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Effect of Raxibacumab on Immunogenicity of Anthrax Vaccine Adsorbed

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02339155
Recruitment Status : Completed
First Posted : January 15, 2015
Results First Posted : January 9, 2018
Last Update Posted : July 15, 2021
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Emergent BioSolutions

Tracking Information
First Submitted Date  ICMJE January 12, 2015
First Posted Date  ICMJE January 15, 2015
Results First Submitted Date  ICMJE December 12, 2017
Results First Posted Date  ICMJE January 9, 2018
Last Update Posted Date July 15, 2021
Actual Study Start Date  ICMJE February 24, 2015
Actual Primary Completion Date January 3, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2017)
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]).
Original Primary Outcome Measures  ICMJE
 (submitted: January 12, 2015)
Ratio of geometric mean concentrations (GMC) of anti-protective antigen (PA) antibody (Ab) at 4 weeks after the first 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 groups will be assessed to compare the Immunogenicity of AVA at 4 weeks after the first AVA dose (prior to the third AVA dose).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2015)
  • Ratio of GMC of anti-PA Ab at Weeks 8 and 26 after the first AVA dose between the AVA alone and the AVA with raxibacumab treatment groups. [ Time Frame: Days 57 and 183 ]
    Ratio of GMC of anti-PA Ab between AVA alone and the AVA with raxibacumab treatment groups will be assessed to compare the Immunogenicity of AVA at Weeks 8 and 26 after the first AVA dose, when AVA is administered alone or concomitantly with raxibacumab.
  • Percentage of subjects who seroconvert, at Weeks 4, 8 and 26 after the first AVA dose, between the AVA alone and the AVA with raxibacumab treatment groups. [ Time Frame: Days 29, 57, and 183 ]
    Seroconversion, defined as a >= 4-fold increase in toxin neutralizing activity (TNA) titer from baseline, will be estimated at Weeks 4, 8 and 26 after the first AVA dose, when AVA is administered alone or concomitantly with raxibacumab.
  • Number of participants with adverse events. [ Time Frame: Approximately 31 weeks ]
    Adverse events will be collected from the start of study treatment until the follow-up contact.
  • Vital signs assessment as a safety measure. [ Time Frame: Approximately 31 weeks ]
    Vital signs will include temperature, systolic and diastolic blood pressure and pulse rate and respiratory rate.
  • Urinalysis as a safety measure [ Time Frame: Day 57 ]
    Urinalysis will be performed
  • Clinical laboratory assessment as a safety measure. [ Time Frame: Approximately 31 weeks ]
    Laboratory parameters include hematology, and clinical chemistry
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Raxibacumab on Immunogenicity of Anthrax Vaccine Adsorbed
Official Title  ICMJE A Randomized, Open-label Study to Evaluate the Immunogenicity of Anthrax Vaccine Adsorbed Alone or Concomitantly With Raxibacumab (GSK3068483)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Infections, Bacterial
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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).
    Intervention: Biological: AVA
  • 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.
    Interventions:
    • Biological: AVA
    • Biological: Raxibacumab
    • Drug: Diphenhydramine
Publications * Skoura N, Wang-Jairaj J, Della Pasqua O, Chandrasekaran V, Billiard J, Yeakey A, Smith W, Steel H, Tan LK. Effect of raxibacumab on immunogenicity of Anthrax Vaccine Adsorbed: a phase 4, open-label, parallel-group, randomised non-inferiority study. Lancet Infect Dis. 2020 Aug;20(8):983-991. doi: 10.1016/S1473-3099(20)30069-4. Epub 2020 Apr 22.

*   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 20, 2017)
573
Original Estimated Enrollment  ICMJE
 (submitted: January 12, 2015)
30
Actual Study Completion Date  ICMJE June 6, 2017
Actual Primary Completion Date January 3, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 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 NCT02339155
Other Study ID Numbers  ICMJE 201436
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Emergent BioSolutions
Original Responsible Party GlaxoSmithKline
Current Study Sponsor  ICMJE Emergent BioSolutions
Original Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE GlaxoSmithKline
Investigators  ICMJE
Study Director: Paul-Andre deLame, MD Emergent BioSolutions Inc
PRS Account Emergent BioSolutions
Verification Date July 2021

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