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Effect of Raxibacumab on Immunogenicity of Anthrax Vaccine Adsorbed

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ClinicalTrials.gov Identifier: NCT02339155
Recruitment Status : Completed
First Posted : January 15, 2015
Results First Posted : January 9, 2018
Last Update Posted : February 8, 2019
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Emergent BioSolutions

Brief Summary:
This study, as a post-marketing commitment to the Food and Drug Administration, is designed to detect the effect of raxibacumab on anthrax vaccine adsorbed (AVA) immunogenicity in a healthy volunteer population. This is a randomized, open-label, parallel group, two arm study to compare the immunogenicity of AVA at 4 weeks after the first AVA dose, when AVA is administered alone or concomitantly with raxibacumab. The study is planned to enroll approximately 30 to 534 subjects in up to 3 cohorts. The total duration of the study will be approximately 26 weeks. The dates reflect cohort 1.

Condition or disease Intervention/treatment Phase
Infections, Bacterial Biological: AVA Biological: Raxibacumab Drug: Diphenhydramine Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 573 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label Study to Evaluate the Immunogenicity of Anthrax Vaccine Adsorbed Alone or Concomitantly With Raxibacumab (GSK3068483)
Actual Study Start Date : February 24, 2015
Actual Primary Completion Date : January 3, 2017
Actual Study Completion Date : June 6, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anthrax

Arm Intervention/treatment
Experimental: Anthrax Vaccine Adsorbed
Subjects will be administered subcutaneous (SC) 0.5 mL AVA doses on Days 1, 15, and 29 (0, 2, and 4 weeks).
Biological: AVA
Sterile, milky-white suspension with dosage level of 0.5 mL for SC administration

Experimental: AVA + Raxibacumab
Subjects will be administered SC 0.5 mL AVA doses on Days 1, 15, and 29 (0, 2, and 4 weeks), with the first AVA dose administered immediately after completion of a single intravenous (IV) infusion 40 milligram (mg)/kilogram (kg) raxibacumab dose. Subjects will be premedicated with 25-50 mg of diphenhydramine up to 1 hour prior to the raxibacumab infusion to reduce the risk of infusion reactions.
Biological: AVA
Sterile, milky-white suspension with dosage level of 0.5 mL for SC administration

Biological: Raxibacumab
Sterile, liquid formulation with unit dose strength of 40 mg/ kg for IV administration

Drug: Diphenhydramine
Depending upon the labelling of the specific product chosen, 25 - 50 mg will be administered orally or IV




Primary Outcome Measures :
  1. Ratio of Geometric Mean Concentrations (GMC) of Anti-protective Antigen (PA) Antibody (Ab) at 4 Weeks (Day 29) After the First AVA Dose (Prior to the Third AVA Dose), Between the AVA Alone and the AVA With Raxibacumab Treatment Groups [ Time Frame: Day 29 ]
    Ratio of the GMC of anti-PA Ab between AVA alone and the AVA with raxibacumab treatment group was assessed to compare the immunogenicity of AVA at 4 weeks after the first AVA dose (prior to the third AVA dose). Serum AVA derived anti-PA Ab concentrations were determined using an approved immunoassay. Per Protocol (PP) population was used in analysis which comprised of all analyzable participants (those who received at least the Week 0 [Day 1] and Week 2 [Day 15] AVA doses within the protocol specified visit window; receive the raxibacumab dose, if randomized to Treatment Group 2 and; completed the primary study endpoint assessment [anti-PA Ab concentration at Week 4]).


Secondary Outcome Measures :
  1. Ratio of GMC of Anti-PA Ab at Weeks 8 and 26 (Days 57 and 183) After the First AVA Dose, Between the AVA Alone and AVA With Raxibacumab Treatment Groups [ Time Frame: Days 57 and 183 ]
    Anti-PA antibody concentrations were collected at Weeks 8 and 26 after the first AVA dose. Serum AVA derived anti-PA Ab concentrations were determined using an approved immunoassay. The GMCs with corresponding 95% CI were calculated for each treatment group at each timepoint. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  2. Percentage of Participants Who Seroconvert, at Weeks 4, 8, and 26 (Days 29, 57 and 183) After the First AVA Dose, Between the AVA Alone and the AVA With Raxibacumab Treatment Groups [ Time Frame: Days 29, 57 and 183 ]
    The percentage of participants, with corresponding 95% CI based on Wilson's method, who seroconvert (seroconversion is defined as a >4-fold increase in toxin neutralizing activity [TNA] titer) was summarized, at Weeks 4, 8 and 26 after the first AVA dose for both arms separately. Serum TNA titer was determined using a cell-based assay.

  3. Number of Participants With Any Serious Adverse Event (SAE) and Any Non-serious Adverse Event (AE) [ Time Frame: Up to Day 183 ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE resulting in death, is life threatening (ie, an immediate threat to life), inpatient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or any other situation which is medically important and may jeopardize the participant or may require medical or surgical intervention or events associated with liver injury and impaired liver function is categorized as SAE. The Safety population was comprised of all randomized participants who received at least one dose of AVA.

  4. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points [ Time Frame: Baseline and up to Day 183 ]
    SBP and DBP were measured in semi-supine position after 5 minutes rest. Values at Day -1 were considered as Baseline values. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  5. Change From Baseline in Heart Rate at Indicated Time Points [ Time Frame: Baseline and up to Day 183 ]
    Heart rate was measured in semi-supine position after 5 minutes rest. Values at Day -1 were considered as Baseline values. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  6. Change From Baseline in Respiratory Rate at Indicated Time Points [ Time Frame: Baseline and up to Day 183 ]
    Respiratory rate was measured in semi-supine position after 5 minutes rest. Values at Day -1 were considered as Baseline values. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  7. Change From Baseline in Temperature at Indicated Time Points [ Time Frame: Baseline and up to Day 183 ]
    Temperature was measured in semi-supine position after 5 minutes rest. Values at Day -1 were considered as Baseline values. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  8. Number of Participants With Hematology Parameters Outside Normal Range [ Time Frame: Up to Day 57 ]
    Hematology parameters included assessment of platelet count, erythrocytes, leukocytes , reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin and hematocrit. Here high is equal to above the upper limit of the normal range, low is equal to below the lower limit of the normal range. Participants are counted in the category that their value changes to (low, normal or high), unless there is no change in their category. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  9. Number of Participants With Clinical Chemistry Parameters Outside Normal Range [ Time Frame: Up to Day 57 ]
    Blood samples were collected to evaluate clinical chemistry parameters, which included assessment of urea nitrogen (UN), creatinine, chloride, glucose, magnesium, total protein, potassium, chloride, total Carbon dioxide (CO2), sodium, calcium (cal), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total and direct bilirubin ( D.bili), albumin and calculated creatinine clearance. Here high is equal to above the upper limit of the normal range, low is equal to below the lower limit of the normal range. Participants are counted in the category that their value changes to (low, normal or high), unless there is no change in their category. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

  10. Number of Participants With Urinalysis Parameters [ Time Frame: Day 57 ]
    Urinalysis parameters included amorphous crystals, bacteria, bilirubin, calcium oxalate (Ca Ox) crystals, choriogonadotropin beta, clarity, color, crystals of Ca Ox, erythrocytes, glucose, hemoglobin, ketone bodies, ketones, leukocyte cell clumps, leukocyte esterase, leukocytes, mucous threads, nitrite, occult blood, protein, specific gravity, squamous epithelial cells, turbidity, urobilinogen, and transitional epithelial cells. In urinalysis test plus sign (+) indicates increase in the level of the parameters.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination and laboratory tests
  • Men and women between 18 to 65 years of age
  • Willing and able to adhere to the procedures stated in the protocol.
  • Female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as:

Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.

Reproductive potential and agrees to follow one of the options listed in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP), from 30 days prior to the first dose of study medication and until after the last dose of study medication and completion of the follow-up visit at Day 183 (at least five terminal half-lives for raxibacumab).

Exclusion Criteria:

  • Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or non-investigational study vaccine/product (pharmaceutical product or device).
  • Be a member of the military, a laboratory worker, first responder, health care worker, or otherwise be at higher risk of exposure to anthrax.
  • History of regular alcohol consumption within 1 month of the study defined as:

An average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

  • Female planning to become pregnant or planning to discontinue contraceptive precautions before the Day 183 study visit.
  • Pregnant (confirmed by a serum or urine hCG test) or lactating female.
  • Alanine aminotransferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., malignancy, human immunodeficiency virus [HIV] infection) or immunosuppressive/cytotoxic therapy (e.g., medications used during cancer chemotherapy, organ transplantation or to treat autoimmune disorders).
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test results at screening or within 3 months prior to first dose of study treatment.
  • A positive pre-study drug/alcohol screen.
  • A positive test for HIV antibody.
  • History of sensitivity to any of the study medications, or components thereof (especially latex and aluminium) or a history of other known drug allergies that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
  • Have previously been vaccinated against PA.
  • Have an anti-PA Ab concentration >2 times the lower limit of quantitation at screening.
  • Administration of immunoglobulins not included in this trial and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period.
  • Administration of long-acting immune-modifying drugs (e.g. infliximab) within six months prior to the first vaccine dose or expected administration at any time during the study period.
  • Chronic administration (defined as more than 14 consecutive days) of systemic immunosupressants or other immune-modifying drugs within six months prior to the first vaccine dose. Inhaled, topical and intra-articular corticosteroids are allowed.
  • Administration or planned administration of a vaccine not foreseen by the study protocol within the period starting 35 days before the first dose of study vaccine(s) and ending 30 days after the last dose of study vaccine. This includes any type of vaccine such as (but not limited to) live, inactivated, and subunit vaccines. Influenza vaccines are permitted after Week 8.
  • Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study.
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Any condition which, in the opinion of the investigator, prevents the subject from participating in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02339155


Locations
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United States, Florida
GSK Investigational Site
Edgewater, Florida, United States, 32132
United States, Kansas
GSK Investigational Site
Overland Park, Kansas, United States, 66211
United States, Tennessee
GSK Investigational Site
Knoxville, Tennessee, United States, 37920
Sponsors and Collaborators
Emergent BioSolutions
GlaxoSmithKline
Investigators
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Study Director: Paul-Andre deLame, MD Emergent BioSolutions Inc
  Study Documents (Full-Text)

Documents provided by Emergent BioSolutions:
Study Protocol  [PDF] April 25, 2016
Statistical Analysis Plan  [PDF] April 24, 2015


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Responsible Party: Emergent BioSolutions
ClinicalTrials.gov Identifier: NCT02339155     History of Changes
Other Study ID Numbers: 201436
First Posted: January 15, 2015    Key Record Dates
Results First Posted: January 9, 2018
Last Update Posted: February 8, 2019
Last Verified: January 2019
Keywords provided by Emergent BioSolutions:
Anthrax Vaccine Adsorbed
Raxibacumab
Immunogenicity
Additional relevant MeSH terms:
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Anthrax
Bacterial Infections
Bacillaceae Infections
Gram-Positive Bacterial Infections
Diphenhydramine
Promethazine
Vaccines
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Sleep Aids, Pharmaceutical
Hypnotics and Sedatives
Central Nervous System Depressants
Anesthetics, Local
Anesthetics
Sensory System Agents
Peripheral Nervous System Agents
Antiemetics
Autonomic Agents
Gastrointestinal Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Allergic Agents
Antipruritics
Dermatologic Agents