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Live Zoster Vaccine in HIV-Infected Adults on Antiretroviral Therapy

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ClinicalTrials.gov Identifier: NCT00851786
Recruitment Status : Completed
First Posted : February 26, 2009
Results First Posted : October 10, 2012
Last Update Posted : February 1, 2018
Sponsor:
Collaborators:
Adult AIDS Clinical Trials Group
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Prevention
Conditions Herpes Zoster
HIV Infections
Interventions Biological: ZOSTAVAX
Biological: Placebo
Enrollment 395
Recruitment Details The first person was accrued on 04/29/2009. Accrual in the high CD4 stratum was closed in 02/2010 (n=203; 152 on ZOSTAVAX and 51 on placebo). Accrual to the low CD4 stratum proceeded more slowly with the last subject enrolled on 06/30/2011 (n=192; 144 on ZOSTAVAX and 48 on placebo). All 43 participating sites enrolled at least 1 subject.
Pre-assignment Details Enrollment took place in two stages: Stage I were to enroll 48 subjects (24 in the low CD4 stratum and 24 in the high CD4 stratum). Subjects were randomized 3:1 to receive ZOSTAVAX or placebo. Stage II were to enroll approximately 352 subjects who would be randomized and stratified according to the same schedule.
Arm/Group Title ZOSTAVAX Placebo
Hide Arm/Group Description Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted. Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted
Period Title: Overall Study
Started 296 [1] 99 [2]
Completed 291 97
Not Completed 5 2
Reason Not Completed
Withdrawal by Subject             0             1
Protocol Violation             0             1
Lost to Follow-up             1             0
Incarceration             1             0
Site Closure             1             0
Cannot Adhere to Protocol Requirement             2             0
[1]
One subject cannot adhere to protocol requirement and was off study with no vaccine.
[2]
Two subjects (one found ineligible and one withdrew consent) were off study with no vaccine.
Arm/Group Title ZOSTAVAX Placebo Total
Hide Arm/Group Description Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted. Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted Total of all reporting groups
Overall Number of Baseline Participants 296 99 395
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
285
  96.3%
94
  94.9%
379
  95.9%
>=65 years
11
   3.7%
5
   5.1%
16
   4.1%
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 296 participants 99 participants 395 participants
49
(44 to 56)
49
(44 to 55)
49
(44 to 56)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
Female
44
  14.9%
18
  18.2%
62
  15.7%
Male
252
  85.1%
81
  81.8%
333
  84.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
White Non-Hispanic 141 44 185
Black Non-Hispanic 90 26 116
Hispanic (regardless of race) 60 27 87
Asian, Pacific islander 1 1 2
American Indian, Alaskan Native 2 1 3
More than one race 1 0 1
Unknown/missing 1 0 1
IV drug history  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
Never 244 86 330
Previously 52 13 65
Nadir CD4  
Median (Inter-Quartile Range)
Unit of measure:  cells/µL
Number Analyzed 296 participants 99 participants 395 participants
197
(109 to 287)
178
(104.5 to 285)
188
(108 to 287)
Screen CD4  
Median (Inter-Quartile Range)
Unit of measure:  cells/µL
Number Analyzed 296 participants 99 participants 395 participants
373
(286 to 634.5)
353
(278 to 561)
372
(286 to 606)
Entry CD4  
Median (Inter-Quartile Range)
Unit of measure:  cells/µL
Number Analyzed 296 participants 99 participants 395 participants
399
(282 to 607)
362
(276 to 579)
394
(281 to 605)
HIV-1 RNA  
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 296 participants 99 participants 395 participants
1.68
(1.68 to 1.70)
1.68
(1.68 to 1.70)
1.68
(1.68 to 1.70)
Prior History of AIDS  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
Yes 288 97 385
No 8 2 10
History of Chickenpox  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
>5 years 219 77 296
Zoster/no Chickpox 17 7 24
None 60 15 75
History of most recent Zoster  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
0-1 year 2 1 3
>1-2 years 13 1 14
>2-5 years 23 7 30
>5 years 65 22 87
None 193 68 261
Duration from Historary Retinal Necrosis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 296 participants 99 participants 395 participants
>5 years 2 0 2
None 294 99 393
1.Primary Outcome
Title Number of Participants With Composite Safety Endpoint of the Occurrence of Serious Adverse Events (SAEs) or Division of AIDS (DAIDS) Grade 3 and 4 Signs and Symptoms, Excluding SAEs Related to Trauma
Hide Description Although the study was designed as a randomized trial, it was not powered to detect safety related differences between treatment arms. The safety of ZOSTAVAX was determined by comparing the number of subjects from the active arm who experienced safety endpoint to the number from a pre-specified decision rule, which was calculated based on a similar population and calibrated using the number of safety endpoints observed from the placebo arm. The pre-specified decision rule is that ZOSTAVAX would be considered to have acceptable safety if no more than 18 subjects experience a study-defined composite safety endpoint.
Time Frame During the 6 week study period after receipt of any dose of ZOSTAVAX
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least one dose of study vaccine/placebo
Arm/Group Title ZOSTAVAX Placebo
Hide Arm/Group Description:
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted.
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted
Overall Number of Participants Analyzed 295 97
Measure Type: Number
Unit of Measure: participants
15 2
2.Secondary Outcome
Title VZV Antibodies as Measured by gpELISA
Hide Description VZV antibody titer measured by gpELISA after one or two doses of ZOSTAVAX/placebo
Time Frame Within 6 weeks following one or two doses of ZOSTAVAX
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects with both baseline gpELISA result and at least one post vaccination gpELISA result available
Arm/Group Title ZOSTAVAX Placebo
Hide Arm/Group Description:
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted.
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted
Overall Number of Participants Analyzed 280 96
Mean (Standard Deviation)
Unit of Measure: log gpELISA antibody titer
Baseline 5.68  (1.03) 5.52  (1.26)
6 weeks after 1st ZOSTAVAX/Placebo 6.28  (0.92) 5.57  (1.27)
6 weeks after 2nd ZOSTAVAX/Placebo 6.27  (0.87) 5.52  (1.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ZOSTAVAX, Placebo
Comments Null hypothesis: VZV antibody titer measured by gpELISA, after 1 or 2 doses of ZOSTAVAX/placebo is the same between ZOSTAVAX arm and the placebo arm
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments The p-value was adjusted for baseline gpELISA titer, measurement time (week 6 vs. week 12), CD4 stratum and age.
Method Linear mixed effect model
Comments Natural log transformed gpELISA titers after one or two doses of vaccine was modeled.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.57
Confidence Interval (2-Sided) 95%
0.45 to 0.69
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.06
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses
Hide Description VZV-specific cellular immune responses in peripheral blood mononuclear cells (PBMC) were tested by ELISpot assay in a subset of participants pooled across CD4 strata. GMFR is the geometric mean of the ratios of Week 6 or Week 12 post-vaccination antibody to the pre-vaccination antibody.
Time Frame Entry, Week 6, Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with ELISpot results available at entry and at the post-entry week (week 6 or week 12, respectively).
Arm/Group Title ZOSTAVAX Placebo
Hide Arm/Group Description:
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted.
Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted
Overall Number of Participants Analyzed 56 18
Geometric Mean (90% Confidence Interval)
Unit of Measure: fold rise
Week 6 GMFR Number Analyzed 56 participants 18 participants
1.8
(0.8 to 3.7)
0.4
(0.2 to 1.1)
Week 12 GMFR Number Analyzed 54 participants 16 participants
3.8
(1.8 to 8.0)
1.1
(0.3 to 3.4)
Time Frame From study entry to study exit, approximately 24 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title ZOSTAVAX Placebo
Hide Arm/Group Description Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. >=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted. Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-<349 cells/uL vs. >=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted
All-Cause Mortality
ZOSTAVAX Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   1/296 (0.34%)   0/99 (0.00%) 
Hide Serious Adverse Events
ZOSTAVAX Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   15/296 (5.07%)   7/99 (7.07%) 
Cardiac disorders     
Atrial fibrillation  1  0/296 (0.00%)  1/99 (1.01%) 
Atrial flutter  1  0/296 (0.00%)  1/99 (1.01%) 
Myocardial infarction  1  1/296 (0.34%)  0/99 (0.00%) 
Gastrointestinal disorders     
Pancreatitis acute  1  1/296 (0.34%)  0/99 (0.00%) 
Infections and infestations     
Bronchitis  1  0/296 (0.00%)  1/99 (1.01%) 
Bronchopulmonary aspergillosis  1  1/296 (0.34%)  0/99 (0.00%) 
Cellulitis  1  1/296 (0.34%)  0/99 (0.00%) 
Herpes zoster  1  1/296 (0.34%)  0/99 (0.00%) 
Osteomyelitis  1  0/296 (0.00%)  1/99 (1.01%) 
Pneumonia  1  1/296 (0.34%)  1/99 (1.01%) 
Urinary tract infection  1  1/296 (0.34%)  0/99 (0.00%) 
Injury, poisoning and procedural complications     
Gun shot wound  1  1/296 (0.34%)  0/99 (0.00%) 
Ligament sprain  1  1/296 (0.34%)  0/99 (0.00%) 
Musculoskeletal and connective tissue disorders     
Osteonecrosis  1  0/296 (0.00%)  1/99 (1.01%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
B-cell lymphoma  1  1/296 (0.34%)  0/99 (0.00%) 
Hepatic neoplasm malignant  1  0/296 (0.00%)  1/99 (1.01%) 
Lung carcinoma cell type unspecified recurrent  1  1/296 (0.34%)  0/99 (0.00%) 
Malignant melanoma  1  1/296 (0.34%)  0/99 (0.00%) 
Nervous system disorders     
Migraine  1  1/296 (0.34%)  0/99 (0.00%) 
Psychiatric disorders     
Bulimia nervosa  1  1/296 (0.34%)  0/99 (0.00%) 
Delirium  1  1/296 (0.34%)  0/99 (0.00%) 
Depression  1  1/296 (0.34%)  0/99 (0.00%) 
Renal and urinary disorders     
Renal failure acute  1  0/296 (0.00%)  1/99 (1.01%) 
1
Term from vocabulary, MedDRA 15.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ZOSTAVAX Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   98/296 (33.11%)   15/99 (15.15%) 
General disorders     
Injection site erythema  1  34/296 (11.49%)  0/99 (0.00%) 
Injection site pain  1  52/296 (17.57%)  4/99 (4.04%) 
Injection site swelling  1  16/296 (5.41%)  0/99 (0.00%) 
Pyrexia  1  13/296 (4.39%)  8/99 (8.08%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  17/296 (5.74%)  1/99 (1.01%) 
Nervous system disorders     
Headache  1  18/296 (6.08%)  4/99 (4.04%) 
1
Term from vocabulary, MedDRA 15.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone: (301) 628-3313
EMail: ACTGCT.Gov@s-3.com
Publications:
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00851786    
Other Study ID Numbers: A5247
10519 ( Registry Identifier: DAIDS ES Registry ID )
ACTG A5247
First Submitted: February 25, 2009
First Posted: February 26, 2009
Results First Submitted: September 7, 2012
Results First Posted: October 10, 2012
Last Update Posted: February 1, 2018