Shingles Prevention Study (SPS)

July 2, 2013 updated by: US Department of Veterans Affairs

CSP #403 - Trial of Varicella Zoster Vaccine for the Prevention of Herpes Zoster and Its Complications

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

38456

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • VA Medical Center, Birmingham
    • California
      • Palo Alto, California, United States, 94304-1290
        • VA Palo Alto Health Care System
      • San Diego, California, United States, 92161
        • VA San Diego Healthcare System, San Diego
    • Colorado
      • Denver, Colorado, United States, 80262
        • University of Colorado
    • Florida
      • Tampa, Florida, United States, 33612
        • James A. Haley Veterans Hospital, Tampa
    • Illinois
      • Hines, Illinois, United States, 60141-5000
        • Edward Hines, Jr. VA Hospital
    • Kentucky
      • Lexington, Kentucky, United States, 40502
        • VA Medical Center, Lexington
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • VA Maryland Health Care System, Baltimore
      • Bethesda, Maryland, United States, 20892
        • NIH-NIAID (Bethesda, MD)
    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • VA Medical Center, Jamaica Plain Campus
    • Michigan
      • Ann Arbor, Michigan, United States, 48113
        • VA Ann Arbor Healthcare System
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417
        • VA Medical Center, Minneapolis
    • Missouri
      • St Louis, Missouri, United States, 63106
        • VA Medical Center, St Louis
    • New Mexico
      • Albuquerque, New Mexico, United States, 87108-5153
        • New Mexico VA Health Care System, Albuquerque
    • New York
      • New York, New York, United States, 10010
        • New York Harbor HCS
      • Northport, New York, United States, 11768
        • VA Medical Center, Northport
      • Rochester, New York, United States, 14642
        • Rochester, NY (NIH)
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • VA Medical Center, Durham
    • Tennessee
      • Nashville, Tennessee, United States, 37212-2637
        • Vanderbilt University
    • Texas
      • Houston, Texas, United States, 77030
        • Baylor University
      • San Antonio, Texas, United States, 78229
        • University of Texas at San Antonio
    • Washington
      • Seattle, Washington, United States, 98108
        • VA Puget Sound Health Care System, Seattle

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1
varicella-zoster vaccine
Biological: Varicella-zoster vaccine
Immunization with 0.5 ml, live, attenuated (Oka/Merck) varicella-zoster vaccine.
Placebo Comparator: Arm 2
vaccine placebo
Biological: Placebo
Placebo vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

US Department of Veterans Affairs

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Merck Sharp & Dohme LLC

Investigators

  • Study Chair: Michael N. Oxman, VA San Diego Healthcare System, San Diego

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 1998

Primary Completion (Actual)

April 1, 2004

Study Completion (Actual)

February 1, 2011

Study Registration Dates

First Submitted

December 29, 2000

First Submitted That Met QC Criteria

December 30, 2000

First Posted (Estimate)

January 1, 2001

Study Record Updates

Last Update Posted (Estimate)

July 4, 2013

Last Update Submitted That Met QC Criteria

July 2, 2013

Last Verified

July 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 403

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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