The Effects of GLA on Human Volunteers

This study has been completed.
Sponsor:
Collaborators:
IDRI Corporation
Immune Design
Information provided by (Responsible Party):
Rockefeller University
ClinicalTrials.gov Identifier:
NCT01397604
First received: July 14, 2011
Last updated: September 19, 2013
Last verified: September 2013
  Purpose

The advent of vaccines contributed to major improvements in human morbidity and mortality due to infectious diseases such as polio, small pox, measles and diphtheria. However infectious diseases like HIV, malaria and tuberculosis continue to be major causes of death worldwide and conventional vaccine strategies have not been successful. The fundamental problem is that current protein based vaccines do not elicit the necessary T-cell immunity. Experimentally, adjuvants can be given in conjunction with a vaccine to activate and mature the dendritic cell (DC), which can then direct an immune response to enhance T-cell immunity. One family of potential adjuvants functions through the activation of Toll-like receptors (TLR) on the DC. Major gaps exist in our understanding of adjuvant effects in humans. We hypothesize that a synthetic adjuvant directed to activate TLR4 (GLA) will safely stimulate the innate immune system when administered subcutaneously (SC) or intramuscularly (IM). Importantly, in contrast to other adjuvant trials in which adjuvant is combined with an antigen or vaccine, GLA will be tested in isolation. This is because we anticipate the future administration of GLA with our dendritic cell targeted HIV vaccine. A DC-targeted vaccine cannot be given without an immune stimulating adjuvant due to potential risk of inducing immune tolerance. Therefore, in order to understand the specific contributions of GLA versus the DC-targeted vaccine, we need to understand the GLA effects in isolation. The safety and tolerability of 2 different formulations of GLA (GLA-SE vs. GLA-AF) administered by 3 different routes (SC, ID, IM) will be the major focus of this trial. The second focus will be characterizing the innate immune response by assessing systemic cytokine and chemokine levels and determining global gene regulation following GLA stimulation. The third focus will be on the cellular effects of GLA, specifically on blood monocytes and dendritic cells. Monocytes may represent a large pool of inducible potent DC (monocyte-derived DC), however these cells have not been well characterized in humans. We will investigate the effects of GLA stimulation on the peripheral blood monocyte subsets that might give rise to monocyte-derived DC.


Condition Intervention Phase
Healthy Volunteers
Drug: GLA-AF
Drug: GLA-SE
Other: Squalene
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: A Randomized, Blinded, Placebo-Controlled Phase 1 Study to Evaluate the Safety and Immunogenicity of GLA in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Rockefeller University:

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

    Local reactogenicity events and systemic reactogenicity events will be monitored.

    Local reactogenicity events:Moderate significant events include, but are not limited to, pain, tenderness, erythema, skin discoloration, edema, vesicle formation or ulceration, induration, pruritus, and formation of a crust or scab.

    • Systemic reactogenicity events: Include fever, chills, headache, nausea, vomiting, malaise, myalgia, arthralgia, and rash.



Secondary Outcome Measures:
  • Global Innate Immune Responses [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    Serum will be analyzed for the expression of soluble immune molecules including cytokines and chemokines.

    Examining the expression of cell surface molecules using multicolor flow cytometry will assess peripheral monocyte subset activation and characterization.

    Whole blood global gene arrays will be used to assess GLA stimulated gene regulation.



Estimated Enrollment: 32
Study Start Date: July 2011
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Saline Placebo

The trial will consist of a total of 32 people. An over-enrollment of about 10% (3 volunteers) will be permitted.

Each cohort will be recruited in sequence. Cohort I will include 16 subjects that will receive a subcutaneous injection, randomized equally so that 5 individuals will receive GLA-AF (2µg), 5 individuals will receive GLA-SE, 3 individuals will receive saline placebo and 3 individuals will receive SE vehicle. Cohort II will include 16 subjects that will receive intramuscular injections, randomized equally into 5 GLA-AF (2µg) subjects, 5 GLA-SE (2µg) subjects, 3 saline placebo subjects and 3 SE vehicle control subjects.

Placebo Comparator: SE Vehicle

The trial will consist of a total of 32 people. An over-enrollment of about 10% (3 volunteers) will be permitted.

Each cohort will be recruited in sequence. Cohort I will include 16 subjects that will receive a subcutaneous injection, randomized equally so that 5 individuals will receive GLA-AF (2µg), 5 individuals will receive GLA-SE, 3 individuals will receive saline placebo and 3 individuals will receive SE vehicle. Cohort II will include 16 subjects that will receive intramuscular injections, randomized equally into 5 GLA-AF (2µg) subjects, 5 GLA-SE (2µg) subjects, 3 saline placebo subjects and 3 SE vehicle control subjects.

The SE (squalene) vehicle contains the oil emulsion in which the GLA-SE is solubilized.

Other: Squalene
Squalene is a natural organic compound obtained from shark liver oil. In this study, it is used to solubilize GLA in the GLA-SE formulation. Patients randomized to receive the squalene will be given one 2mcg injection of the squalene oil in the upper arm, each patient randomized further to either subcutaneous or intramuscular routes.
Active Comparator: GLA-AF

The trial will consist of a total of 32 people. An over-enrollment of about 10% (3 volunteers) will be permitted.

Each cohort will be recruited in sequence. Cohort I will include 16 subjects that will receive a subcutaneous injection, randomized equally so that 5 individuals will receive GLA-AF (2µg), 5 individuals will receive GLA-SE, 3 individuals will receive saline placebo and 3 individuals will receive SE vehicle. Cohort II will include 16 subjects that will receive intramuscular injections, randomized equally into 5 GLA-AF (2µg) subjects, 5 GLA-SE (2µg) subjects, 3 saline placebo subjects and 3 SE vehicle control subjects.

GLA-AF contains the study drug in an aqueous solution.

Drug: GLA-AF
GLA-AF contains GLA, a new synthetic lipid A molecule that combines 6 acyl chains with a single phosphorylation site. GLA-AF contains GLA in an aqueous solution. One 2 mcg injection will be given per patient in the upper arm, each randomized to either subcutaneous or intramuscular routes.
Active Comparator: GLA-SE

The trial will consist of a total of 32 people. An over-enrollment of about 10% (3 volunteers) will be permitted.

Each cohort will be recruited in sequence. Cohort I will include 16 subjects that will receive a subcutaneous injection, randomized equally so that 5 individuals will receive GLA-AF (2µg), 5 individuals will receive GLA-SE, 3 individuals will receive saline placebo and 3 individuals will receive SE vehicle. Cohort II will include 16 subjects that will receive intramuscular injections, randomized equally into 5 GLA-AF (2µg) subjects, 5 GLA-SE (2µg) subjects, 3 saline placebo subjects and 3 SE vehicle control subjects.

GLA-SE contains the study drug in a squalene oil emulsion.

Drug: GLA-SE
GLA-SE contains GLA, a new synthetic lipid A molecule that combines 6 acyl chains with a single phosphorylation site. GLA-SE contains GLA in a squalene oil emulsion. One 2 mcg injection will be given per patient in the upper arm, each randomized to either subcutaneous or intramuscular routes.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy adult males and females, as assessed by a medical history, physical exam, and laboratory tests
  2. Age of at least 18 years of age on the day of screening and no greater than 60 years at time of administration
  3. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study (screening plus 4 weeks)
  4. Willing to undergo HIV testing and counseling and receive HIV test results
  5. If a female of child bearing potential, must be willing to use two effective methods of contraception (combined oral contraceptive pill; injectable contraceptive; diaphragm; Intra Uterine Device (IUD); condoms; anatomical sterility in self or partner) throughout until 6 weeks after study drug administration. If a sexually active male, must be willing to use two effective methods of contraception (such as condoms, anatomical sterility) from screening until 6 weeks after study drug administration (same as above) and will be advised not to get his partner(s) pregnant during this time.

Exclusion Criteria:

  1. Confirmed HIV-1 or HIV-2 infection
  2. Any clinically significant abnormality on medical history or physical examination including history of immunodeficiency or autoimmune disease
  3. Any use of systemic corticosteroids immunosuppressive anticancer medications
  4. Any clinically significant acute or chronic medical condition requiring care of a physician (e.g., diabetes, coronary artery disease, rheumatologic illness, malignancy, substance abuse) that in the opinion of the investigator would preclude participation
  5. Any laboratory value outside of reference range other than CRP, with the exception of any non-clinically significant Grade I elevations of liver function tests (AST, ALT, direct/total bilirubin), electrolytes (Na, K, Cl, CO2), CBC, urinalysis as determined by the Principal Investigator or his designee.
  6. Within the 12 months prior to enrollment, the subject self reports excessive daily alcohol use, frequent binge drinking or chronic marijuana abuse (defined as greater than 2 times a week) or any other use of illicit drugs
  7. Positive hepatitis B surface antigen, positive hepatitis C antibodies, or active syphilis infection based on clinical evaluation;
  8. If female, pregnant, planning a pregnancy during the trial period, or lactating
  9. Receipt of a live attenuated vaccine within 30 days or other vaccine within 14 days prior to study drug
  10. Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study
  11. In the opinion of the investigator, unlikely to comply with protocol due to medical, social or psychiatric reasons
  12. Allergy to eggs
  13. A glomerular filtration rate that is less than 60mL/min/1.73 m2 as calculated by study team based on laboratory creatinine values.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01397604

Locations
United States, New York
The Rockefeller University
New York, New York, United States, 10065
Sponsors and Collaborators
Rockefeller University
IDRI Corporation
Immune Design
Investigators
Principal Investigator: Marina Caskey, MD Instructor in Clinical Investigation
  More Information

No publications provided

Responsible Party: Rockefeller University
ClinicalTrials.gov Identifier: NCT01397604     History of Changes
Other Study ID Numbers: BYI-0736
Study First Received: July 14, 2011
Last Updated: September 19, 2013
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on August 26, 2014