antigen vaccine lot. A given
patient will receive all 4 doses in the series from the same lot. Each dose of
vaccine/placebo will be administered as a 0.5-mL subcutaneous injection
preferably in the deltoid region of the arm, alternating arms for each
vaccination dose.
Placebo will be the vaccine stabilizer for inactivated VZV vaccine with no
virus antigen. Patients will be randomly allocated in a 1:1 ratio to receive
either inactivated VZV vaccine or placebo.
Study burden and risks
See answer to Question E9.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1. Patient is >=18 years of age on day of signing informed consent.
2. Patient 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 patient is less than 30 years old, attended primary or secondary school in a country with endemic VZV infection.
3. Patient is scheduled to undergo autologous HCT for treatment of lymphoma or other indication, including any other malignancy or an indication that is not a malignancy within 60 days of enrollment.
Exclusion criteria
1. Patient has a history of hypersensitivity reaction to any vaccine component, including gelatin or neomycin (a history of contact dermatitis to neomycin is not a criterion for study exclusion).
2. Patient has a prior history of HZ within 1 year of enrollment.
3. Patient has a prior history of receipt of any varicella or zoster vaccine.
4. Patient has had more than 2 relapses of their underlying cancer. If the patient*s underlying cancer is Hodgkin*s lymphoma, more than 2 relapses are permitted.
5. Patient is expected to undergo a tandem transplant procedure.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020150-34-NL |
| CCMO | NL33607.000.10 |