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

October 20, 2016 updated by: Elizabeth L. Hohmann, MD, Massachusetts General Hospital

The Effect of Alendronate on the Immune Response to Hepatitis B Vaccine in Healthy Adults - a Randomized Placebo-controlled Pilot Study

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

28

Phase

  • Phase 1

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
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

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

40 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Alendronate and Hepatitis B Vaccine
Participants in the experimental arm will receive 4 alendronate doses during their Hepatitis B vaccination course.
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 Names:
  • Recombivax
Experimental: Sugar Pill and Hepatitis B Vaccine
Participants in the experimental arm will receive placebo doses during their Hepatitis B vaccination course.
Drug: Hepatitis B Vaccine
Participants will receive 3 Hepatitis B vaccinations, according to the schedule outlined by the CDC.
Other Names:
  • Recombivax
Drug: Placebo
Participants will receive 4 doses of placebo during the course of the study.
Other Names:
  • Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
5 months after final alendronate administration/second vaccination

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
8 weeks to 5 months after final alendronate dose

Collaborators and Investigators

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

Sponsor

Massachusetts General Hospital

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

April 1, 2014

Primary Completion (Actual)

February 1, 2016

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

February 4, 2014

First Submitted That Met QC Criteria

February 5, 2014

First Posted (Estimate)

February 7, 2014

Study Record Updates

Last Update Posted (Estimate)

October 21, 2016

Last Update Submitted That Met QC Criteria

October 20, 2016

Last Verified

October 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2014-P-000040

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Available upon request

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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