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The Effect of Alendronate on the Immune Response to Hepatitis B Vaccine in Healthy Adults

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ClinicalTrials.gov Identifier: NCT02057263
Recruitment Status : Completed
First Posted : February 7, 2014
Last Update Posted : October 21, 2016
Sponsor:
Information provided by (Responsible Party):
Elizabeth L. Hohmann, MD, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE February 4, 2014
First Posted Date  ICMJE February 7, 2014
Last Update Posted Date October 21, 2016
Study Start Date  ICMJE April 2014
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2014)
Safety/Adverse events [ Time Frame: 5 months after final alendronate administration/second vaccination ]
Safety is assessed by clinical symptoms and exam at final in-person visit. Standardized CTAE will be recorded and graded (mild/moderate/severe) with a special focus on vaccine related adverse events: Temperature, local injection site reactions, fatigue and malaise, AND adverse events related to alendronate which are primarily gastrointestinal: nausea, vomiting, esophagitis, ulceration. Rare, unlikely events such as atypical fractures and jaw osteonecrosis are extremely unlikely with this duration of dosing (4 weekly doses) but will also be specifically sought.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2014)
Efficacy [ Time Frame: 8 weeks to 5 months after final alendronate dose ]
Efficacy is assessed by quantitative Anti Hepatitis B Surface IgG (immunoglobulin G) antibody titers in international units (iU) per ml. All subjects must have levels of ZERO in order to participate. A value of 10 iU/ml is considered protective. Titers directed against hepatitis B surface antigen will be measured by commercially available testing Efficacy will also be assessed as a categorical value: Yes/No for protective level of antibody achieved at either 8 weeks or 6 months (5 months after second vaccination). A protective level of hepatitis B surface antibody is defined as 10 iU/ml; levels of 10-100 are considered protective but "poorly responsive." We will compare mean titers between groups (placebo vs. alendronate). We believe a mean increase of 20% is likely clinically significant/important.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Alendronate on the Immune Response to Hepatitis B Vaccine in Healthy Adults
Official Title  ICMJE The Effect of Alendronate on the Immune Response to Hepatitis B Vaccine in Healthy Adults - a Randomized Placebo-controlled Pilot Study
Brief Summary

Vaccines are one of our most effective public health tools but many who need them don't respond well and are not protected. Adjuvants boost immune responses and are commonly included in vaccine preparations. Bisphosphonates are the most commonly prescribed treatment for osteoporosis and may represent a new class of adjuvant. Bisphosphonates are well tolerated with chronic administration and have very few adverse effects. Research suggests that these medications can stimulate the immune system.

Bisphosphonates are of special interest in populations with impaired immunity and an inability to amount protective antibody responses following immunizations. We propose a pilot study to evaluate the clinical relevance of this finding in humans. We will study the effect of bisphosphonates on quantitative humoral immune response to hepatitis B vaccine in healthy older volunteers who have not previously received this vaccine.

Detailed Description

Background: Immunization is one of the most beneficial and cost-effective disease prevention measures available, but is not always efficacious, especially in older and immunosuppressed populations. This commonly encountered failure to produce protective antibodies following immunization leaves large parts of the population vulnerable to serious morbidity and mortality resulting from potentially preventable communicable diseases. Bisphosphonates, a commonly prescribed treatment for osteoporosis that is well tolerated with few adverse effects, has recently been shown to enhance B cell expansion and antibody production after vaccination in mice, and may represent a new vaccine adjuvant.

Aims: The purpose of this project is to evaluate the effect of bisphosphonates on the immune response to vaccination in adults using two complementary research methodologies:

  1. Evaluating the effect of bisphosphonates on quantitative humoral immune response to hepatitis B vaccine in healthy older volunteers through a randomized clinical trial.
  2. Evaluating the effect of bisphosphonate treatment on protection against influenza and influenza-like illness after seasonal Influenza immunization in the adult population through a population-level retrospective analysis.

Methods: The first part of the study consists of a randomized, placebo-controlled pilot study in which 20 healthy adults 40-70 years of age who are seronegative for Hepatitis B, will be randomized to receive either two doses of intramuscular hepatitis B vaccine with alendronate or hepatitis B vaccine with placebo. The primary outcome evaluated will be quantitative anti-HB surface IgG antibody titers in the study group compared to the placebo group at week 8 and at 6 months. The second part of the study is a retrospective population based case-control study utilizing extensive available data repositories. Rates of influenza, influenza-like illness and lower respiratory tract infections per 1000 subjects will be ascertained and compared between study and control populations for each year, while adjusting for potential confounders.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Hepatitis B
Intervention  ICMJE
  • Drug: Alendronate
    Participants will receive 4 doses of alendronate during the course of the study.
    Other Names:
    • Fosamax
    • Bisphosphonate
  • Drug: Hepatitis B Vaccine
    Participants will receive 3 Hepatitis B vaccinations, according to the schedule outlined by the CDC.
    Other Name: Recombivax
  • Drug: Placebo
    Participants will receive 4 doses of placebo during the course of the study.
    Other Name: Sugar Pill
Study Arms  ICMJE
  • Experimental: Alendronate and Hepatitis B Vaccine
    Participants in the experimental arm will receive 4 alendronate doses during their Hepatitis B vaccination course.
    Interventions:
    • Drug: Alendronate
    • Drug: Hepatitis B Vaccine
  • Experimental: Sugar Pill and Hepatitis B Vaccine
    Participants in the experimental arm will receive placebo doses during their Hepatitis B vaccination course.
    Interventions:
    • Drug: Hepatitis B Vaccine
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 15, 2016)
28
Original Estimated Enrollment  ICMJE
 (submitted: February 5, 2014)
20
Actual Study Completion Date  ICMJE February 2016
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subject willing to undergo hepatitis B vaccination AND be randomized to receive 4 doses of alendronate or placebo
  • Age 40-70
  • Able to consent for self - ascertained by physician assessment at time of history and exam.
  • Chronic stable medical conditions, if well controlled on current therapies are allowed. For example individuals with well-controlled angina, hypertension, diabetes on oral agents, treated or past depression or anxiety, COPD, asthma, metabolic syndrome, NASH, mild chronic renal insufficiency, past history of malignancy, with no therapy for at least 5 years may be included.
  • Willing to use contraception, if a woman of child-bearing potential (WOCBP)

Exclusion Criteria:

  • Pregnant, breastfeeding or planning a pregnancy
  • Prior Hepatitis B infection OR vaccination
  • Autoimmune disorders of any kind (e.g. multiple sclerosis, rheumatoid arthritis, lupus, Psoriasis etc.)
  • HIV or Hepatitis C seropositive
  • Any known immunodeficiency (decompensated cirrhosis, HIV/AIDS, prior bone marrow transplant, or other known immunodeficiency)
  • Patients on any immunosuppressive agents including systemic corticosteroids, calcineurin inhibitors, mTOR inhibitors, lymphocyte depleting biologic agents, anti-TNF agents, and others; chemotherapeutic anti-neoplastic agents within 5 years. Stable doses of inhaled corticosteroids for asthma/COPD are allowed.
  • Gastroesophageal reflux disease (GERD), peptic ulcer disease, chronic proton pump inhibitors, chronic antacid use
  • Chronic non-steroidal anti-inflammatory use; daily ASA for cardiac prophylaxis is allowed.
  • Esophageal disorders of any kind
  • Recent major dental work in the preceding 6 months, excluding dental cleaning and simple cavity filling
  • History of jaw trauma
  • Current or prior bisphosphonate use
  • Prior history of severe reactions to vaccines
  • Yeast or bisphosphonate allergy
  • History of hypocalcemia
  • Inability to stand or sit upright for at least 30 minutes.
  • Any malabsorptive disorder including celiac disease, CF, Inflammatory bowel disease, recurrent C. difficile colitis, other colitis, prior gastrectomy, bariatric surgery or chronic diarrhea.
  • Diabetes requiring insulin
  • Body mass index > 31
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02057263
Other Study ID Numbers  ICMJE 2014-P-000040
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Available upon request
Responsible Party Elizabeth L. Hohmann, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Massachusetts General Hospital
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP