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Shingles Prevention Study (SPS)

Primary Purpose

Herpes Zoster, Postherpetic Neuralgia

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Varicella-zoster vaccine
Placebo
Sponsored by
US Department of Veterans Affairs
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Herpes Zoster focused on measuring varicella-zoster vaccine

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Adults 60 years of age and older. History of Chickenpox. Have given written informed consent prior to enrollment. History of varicella or long-term (greater than or equal to 30 years) residence in the continental USA. Exclusion Criteria: No history of shingles, no current history of immune suppression (e.g. malignancy or neoplastic disease, corticosteroid therapy). No immunosuppression resulting from disease (e.g., malignancy; HIV infection), corticosteroids (except intermittent topical or inhaled corticosteroid [greater than 800 mcg/day beclomethasone dipropionate or equivalent]), or other immunosuppressive/cytotoxic therapy (cancer chemotherapy or organ transplantation). No active neoplastic disease (except local skin cancer or other malignancies [e.g., prostate cancer] that are stable in the absence of immunosuppressive/cytotoxic therapy). No prior Herpes Zoster. No prior receipt of varicella vaccine. No allergic sensitivity to neomycin. No history of anaphylactoid reaction to gelatin. No significant underlying illness that would be expected to prevent completion of the study (e.g., life-threatening disease likely to limit survival to less than 5 years). Not ambulatory (must not be bed-ridden or homebound). No receipt of immune globulin or any other blood product within 3 months before or planned during the 3-5 year study period. No receipt of any other immunizations within one month before study vaccination (2 weeks in the case of inactivated influenza vaccines or other non-replicating immunization products [e.g., dT, pneumococcal vaccine, hepatitis A vaccine, hepatitis B vaccine]), or scheduled within 6 weeks after study vaccination. Not currently receiving antiviral therapy. No other condition (e.g., extensive psoriasis, chronic pain syndrome, cognitive impairment, severe hearing loss) that, in the opinion of the investigator, might interfere with the evaluations required by the study. No intercurrent illness (e.g., urinary tract infection, influenza) that might interfere with the interpretation of the study. No females who are pre-menopausal. No subjects unlikely to adhere to protocol follow-up. No subjects involved in a conflicting (vaccine or investigational drug) clinical trial.

Sites / Locations

  • VA Medical Center, Birmingham
  • VA Palo Alto Health Care System
  • VA San Diego Healthcare System, San Diego
  • University of Colorado
  • James A. Haley Veterans Hospital, Tampa
  • Edward Hines, Jr. VA Hospital
  • VA Medical Center, Lexington
  • VA Maryland Health Care System, Baltimore
  • NIH-NIAID (Bethesda, MD)
  • VA Medical Center, Jamaica Plain Campus
  • VA Ann Arbor Healthcare System
  • VA Medical Center, Minneapolis
  • VA Medical Center, St Louis
  • New Mexico VA Health Care System, Albuquerque
  • New York Harbor HCS
  • VA Medical Center, Northport
  • Rochester, NY (NIH)
  • VA Medical Center, Durham
  • Vanderbilt University
  • Baylor University
  • University of Texas at San Antonio
  • VA Puget Sound Health Care System, Seattle

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm 1

Arm 2

Arm Description

varicella-zoster vaccine

vaccine placebo

Outcomes

Primary Outcome Measures

Reduce burden of illness due to herpes zoster (HZ)

Secondary Outcome Measures

Full Information

First Posted
December 29, 2000
Last Updated
July 2, 2013
Sponsor
US Department of Veterans Affairs
Collaborators
Merck Sharp & Dohme LLC, National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00007501
Brief Title
Shingles Prevention Study
Acronym
SPS
Official Title
CSP #403 - Trial of Varicella Zoster Vaccine for the Prevention of Herpes Zoster and Its Complications
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
November 1998 (undefined)
Primary Completion Date
April 2004 (Actual)
Study Completion Date
February 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
US Department of Veterans Affairs
Collaborators
Merck Sharp & Dohme LLC, National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The incidence and severity of HZ (or shingles), as well as the frequency and severity of its complications, increases markedly with increasing age. More than half of all cases occur in persons over the age of 60. Even without complications, HZ can interfere with an elderly patient's ability to perform essential activities of daily living, resulting in a loss of independence that is emotionally devastating and frequently irreversible. The most common complication of HZ in elderly persons is postherpetic neuralgia (PHN), which frequently results in disordered sleep, chronic fatigue, anxiety and severe depression. Antiviral therapy has a modest impact on the acute phase of HZ. However, it does not appear to prevent the development of PHN. This study is a 5.5 year randomized, double-blind, placebo-controlled, efficacy trial to determine whether vaccination with live-attenuated Oka/Merck varicella-zoster decreases the incidence and/or severity of herpes zoster (HZ) and its complications in adults 60 years of age and older.
Detailed Description
Primary Hypothesis: Immunization with live, attenuated (Oka/Merck) varicella-zoster vaccine will significantly reduce the burden of illness associated with herpes zoster (HZ). Secondary Hypotheses: Immunization with live, attenuated (Oka/Merck) varicella-zoster vaccine will reduce the incidence of postherpetic neuralgia (PHN). Primary Outcomes: The primary outcome is the burden of illness due to HZ defined by the area under the worst pain versus time curve measured during the 6 month period following HZ rash onset in subjects who develop of HZ. The burden of illness outcome is sensitive to the incidence, severity, and duration of HZ-associated pain. The secondary outcome is the incidence of PHN, where PHN is defined as HZ-associated pain rated as greater than or equal to 3 (on a 0 to 10 scale) persisting or appearing more than 30 days after the onset of the HZ rash. Interventions: Immunization with 0.5 ml, live, attenuated (Oka/Merck) varicella-zoster vaccine versus vaccine placebo. Study Abstract: The incidence and severity of HZ (or shingles), as well as the frequency and severity of its complications, increases markedly with increasing age. More than half of all cases occur in persons over the age of 60. Even without complications, HZ can interfere with an elderly patient's ability to perform essential activities of daily living, resulting in a loss of independence that is emotionally devastating and frequently irreversible. The most common complication of HZ in elderly persons is postherpetic neuralgia (PHN), which frequently results in disordered sleep, chronic fatigue, anxiety and severe depression. Antiviral therapy has a modest impact on the acute phase of HZ. However, it does not appear to prevent the development of PHN. This study was a 5.5 year randomized, double-blind, placebo-controlled, efficacy trial to determine whether vaccination with live-attenuated Oka/Merck varicella-zoster decreases the incidence and/or severity of herpes zoster (HZ) and its complications in adults 60 years of age and older; 37,200 subjects over 60 years of age will be randomized at 22 sites to receive either vaccine or placebo. At least one third of the subjects were to be 70 years of age or older. Subjects were followed actively for HZ until at least 750 cases of HZ and at least 62 cases of PHN occurred. Subjects who developed HZ were evaluated for severity and duration of associated pain, extent and duration of rash, and for changes in quality of life associated with the disease for six months after the onset of HZ rash. All adverse events (serious and non-serious) occurring within 42 days after vaccination were recorded. Thereafter, serious adverse events were recorded if assessed as possibly related to the vaccination. An adverse event substudy was to enroll 6000 subjects for recording all adverse events on a vaccination Report Card. Substudy participants were also followed for any hospital admissions during the study. The study was initiated in December 1998. Patient recruitment began in November 1998 at one site, at 20 sites between February 1999 and July 1999, and at one site that was added in January 2000. On September 26, 2001, enrollment in the study was completed with 38,456 randomized subjects. The time point for the study definition of PHN was changed by protocol amendment from 30 days to 90 days after HZ rash onset. A formal sample size re-estimation was performed in June 2003. The Executive Committee and DSMB reviewed these results and approved the increase in event size from 400 to 750 evaluable cases of HZ for the primary endpoint. It was projected that the number of evaluable cases of HZ for the primary endpoint and the number of evaluable cases of PHN for the secondary (co-primary) endpoint would be observed by the end of September 2003. Therefore, the Study initiated its closeout plan beginning in October 2004. Follow-up of the last suspected case of HZ was completed in March 2004 and closeout interviews for the more than 37,000 surviving subjects were completed as of April 28, 2004. The results of the main efficacy and safety analyses were unblinded on December 1, 2004, and presented to the DSMB, Executive Committee, and representatives for Merck & Co., Inc. Letters were sent to the study subjects informing them of the overall results and the treatment they received. The main manuscript was published in the New England Journal of Medicine (June 2005; 352:2271-84). The vaccine was approved for the prevention of shingles by the FDA on May 25, 2006. The main efficacy study is closed. Additionally, three substudies have been conducted: A substudy (CSP#403B) was initiated in November 2005 to offer investigational zoster vaccine to the placebo recipients of CSP#403. Vaccination was completed in March 2007 with 13,681 (75%) of the placebo recipients vaccinated. This substudy is closed. The safety results from the substudy were published in the Journal of Infectious Diseases (J Infect Dis. 2013 May 31 epub). A short-term persistence substudy (CSP#403A) was initiated in September 2004 to extend the follow-up vaccine and placebo recipients to assess the longer term effectiveness of the vaccine. This substudy bridged the period between the end of the efficacy study and the vaccination of placebo recipients and the initiation of a long-term persistence study. The study enrolled 14,270 subjects and completed follow-up in May 2007. This substudy is closed and is in ongoing analysis. The primary results for this study were published in Clinical Infectious Diseases (Clin Infect Dis. 2012 Nov 15;55(10):1320-1328) CSP#403C, the Long-Term Persistence Substudy, was initiated in March 2006 and enrolled 6867 vaccine recipients from the main efficacy study. Enrollment was restricted to vaccine recipients from the main efficacy study with no history of herpes zoster. This study was initiated to complete an additional five-years of follow-up post-vaccination. The objective of this study was to estimate the longer-term durability of zoster vaccine efficacy by following a cohort of vaccine recipients from the primary efficacy study for three study outcomes: 1) the incidence of herpes zoster, 2) the incidence of postherpetic neuralgia (PHN), and 3) the burden of illness (BOI) due to herpes zoster. The study completed surveillance for new cases of herpes zoster as of December 2010 and completed the follow-up of the last case of herpes zoster in February 2011. All study sites have been closed out. This substudy has been completed and is in the final analysis phase.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Herpes Zoster, Postherpetic Neuralgia
Keywords
varicella-zoster vaccine

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
38456 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Experimental
Arm Description
varicella-zoster vaccine
Arm Title
Arm 2
Arm Type
Placebo Comparator
Arm Description
vaccine placebo
Intervention Type
Biological
Intervention Name(s)
Varicella-zoster vaccine
Intervention Description
Immunization with 0.5 ml, live, attenuated (Oka/Merck) varicella-zoster vaccine.
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Placebo vaccine
Primary Outcome Measure Information:
Title
Reduce burden of illness due to herpes zoster (HZ)
Time Frame
Incidence of postherpetic neuralgia (PHN), where PHN is defined as HZ-associated pain greater than or equal to 3 persisting or appearing more than 30 days after the onset of the HZ rash

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Adults 60 years of age and older. History of Chickenpox. Have given written informed consent prior to enrollment. History of varicella or long-term (greater than or equal to 30 years) residence in the continental USA. Exclusion Criteria: No history of shingles, no current history of immune suppression (e.g. malignancy or neoplastic disease, corticosteroid therapy). No immunosuppression resulting from disease (e.g., malignancy; HIV infection), corticosteroids (except intermittent topical or inhaled corticosteroid [greater than 800 mcg/day beclomethasone dipropionate or equivalent]), or other immunosuppressive/cytotoxic therapy (cancer chemotherapy or organ transplantation). No active neoplastic disease (except local skin cancer or other malignancies [e.g., prostate cancer] that are stable in the absence of immunosuppressive/cytotoxic therapy). No prior Herpes Zoster. No prior receipt of varicella vaccine. No allergic sensitivity to neomycin. No history of anaphylactoid reaction to gelatin. No significant underlying illness that would be expected to prevent completion of the study (e.g., life-threatening disease likely to limit survival to less than 5 years). Not ambulatory (must not be bed-ridden or homebound). No receipt of immune globulin or any other blood product within 3 months before or planned during the 3-5 year study period. No receipt of any other immunizations within one month before study vaccination (2 weeks in the case of inactivated influenza vaccines or other non-replicating immunization products [e.g., dT, pneumococcal vaccine, hepatitis A vaccine, hepatitis B vaccine]), or scheduled within 6 weeks after study vaccination. Not currently receiving antiviral therapy. No other condition (e.g., extensive psoriasis, chronic pain syndrome, cognitive impairment, severe hearing loss) that, in the opinion of the investigator, might interfere with the evaluations required by the study. No intercurrent illness (e.g., urinary tract infection, influenza) that might interfere with the interpretation of the study. No females who are pre-menopausal. No subjects unlikely to adhere to protocol follow-up. No subjects involved in a conflicting (vaccine or investigational drug) clinical trial.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael N. Oxman
Organizational Affiliation
VA San Diego Healthcare System, San Diego
Official's Role
Study Chair
Facility Information:
Facility Name
VA Medical Center, Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
VA Palo Alto Health Care System
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304-1290
Country
United States
Facility Name
VA San Diego Healthcare System, San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92161
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
James A. Haley Veterans Hospital, Tampa
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Edward Hines, Jr. VA Hospital
City
Hines
State/Province
Illinois
ZIP/Postal Code
60141-5000
Country
United States
Facility Name
VA Medical Center, Lexington
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40502
Country
United States
Facility Name
VA Maryland Health Care System, Baltimore
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
NIH-NIAID (Bethesda, MD)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
VA Medical Center, Jamaica Plain Campus
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02130
Country
United States
Facility Name
VA Ann Arbor Healthcare System
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48113
Country
United States
Facility Name
VA Medical Center, Minneapolis
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55417
Country
United States
Facility Name
VA Medical Center, St Louis
City
St Louis
State/Province
Missouri
ZIP/Postal Code
63106
Country
United States
Facility Name
New Mexico VA Health Care System, Albuquerque
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87108-5153
Country
United States
Facility Name
New York Harbor HCS
City
New York
State/Province
New York
ZIP/Postal Code
10010
Country
United States
Facility Name
VA Medical Center, Northport
City
Northport
State/Province
New York
ZIP/Postal Code
11768
Country
United States
Facility Name
Rochester, NY (NIH)
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
VA Medical Center, Durham
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212-2637
Country
United States
Facility Name
Baylor University
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
VA Puget Sound Health Care System, Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
15930418
Citation
Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84. doi: 10.1056/NEJMoa051016.
Results Reference
result
PubMed Identifier
20439572
Citation
Simberkoff MS, Arbeit RD, Johnson GR, Oxman MN, Boardman KD, Williams HM, Levin MJ, Schmader KE, Gelb LD, Keay S, Neuzil K, Greenberg RN, Griffin MR, Davis LE, Morrison VA, Annunziato PW; Shingles Prevention Study Group. Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial. Ann Intern Med. 2010 May 4;152(9):545-54. doi: 10.7326/0003-4819-152-9-201005040-00004.
Results Reference
result
PubMed Identifier
18419349
Citation
Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, Caulfield MJ, Irwin MR, Smith JG, Clair J, Chan IS, Williams H, Harbecke R, Marchese R, Straus SE, Gershon A, Weinberg A; Veterans Affairs Cooperative Studies Program Shingles Prevention Study Investigators. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis. 2008 Mar 15;197(6):825-35. doi: 10.1086/528696.
Results Reference
result
PubMed Identifier
19475609
Citation
Harbecke R, Oxman MN, Arnold BA, Ip C, Johnson GR, Levin MJ, Gelb LD, Schmader KE, Straus SE, Wang H, Wright PF, Pachucki CT, Gershon AA, Arbeit RD, Davis LE, Simberkoff MS, Weinberg A, Williams HM, Cheney C, Petrukhin L, Abraham KG, Shaw A, Manoff S, Antonello JM, Green T, Wang Y, Tan C, Keller PM; Shingles Prevention Study Group. A real-time PCR assay to identify and discriminate among wild-type and vaccine strains of varicella-zoster virus and herpes simplex virus in clinical specimens, and comparison with the clinical diagnoses. J Med Virol. 2009 Jul;81(7):1310-22. doi: 10.1002/jmv.21506.
Results Reference
result
PubMed Identifier
19712037
Citation
Weinberg A, Zhang JH, Oxman MN, Johnson GR, Hayward AR, Caulfield MJ, Irwin MR, Clair J, Smith JG, Stanley H, Marchese RD, Harbecke R, Williams HM, Chan IS, Arbeit RD, Gershon AA, Schodel F, Morrison VA, Kauffman CA, Straus SE, Schmader KE, Davis LE, Levin MJ; US Department of Veterans Affairs (VA) Cooperative Studies Program Shingles Prevention Study Investigators. Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine. J Infect Dis. 2009 Oct 1;200(7):1068-77. doi: 10.1086/605611.
Results Reference
result
PubMed Identifier
22828595
Citation
Schmader KE, Oxman MN, Levin MJ, Johnson G, Zhang JH, Betts R, Morrison VA, Gelb L, Guatelli JC, Harbecke R, Pachucki C, Keay S, Menzies B, Griffin MR, Kauffman C, Marques A, Toney J, Keller PM, Li X, Chan IS, Annunziato P; Shingles Prevention Study Group. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012 Nov 15;55(10):1320-8. doi: 10.1093/cid/cis638. Epub 2012 Jul 24.
Results Reference
result
PubMed Identifier
20863322
Citation
Schmader KE, Johnson GR, Saddier P, Ciarleglio M, Wang WW, Zhang JH, Chan IS, Yeh SS, Levin MJ, Harbecke RM, Oxman MN; Shingles Prevention Study Group. Effect of a zoster vaccine on herpes zoster-related interference with functional status and health-related quality-of-life measures in older adults. J Am Geriatr Soc. 2010 Sep;58(9):1634-41. doi: 10.1111/j.1532-5415.2010.03021.x.
Results Reference
result
PubMed Identifier
23633406
Citation
Morrison VA, Oxman MN, Levin MJ, Schmader KE, Guatelli JC, Betts RF, Gelb LD, Pachucki CT, Keay SK, Menzies B, Griffin MR, Kauffman CA, Marques AR, Toney JF, Simberkoff MS, Serrao R, Arbeit RD, Gnann JW, Greenberg RN, Holodniy M, Keitel WA, Yeh SS, Davis LE, Crawford GE, Neuzil KM, Johnson GR, Zhang JH, Harbecke R, Chan IS, Keller PM, Williams HM, Boardman KD, Silber JL, Annunziato PW; Shingles Prevention Study Group. Safety of zoster vaccine in elderly adults following documented herpes zoster. J Infect Dis. 2013 Aug 15;208(4):559-63. doi: 10.1093/infdis/jit182. Epub 2013 Apr 30.
Results Reference
result
Links:
URL
http://www.research.va.gov/programs/csrd/csp.cfm
Description
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