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Study to Assess Safety and Ability to Induce Immune Responses of HIV-1 Vaccines M3 and M4 Given Alone or in Combination in HIV-infected Adults (M&M)

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ClinicalTrials.gov Identifier: NCT03844386
Recruitment Status : Recruiting
First Posted : February 18, 2019
Last Update Posted : March 8, 2019
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:

This is a double blind, randomized, placebo-controlled, parallel design, study in which 27 HIV-infected participants with durable viral suppression will be randomly assigned to receive vaccination with MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), M3+M4 combined, or placebo. Participants will be randomized 8:8:8:3 to one of four study arms, and receive study treatment or placebo at Day 0. Each enrolled participant will complete the study in approximately 33.5 weeks (8.4 months).

The purpose of this study is to find out:

  • If it is safe for people to receive injections of two investigational HIV vaccines, called MVAtHIVconsv3 and MVAtHIVconsv4 alone or in combination.
  • If giving participants these vaccine doses will increase their immune system's ability to kill HIV virus.

Condition or disease Intervention/treatment Phase
HIV-1 Infection Biological: MVA.tHIVconsv3 Biological: MVA.tHIVconsv4 Other: Placebo Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomized 8(M3):8(M4):8(M3+M4):3(Placebo) to one of four study arms, and receive study treatment or placebo at Day 0.
Masking: Double (Participant, Investigator)
Masking Description: This is a double-blind study in which both the participant and the investigator are blinded to what the participant receives.
Primary Purpose: Treatment
Official Title: A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1-Infected Adults Suppressed on Antiretroviral Therapy - The M&M Study
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: MVA.tHIVconsv3 (M3)
Participants in this arm receive one vaccine dose of MVA.tHIVconsv3 (M3) given IM at Day 0
Biological: MVA.tHIVconsv3
viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1
Other Name: M3

Experimental: MVA.tHIVconsv4 (M4)
Participants in this arm receive one vaccine dose of MVA.tHIVconsv4 (M4) given IM at Day 0
Biological: MVA.tHIVconsv4
viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1
Other Name: M4

Experimental: MVA.tHIVconsv3 (M3)+MVA.tHIVconsv4 (M4)
Participants in this arm receive a single combined dose containing each vaccine type MVA.tHIVconsv4 (M3) + MVA.tHIVconsv4 (M4) given IM at Day 0
Biological: MVA.tHIVconsv3
viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1
Other Name: M3

Biological: MVA.tHIVconsv4
viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1
Other Name: M4

Placebo Comparator: Placebo
Participants in this arm receive one saline (placebo) dose given IM at Day 0
Other: Placebo
The appropriate amount of Sodium Chloride for Injection USP, 0.9% will be drawn into a syringe.
Other Name: Normal saline, Sodium Chloride




Primary Outcome Measures :
  1. Percent of Participants with a Grade 3 or higher Treatment-Related Adverse Event (AE) [ Time Frame: First day of study treatment through 28 days following vaccination ]
    The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017 will be used to measure safety where Grade 3 is defined as severe and Grade 4 is defined as potentially life-threatening. Treatment-Related AEs will be assessments that are considered related to study product as possible, probable, or definite as defined in the protocol.


Secondary Outcome Measures :
  1. Percent of Participants with a Grade 1 or higher Treatment-Related Adverse Event (AE) [ Time Frame: First day of study treatment through Day 168 (Week 24) following vaccination ]
    The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017 will be used to measure safety where Grade 1 is defined as mild, Grade 2 is defined as moderate, Grade 3 is defined as severe, and Grade 4 is defined as potentially life-threatening. Treatment-Related AEs will be assessments that are considered related to study product as possible, probable, or definite as defined in the protocol.



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral assay.

    A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

    WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment.

  2. Ages ≥ 18 to ≤ 45 years old
  3. Able and willing to give written informed consent.
  4. Able and willing to provide adequate locator information.
  5. Able and willing to comply with time requirements for protocol-specified visits and evaluations.
  6. Able and willing to commit to all study visits including follow-up through Week 24.
  7. Continuous ART prior to screening, defined as not missing more than 4 total days and never more than 2 consecutive days in the last 3 months.
  8. On a stable ART regimen defined as no changes in any ART medication within the 3 months prior to screening.
  9. Permitted ART regimens include:

    • 1) At least 3 ART agents (not counting ritonavir or cobicistat as one of the agents if less than a 200mg total daily dose). One of the agents must include an integrase inhibitor, NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors), or a boosted-PI (protease inhibitor).

    OR

    • 2) Two ART agents in which one of the agents is either a boosted protease inhibitor or an integrase inhibitor.

    NOTE: Other potent fully suppressive antiretroviral combinations will be considered on a case-by-case basis.

    NOTE: Changes in drug formulation or dose are allowed (e g, TDF to TAF, ritonavir to cobicistat or separate ART agent dosing to fixed-dose combination), but none within 30 days prior to screening.

    NOTE: Prior changes in, or elimination of, medications for easier dosing schedule, intolerance, toxicity, an improved side effect profile or within a drug class are permitted if an alternative suppressive regimen was maintained, but not within 3 months prior to screening.

  10. Ability and willingness of participant to continue ART throughout the study.
  11. Plasma HIV-1 RNA <50 copies/mL at 3 time points in the previous 24 months prior to screening and never ≥50 copies/mL on 2 consecutive time points in the last 24 months.
  12. At least 1 documented HIV-1 RNA result <50 copies/mL ≥24 months but ≤ 36 months prior to screening.
  13. Plasma HIV-1 RNA level <50 copies/mL on an FDA-approved HIV RNA assay performed at a US CLIA Certified Laboratory (or its equivalent).
  14. CD4 cell count ≥ 350 cells/mm3, performed at any US laboratory that has a CLIA certification or its equivalent.
  15. No history of auto-immune disease, auto-immune manifestations or chronic inflammatory conditions including but not limited to inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insufficiency, autoimmune thyroiditis, hypophysitis, or sarcoidosis.

    Note: The following conditions are not exclusionary: vitiligo, resolved childhood atopic dermatitis, Graves' disease with subsequent return to a euthyroid state (clinically and by laboratory testing).

  16. Hepatitis C (HCV) antibody negative result at screening or, if the participant is HCV antibody positive, a negative HCV RNA at screening.
  17. Hepatitis B surface antigen (HBsAg) negative at screening.
  18. Adequate vascular access for leukapheresis.
  19. Able and willing to receive IM injections without difficulty.
  20. All women must have a negative serum pregnancy test at screening regardless of reproductive potential.
  21. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) while on study and for 4 months after their vaccination.

    Note: Women of child bearing potential is defined as women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy

  22. All men and women participating in sexual activity that could lead to pregnancy must agree to consistently use at least one of the following forms of birth control for at least 21 days prior to Visit 4 (Day 0) and for 4 months after their vaccination:

    • Condoms (male or female) with or without a spermicidal agent
    • Diaphragm or cervical cap with spermicide
    • Intrauterine device (IUD)
    • Tubal ligation
    • Hormone-based contraceptive

    NOTE: For female participants receiving ritonavir or cobicistat, estrogen-based contraceptives are not reliable and an alternative method should be suggested.

  23. Men and women who are not of reproductive potential are eligible without requiring the use of contraceptives. Acceptable documentation detailing sterilization and menopause are specified below.

    Note: Men who have sex with men only will not be required to use contraception.

    Written or oral documentation communicated by clinician or clinician's staff of one of the following:

    • Physician report/letter
    • Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy)
    • Discharge summary
    • Follicle stimulating hormone-release factor (FSH) measurement elevated into the menopausal range as established by the reporting laboratory
  24. Agrees not to enroll on another study of an investigational research agent during the study period.
  25. Willingness to defer routine vaccination except for influenza from screening through 28 days after vaccination at Day 0.
  26. Adequate organ function as indicated by the following laboratory values:

Hematological: Absolute neutrophil count (ANC) ≥ 1,000 /mcL; Platelets ≥ 100,000/mcL; Hemoglobin ≥ 12 g/dL (male) and ≥ 11.5 g/dL (females)

Coagulation: Prothrombin Time or INR<1.1 x ULN (upper limit of normal)

Chemistries: Serum potassium levels within normal limits; Serum magnesium levels ≥ 1.4 mEq/L; Glucose - Screening serum glucose ≤ Grade 1 (fasting or non-fasting)

Renal: Creatinine clearance determined by the CKD-Epi equation - eGFR > 60mL/min

Hepatic: Serum total bilirubin - Total bilirubin <1.1 x ULN. If total bilirubin is elevated, direct bilirubin must be <2 x ULN

If the participant is on an atazanavir -containing therapy then a direct bilirubin should be measured instead of the total bilirubin and must be ≤1.0mg/dL.

AST (SGOT) and ALT (SGPT)<1.25 X ULN Alkaline Phosphatase <1.25 X ULN

Urinalysis: Protein < 2+; Blood < 2+ (for women, before or after menses)

Exclusion Criteria:

  1. If the HIV provider or study investigator is unable, as assessed by the study PI or protocol team, to construct a fully active alternative regimen based on previous resistance testing and/or treatment history.
  2. Women of childbearing age/potential must not be breast feeding, pregnant, or planning pregnancy any time from enrollment to 4 months after vaccination at Day 0.
  3. Body Mass Index (BMI) ≥40 kg/m2
  4. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without clear documentation of treatment).
  5. Current treatment for HCV with antiviral therapy or participants who have received HCV treatment within 6 months prior to screening.
  6. HIV RNA ≥150 copies/mL in the 6 months prior to screening.
  7. Received any infusion blood product, immune globulin, or hematopoetic growth factors within 6 months prior to screening.
  8. Use of any of the following within 90 days prior to screening: immunomodulatory, cytokine, or growth stimulating factors such as systemic cytotoxic chemotherapy, , immune globulin, interferon, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide, sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]), growth factors, dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, polyribonucleoside, or diticarb sodium, coumadin, warfarin, or other Coumadin derivative anticoagulants.
  9. Intent to use immunomodulators (e.g., IL-2, IL-12, interferons or TNF modifiers) during the course of the study.
  10. Use of systemic corticosteroids or topical steroids over a total area exceeding 15 cm2 within 30 days prior to screening, or anticipated need for periodic use of corticosteroids during the study.

    NOTE: For participants receiving ritonavir or cobicistat, (either as a booster or protease inhibitor [PI]) as part of their ART regimen, the concomitant use of oral/systemic/topical/inhaled/ intranasal corticosteroids is prohibited.

  11. Use of any prior HIV vaccine (prophylactic and/or therapeutic).
  12. Any experimental non-HIV vaccination within 1 year prior to screening.
  13. Prior immunization with a recombinant Adenovirus or MVA vaccine
  14. Prior immunization with small pox vaccine.
  15. Live attenuated vaccines received within 60 days prior to screening (i.e., varicella; measles, mumps, rubella [MMR]; yellow fever, oral polio, shingles).
  16. Receipt of other vaccines, excluding influenza vaccine, within the previous 28 days of screening.
  17. History of prior IgG therapy or immunization with any experimental immunogens (antibodies) within 6 months of screening.
  18. Use of any investigational treatment within 6 months prior to screening, with the exception of Phase II studies of antiretroviral agents.

    NOTE: Co-enrollment with other studies under an IND using an FDA approved medication that are not otherwise listed as prohibited will be considered on a case-by-case basis.

  19. For any serious illness requiring systemic treatment or hospitalization, the participant must either complete therapy or be clinically stable on therapy, in the opinion of the site investigator, for at least 90 days prior to screening.
  20. Treatment for an active HIV-related opportunistic infection within 90 days prior to screening.
  21. History of malignancy within the last 5 years.

    NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary with documentation of complete resection at least 3 months prior to enrollment).

  22. Immune deficiency other than that caused by HIV infection.
  23. Any medical, psychiatric, occupational or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence or assessment of safety.
  24. Hypertension

    • If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these participants, blood pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment.
    • If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment.

    Note: Elevated BP occurring during research leukapheresis procedures completed within the past 12 months are excluded from this requirement. Other isolated incidences of elevated BP should be reviewed by study PI to determine whether exclusionary. Isolated elevations must be noted as acceptable and signed by study PI or designee.

  25. Seizure disorder or any history of prior seizure.
  26. History of unexplained syncope or fainting episodes within 12 months of study screening.
  27. History of Asplenia - absence of normal spleen function as indicated by:

    • Splenectomy
    • Sickle cell disease
  28. Bleeding disorder including factor deficiency, coagulopathy or platelet disorder that requires special precautions (easy bruising without a formal diagnosis is not exclusionary).
  29. Allergy to eggs and/or egg products.
  30. History of anaphylaxis or severe adverse reaction to vaccines including symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
  31. History of hereditary angioedema, acquired angioedema or idiopathic angioedema.
  32. Known or suspected hypersensitivity to any vaccine component.
  33. Unstable asthma (e.g. sudden acute attacks occurring without an obvious trigger) or asthma requiring:

    • Daily steroid or long acting beta-agonist prevention
    • Hospitalization in the last two years
  34. Extensive tattoos or depo-provera injection at the site of administration (upper left or right medial deltoid muscles).
  35. History of allergy to latex.
  36. Active chronic skin problems such as eczema or psoriasis.
  37. Known psychiatric or substance abuse disorder/dependence that, in the opinion of the site investigator, would interfere with cooperation with the requirements of the trial.
  38. Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease.
  39. Prisoner recruitment and participation is not permitted.
  40. Inability to communicate effectively with study personnel.

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): NCT03844386


Contacts
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Contact: JoAnn Kuruc, MSN, RN 919-966-8533 joann_kuruc@med.unc.edu
Contact: Cindy L Gay, MD, MPH 919-843-2726 cynthia_gay@med.unc.edu

Locations
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United States, North Carolina
University of North Carolina Health Care Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: JoAnn Kuruc, MSN, RN    919-966-8533    joann_kuruc@med.unc.edu   
Contact: Cindy L Gay, MD, MPH    919-843-2726    cynthia_gay@med.unc.edu   
Sub-Investigator: David M Margolis, MD         
Sub-Investigator: Joseph J Eron, Jr., MD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Cindy L Gay, MD, MPH UNC-Chapel Hill
Principal Investigator: Nilu Goonetilleke, PhD UNC-Chapel Hill

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT03844386     History of Changes
Other Study ID Numbers: 18-2502
U01AI131310-01 ( U.S. NIH Grant/Contract )
IGHID 11810 ( Other Identifier: University of North Carolina at Chapel Hill )
First Posted: February 18, 2019    Key Record Dates
Last Update Posted: March 8, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of North Carolina, Chapel Hill:
HIV-1
Infection
Suppressed
ART
Vaccines
Alone
Combination
Immunogenicity

Additional relevant MeSH terms:
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Vaccines
Immunologic Factors
Physiological Effects of Drugs